WO2012068519A2 - Markers associated with response to activated protein c administration, and uses thereof - Google Patents

Markers associated with response to activated protein c administration, and uses thereof Download PDF

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WO2012068519A2
WO2012068519A2 PCT/US2011/061494 US2011061494W WO2012068519A2 WO 2012068519 A2 WO2012068519 A2 WO 2012068519A2 US 2011061494 W US2011061494 W US 2011061494W WO 2012068519 A2 WO2012068519 A2 WO 2012068519A2
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snp
group
rsl
subject
genotype
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WO2012068519A3 (en
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Francis Hugh Wellman
Alexandra Mancini
James Russell
Mauricio Neira
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Sirius Genomics Inc.
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    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12QMEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12Q1/00Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813Hybridisation assays
    • C12Q1/6834Enzymatic or biochemical coupling of nucleic acids to a solid phase
    • C12Q1/6837Enzymatic or biochemical coupling of nucleic acids to a solid phase using probe arrays or probe chips
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    • C12Q2600/00Oligonucleotides characterized by their use
    • C12Q2600/106Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
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    • C12Q2600/00Oligonucleotides characterized by their use
    • C12Q2600/156Polymorphic or mutational markers
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    • C12Q2600/00Oligonucleotides characterized by their use
    • C12Q2600/172Haplotypes

Definitions

  • the present invention provides methods to identify a subject with an improved response to a treatment with an anti-inflammatory agent or an anti-coagulant agent, for example, activated protein C, protein C, or an activator of protein C, by determining a genotype for that trait.
  • an anti-inflammatory agent or an anti-coagulant agent for example, activated protein C, protein C, or an activator of protein C
  • IRG improved response genotype
  • improved response polymorphic variant refers to an allelic variant or genotype at a polymorphic site described herein or a polymorphic site in linkage disequilibrium with a described polymorphic site as being predictive of a subject's increased likelihood of survival or improved condition in response to treatment with an anti-inflammatory agent or an anti-coagulant agent or a reduction in serious adverse events or adverse events in response to treatment with an anti-inflammatory agent or an anti-coagulant agent as described herein, for example, with an activated protein C.
  • a subject may have already provided a biological sample for other purposes or may have even had their genetic sequence determined in whole or in part and stored for future use.
  • Genetic sequence information may be obtained in numerous different ways and may involve the collection of a biological sample that contains genetic material, particularly genetic material containing the sequence or sequences of interest.
  • Genetic material includes any nucleic acid and can be a deoxyribonucleotide or ribonucleotide polymer in either single or double-stranded form. Many methods are known in the art for collecting biological samples and extracting genetic material from those samples. Genetic material can be extracted from blood, tissue, hair, and other biological material. There are many methods known to isolate DNA and RNA from biological material.
  • linkage disequilibrium can be determined according to Johnson et al, "SNAP: A Web-Based Tool for Identification and Annotation of Proxy SNPs Using HapMap," Bioinformatics, 24 (2 ' 4) :2938-2939 (2008), using SNAP Version 2.2 (Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142). Default parameters are applied. Genotyping is carried out using the Illumina® Human lM-Duo BeadChip (Illumina, 9885 Towne Centre Drive, San Diego, CA 92121).
  • an improved response may be associated with a pair of genotypes, or markers in linkage disequilibrium with pairs of genotypes, including the polymorphic sites rsl042327, rsl0822315, rsl2380611, rsl2529871, rsl7781459, rsl805100, rs2016224, rs2073721, rs2989946, rs3179969, rs3751501, rs4354185, rs4371530, rs4525972, rs4936280, rs640098, rs684923, rs6925087, rs7535528, rs7572996, rs7940667, rs8028880, rs8128, and rs958738.
  • a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 10026134 in the NCBI db SNP Build 134 and having a genotype AA GG.
  • a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 10026134 and having a genotype AA GG.
  • a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 10275461 in the NCBI db SNP Build 134 and having a genotype GG.
  • a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 0275461 and having a genotype GG.
  • a Group B SNP may be found within - 48130 and 868 base pairs of SNP rsl0275461 located at 46450230 of the human genome assembly GRCh37.2 sequence on chromosome 7. In an aspect, a Group B SNP may be found within -9556 and 62575 base pairs of SNP rsl0275461.
  • a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl7168132(AA) and rs2357958(AA).
  • a Group B SNP may be found within 6096 and 7467 base pairs of SNP rs 10950521 located at 14429350 of the human genome assembly GRCh37.2 sequence on chromosome 7.
  • a Group B SNP may be found within -2238 base pairs of SNP rsl0950521.
  • a Group B SNP may be within 1 cM of SNP rsl0950521.
  • a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rs73039941(CT), rsl 1063669(GT), and rsl 1063673(CG).
  • a Group B SNP may be found within -7809 and -1941 base pairs of SNP rsl 1063674 located at 5539134 of the human genome assembly GRCh37.2 sequence on chromosome 12.
  • a Group B SNP may be within 1 cM of SNP rsl 1063674.
  • a Group B SNP may be found within -169661 and -6644 base pairs of SNP rsl 1159859 located at 89027891 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -60555 and -2515 base pairs of SNP rsl 1159859. In an aspect, a Group B SNP may be found within 3193 base pairs of SNP rsl 1159859. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 1159859.
  • a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl 6832058(AG), rs41315858(AG), and rsl 11695681(GT).
  • a Group B SNP may be found within -20550 and -18044 base pairs of SNP rsl 1585501 located at 237797452 of the human genome assembly GRCh37.2 sequence on chromosome 1.
  • a Group B SNP may be found within -21767 and -923 base pairs of SNP rsl 1585501.
  • a Group B SNP may be within 1 cM of SNP rsl 1585501.
  • a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs73171007(AA), rs8141330(AA), rs56169543(GG), rs7284506(CC), and rs73171017(TT).
  • a Group B SNP may be found within 7010 and 18762 base pairs of SNP rsl2159200 located at 41042091 of the human genome assembly GRCh37.2 sequence on chromosome 22.
  • a Group B SNP may be found within -9228 and 10665 base pairs of SNP rs 12159200.
  • a Group B SNP may be within 1 cM of SNP rsl2159200.
  • a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl2327456 in the NCBI db SNP Build 134 and having a genotype AT TT.
  • a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl2327456 and having a genotype AT TT.
  • a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rs7042625(CC), rs7037462(CC), and rs4838084(GG).
  • a Group B SNP may be found within -5236 and 1864 base pairs of SNP rsl2335840 located at 126713411 of the human genome assembly GRCh37.2 sequence on chromosome 9.
  • a Group B SNP may be within 1 cM of SNP rsl2335840.
  • a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 12380611 in the NCBI db SNP Build 134 and having a genotype CC.
  • a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 12380611 and having a genotype CC.
  • the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl2555472(CC) and rsl2376586(AA).
  • a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs79579293(GG), rs60310240(CC), rsl7772064(TT), rsl 7698817(CC), rsl2589467(CC), rsl2433464(GG), rs56987357(AA), rsl955599(TT), rsl955600(AA), rsl7772222(GG), rs7145588(AA), rs61977049(CC), rsl7772288(AA), rsl2587386(TT), rs61579615 (TT), rs60213984(AA), rs55722539(AA), rsl2589480(TT), rs61977058(CC), rs74071851(AA), rsl 11598
  • a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 1265140 in the NCBI db SNP Build 134 located at 103201058 of the human genome assembly GRCh37.2 sequence on chromosome 8 and having a genotype CG.
  • the Group B SNP may further include a Group B SNP
  • the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2718011(CT), rs78749960(CT), and rs7791437(AG).
  • a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2700943(AT), rs2710809(AG), and rs6462645(AC).
  • a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl2204300(CC).
  • a Group B SNP may be found within 51945 base pairs of SNP rsl348181 located at 50239686 of the human genome assembly GRCh37.2 sequence on chromosome 6.
  • a Group B SNP may be found within 6397 base pairs of SNP rs 1348181.
  • a Group B SNP may be within 1 cM of SNP rs 1348181.
  • the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2605144(CC), rs921985(AA), rs4925179(TT), and rs2688036(AA).
  • a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl74957 in the NCBI db SNP Build 134 and having a genotype AG.
  • a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl74957 and having a genotype AG.
  • the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl74960(AG).
  • the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs7643124(GG TT), rs6549655(AA GG), rs6549656(CC TT), rs34728067(AA CC), rs7612314(CC GG), rs9838240(CC TT), rs4521282(AA GG), rs9855537(AA TT), rsl918390(AA TT), rsl3064972(CC GG), rsl0222550(CC TT), rs34454189(AA GG), rs2049623(AA GG), rs9877628(AA CC), rsl 1128403(CC TT), rsl0865686(AA GG), rsl0
  • a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs77382318(GG), rs61977053(AA), rsl7124652(GG), rs61975260(CC), rs4375590(GG), rsl864748(GG), rs2274735(CC), rs4516145(TT), rs7143853(GG), and rs57118463(CC).
  • the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs7655203(AA GG), rs66614520(CC TT), rs35201112(GG TT),
  • the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs56174823(CC CT), rs62479773(CC CT), rs56389625(CC CG), rsl7169325(CT TT), rs62479797(CC CG), rs56088922(AA AG), and rs58911561(CC CT).
  • the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs62411911(CG GG), rsl 13952954(CG GG), rs9473541(AA AC), rs73425947(GT TT), rsl924999(GT TT), rs2477402(AC CC), rs2182012(AA AG), rs2182013(AT TT), rs2493439(AA AG), rs2147570(AG GG), rs2493440(AA AT), rs2501977(CT TT), rs2477405(AC CC), rs2477406(AG GG), rs2501979(CC CT), rs9473547(AA AG), rs2501980(CC CT), and rs4573082(GG GT).
  • a Group B SNP selected from the group consist
  • a Group B SNP may be found within -36319 and 20339 base pairs of SNP rs2728981 located at 22253194 of the human genome assembly GRCh37.2 sequence on chromosome 3.
  • a Group B SNP may be found within -40251 and 22293 base pairs of SNP rs2728981.
  • a Group B SNP may be found within -26709 and -9553 base pairs of SNP rs2728981.
  • a Group B SNP may be within 1 cM of SNP rs2728981.
  • a Group B SNP may be found within -36321 and 44626 base pairs of SNP rs2941483 located at 76478616 of the human genome assembly GRCh37.2 sequence on chromosome 8. In an aspect, a Group B SNP may be found within -23209 and 1334 base pairs of SNP rs2941483. In an aspect, a Group B SNP may be found within -9585 and 1706 base pairs of SNP rs2941483. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2941483.
  • a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3024496 in the NCBI db SNP Build 134 and having a genotype GG.
  • a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3024496 and having a genotype GG.
  • a Group B SNP may be found within 16980 base pairs of SNP rs3118050 located at 58219167 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within 14966 and 22270 base pairs of SNP rs3118050. In an aspect, a Group B SNP may be found within - 1383 and 91 base pairs of SNP rs3118050. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3118050.
  • a Group B SNP may be found within -26246 and 17188 base pairs of SNP rs321224 located at 20221607 of the human genome assembly GRCh37.2 sequence on chromosome 9. In an aspect, a Group B SNP may be found within -30769 and - 1587 base pairs of SNP rs321224. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs321224.
  • a Group B SNP may be found within -9383 and 51645 base pairs of SNP rs3212439. In an aspect, a Group B SNP may be found within -14330 and 6263 base pairs of SNP rs3212439. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3212439.
  • the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9 selected from the group consisting ofrsl l629561(GG GT), rsl 1631100(AA AG), rs2044098(GT TT), rsl2904700(AG GG), rs2868607(AA AG), rsl2911405(AC CC), rsl2910386(AA AC), and rsl2915634(AA AG).
  • the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs34063054(TT), rs892856(AA), rs2572942(CC), rsl2272277(TT), rs60466677(CC), rs67867011(CC), rs4910491(TT), rs920080(AA), rs4910495(TT), rs414109(GG), rs429546(CC),
  • a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl0770056(GG), rs4993191(TT), rs892856(AA), rs892855(AA),
  • a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs77608740(TT), rs9473566(CC),
  • a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs4953536(AG GG), rsl l l25158(CG GG), rs6545010(CC CT), rs60379088(CT TT), rs4953543(CT TT), rsl471681(AA AT), rs6712238(AA AC), rs4952905(AA AG), rs2136456(CC CG), rs58178746(CT TT), and rs973894(CC CG).
  • a Group B SNP may be found within -40688 and 149192 base pairs of SNP rs4952903 located at 48254907 of the human genome assembly GRCh37.2 sequence on chromosome 2. In an aspect, a Group B SNP may be found within -43188 and 146800 base pairs of SNP rs4952903. In an aspect, a Group B SNP may be found within -16966 and 73258 base pairs of SNP rs4952903. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4952903.
  • a Group B SNP may be found within -33552 and 33635 base pairs of SNP rs530461 located at 48467716 of the human genome assembly GRCh37.2 sequence on chromosome 20.
  • a Group B SNP may be found within -37036 and 26462 base pairs of SNP rs530461.
  • a Group B SNP may be within 1 cM of SNP rs530461.
  • a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6864 in the NCBI db SNP Build 134 and having a genotype AC.
  • a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6864 and having a genotype AC.
  • the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2429024(AC), rs2487701(AG), rs2255607(CT), rsl7471869(AG), rs2487702(CG), rs2429030(CT), rs2491023(AG), rs2429031(AG), rs2487706(AG), rs2487707(GT), rs2487708(AG), and rs2491020(AG).

Abstract

The present invention includes and provides biomarkers and methods for determining the effectiveness of treatment of immunological disorders with an anti-inflammatory agent or an anti-coagulant agent. Included are materials such as nucleic acid molecules capable to detecting genetic polymorphisms that are predictive of an improved response to an anti-inflammatory agent or an anti-coagulant agent.

Description

MARKERS ASSOCIATED WITH RESPONSE TO
ACTIVATED PROTEIN C ADMINISTRATION, AND USES THEREOF
FIELD OF THE INVENTION
The present invention includes and provides biomarkers and methods for determining the effectiveness of treating an inflammatory condition with an anti-inflammatory agent or an anti-coagulant agent. Also included are materials such as nucleic acid molecules capable of detecting genetic polymorphisms that are associated with an improved response to the administration of an anti-inflammatory agent or an anti-coagulant agent. BACKGROUND OF THE INVENTION
Recent studies have demonstrated a relationship between genotype and response to pharmacological therapeutics (i.e., pharmaco genomics). For example, Genentech's
HERCEPTIN® was not effective in its overall Phase III trial but was shown to be of therapeutic benefit in a genetic subset of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Similarly, Novartis' GLEEVEC® is only indicated for the subset of chronic myeloid leukemia patients who carry a reciprocal translocation between chromosomes 9 and 22 (i.e., the Philadelphia chromosome). Also, the effectiveness of PLAVIX® depends upon its conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. Genotypic variants of CYP2C19 can be used to identify "poor metabolizers" of PLAVIX®.
The septic inflammatory response involves complex cross-talk within and between the inflammation, coagulation and apoptosis pathways. Homeostatic imbalance of these and other counter-regulatory pathways can lead to altered clinical outcome in subjects with inflammatory conditions such as severe sepsis. Severe sepsis is a systemic inflammatory response syndrome that results from infection and is associated with acute organ dysfunction. Severe sepsis is characterized as a state of uninhibited coagulation, inflammation, and impaired fibrinolysis leading to organ failure. In the United States, approximately 750,000 cases of severe sepsis occur annually (Angus et al., Crit. Care Med., 2 :1303-1310 (2001)).
Decreased plasma levels of protein C are observed in association with the
inflammatory response arising from sepsis, major surgery, or shock (Griffin et al., Blood, 60(l) 26\-4 (1982); Blarney et al, Thromb Haemost., 54(3):622-5 (1985); Taylor et al, Journal of Clinical Investigation, 79(3):9\^>-25 (1987); Hesselvik et al, Thromb. Haemost., 65(2):\26-9 (1991); Fijnvandraat et al, Thromb. Haemost., 73(l):l5-20 (1995); and Faust et al., N. Engl. J. Med., 345(6) 40%-16 (2001)) and is related to poor outcome (Lorente et al., Chest, 103 (5) :1536-42 (1993); Vervloet et al, Semin. Thromb. Hemost., 24(l):33-44 (1998); Fisher et al., Crit. Care Med., 28(9 Suppl):S49-56 (2000); Yan et al., Crit. Care Med., 29(7 Suppl) S69-74 (2001); and Lay et al., Blood, 109(5): 1984-91 (2007). The expression of endothelial cell proteins such as thrombomodulin and protein C receptor (PROCR) is also impaired by pro-inflammatory cytokines, and thus may also serve as a mechanism by which protein C function is abrogated (Stearns-Kurosawa et al. , Proceedings of the National Academy of Sciences of the United States of America, 93(19): \02\2-6 (1996)).
Therapeutic agents for severe sepsis often target one or more of the pathways intrinsic to inflammation and infection. In particular, XIGRIS™ (drotrecogin alfa (activated), activated protein C, DrotAA) having anti-inflammatory, anti-coagulant, pro-fibrino lytic, and anti-apoptotic activity, has been observed to decrease 28-day mortality in both experimental sepsis models (Lay et al., Blood, 109(5): 1984-91 (2007)) and the Phase III PROWESS severe sepsis trial (Bernard et al., New England Journal of Medicine, 344(10) 699-709 (2001); Macias et al., Crit. Care, 9(Suppl4) S38-45 (2005)).
Although DrotAA therapy decreases the mortality rate in severe sepsis, as with many treatments, efficacy is variable, with some patients responding better than others. Over the past 20 years, numerous clinical trials have been undertaken with potential new therapies to improve mortality outcomes in severe sepsis and septic shock. DrotAA is the only successful drug approved for the treatment of severe sepsis, and its efficacy and safety remain controversial among experts and regulators. As a result, the use of DrotAA is low in clinical practice. Therefore, a genomic biomarker that would help identify patients who are more likely to benefit from DrotAA treatment would improve the benefit-risk ratio for treatment with DrotAA and contribute to improved survival outcomes in the syndromes of severe sepsis and septic shock. As such, a clear benefit would be an approach that provided guidance on the response of patients to therapeutic agents that target inflammation and infection.
SUMMARY OF THE INVENTION
In one aspect, single nucleotide polymorphism (SNP) biomarkers that predict an improved response to an anti-inflammatory agent or an anti-coagulant agent in subjects having diseases or conditions associated with an inflammatory condition are provided. Also provided are single nucleotide polymorphisms and combinations of single nucleotide polymorphisms for which the genotypic variants predict responsiveness to therapy for inflammatory conditions such as sepsis with activated protein C, protein C, or an activator of protein C.
The present invention includes and provides a method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C, comprising determining a genotype at a Group A SNP as provided in Table 1 and SEQ ID NOs: 1 to 293, a Group B SNP provided by SEQ ID NOs: 318 to 7046 and on pages 39 to 196, or a Group A and a Group B SNP, where an improved response genotype at a Group A, Group B, or Group A and Group B SNP is indicative of a subject having a phenotype of an improved response to a treatment with activated protein C.
The present invention also includes and provides a method of selecting a subject comprising determining a genotype at a a polymorphic site selected from the group consisting of rs684923 (AA), rsl0822315 (GG), rs8028880 (GG), rs958738 (AA GG), rsl2380611 (GG), rsl2529871 (AA), rs6925087 (TT), rsl7781459 (AG GG), rs4525972 (AG), rs7572996 (AG), rs3179969 (AA), rs640098 (AA), rs4371530 (AA), rs2016224 (GG), rs4936280 (AA), rs3751501 (AA AG), rs4354185 (AA), rs7535528 (AA), rs7940667 (AC AA), rsl042327 (AA), rs2989946 (CT), rs2073721 (AG), rsl805100 (AA), and rs8128 (TT).
The present invention further includes and provides a method for determining whether a subject having an inflammatory condition will benefit from treatment with an activated protein C comprising determining a genotype at a Group A SNP, a Group B SNP, or a Group A and a Group B SNP, where an improved response genotype at a Group A, Group B, or Group A and Group B SNP is indicative of a subject having a phenotype of an improved response to a treatment with activated protein C.
The present invention also includes and provides a method for determining whether a subject having an inflammatory condition will benefit from treatment with an activated protein C, protein C, or an activator of protein C comprising determining a genotype at a polymorphic site selected from the group consisting of rs684923 (AA), rs 10822315 (GG), rs8028880 (GG), rs958738 (AA GG), rsl2380611 (GG), rsl2529871 (AA), rs6925087 (TT), rsl7781459 (AG GG), rs4525972 (AG), rs7572996 (AG), rs3179969 (AA), rs640098 (AA), rs4371530 (AA), rs2016224 (GG), rs4936280 (AA), rs3751501 (AA AG), rs4354185 (AA), rs7535528 (AA), rs7940667 (AC AA), rs 1042327 (AA), rs2989946 (CT), rs2073721 (AG), rs 1805100 (AA), and rs8128 (TT).
The present invention also includes and provides a method for determining whether a subject having an inflammatory condition will not benefit from treatment with an activated protein C comprising determining a genotype at a Group A SNP, a Group B SNP, or a Group A and a Group B SNP, where a non-response genotype at a Group A, Group B, or Group A and Group B SNP is indicative of a subject having a phenotype of not benefiting from treatment with an anti-inflammatory agent or an anti-coagulant agent, for example, activated protein C, protein C, or an activator of protein C.
The present invention also includes and provides a method for determining whether a subject having an inflammatory condition will not benefit from treatment with an antiinflammatory agent or an anti-coagulant agent, for example, activated protein C, protein C, or an activator of protein C, comprising determining a genotype at a SNP wherein the genotype is in linkage disequilibrium with a polymorphic site selected from the group consisting of rs684923 (AG GG), rsl0822315 (AG AA), rs8028880 (GA GG), rs958738 (A G), rsl2380611 (AG AA), rsl2529871 (AC CC), rs6925087 (TA AA), rsl7781459 (AA), rs4525972 (AA GG), rs7572996 (AA GG), rs3179969 (AG GG), rs640098 (AG GG), rs4371530 (AG GG), rs2016224 (GA AA), rs4936280 (AG GG), rs3751501 (GG), rs4354185 (AG GG), rs7535528 (AG GG), rs7940667 (CC), rsl042327 (GA GG), rs2989946 (CC TT), rs2073721 (AA GG), rsl805100 (AG GG), and rs8128 (TG GG).
The present invention also includes and provides a method for predicting the benefit of treatment with an activated protein C of a subject comprising determining a genotype at a a polymorphic site selected from the group consisting of rs684923 (AA), rs 10822315 (GG), rs8028880 (GG), rs958738 (AA GG), rsl2380611 (GG), rsl2529871 (AA), rs6925087 (TT), rsl7781459 (AG GG), rs4525972 (AG), rs7572996 (AG), rs3179969 (AA), rs640098 (AA), rs4371530 (AA), rs2016224 (GG), rs4936280 (AA), rs3751501 (AA AG), rs4354185 (AA), rs7535528 (AA), rs7940667 (AC AA), rs 1042327 (AA), rs2989946 (CT), rs2073721 (AG), rsl805100 (AA), and rs8128 (TT), and the benefit is predicted by a combination of markers.
The present invention also includes a method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising annealing a primer to template DNA 5 ' to a Group A SNP site or adjacent to a Group B SNP site in linkage disequilibrium with said Group A SNP, synthesizing a complementary DNA, incorporating an allele-specific nucleotide at the SNP site and identifying an allele-specific nucleotide.
The present invention also includes a method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising annealing a primer to template DNA next to a Group A SNP site or adjacent to a Group B SNP site in linkage disequilibrium with said Group A SNP, synthesizing a complementary DNA, incorporating an allele-specific nucleotide at the SNP site, hybridizing a probe hybridizing a probe comprising a Group A SNP or a Group B SNP- specific nucleotide to said synthesized DNA, washing the hybridized probe - DNA complex so that any probe stuck to DNA with mismatched DNA basepairs are washed away, and identifying a SNP-specific nucleotide based on which hybridized probe - DNA complexes remain after washing.
The present invention includes and provides a method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising annealing a primer to template DNA from said subject, wherein the primer anneals adjacent to a Group A SNP or a Group B SNP, synthesizing DNA
complementary to the template DNA, wherein the synthesizing incorporates a nucleotide complementary to the SNP site nucleotide, hybridizing a probe comprising a Group A SNP- specific nucleotide or a Group B SNP-specific nucleotide to the synthesized DNA with a fluorescent label and a quencher before the synthesizing, and identifying the subject genotype at the SNP site based on whether the hybridized probe releases the fluorescent label after synthesizing.
The present invention includes and provides a method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising annealing a SNP-specific probe ending with a nucleotide
complementary to a nucleotide at a Group A SNP or Group B SNP to template DNA from the subject, annealing a ligation probe that binds to the template DNA immediately adjacent to the SNP site in the SNP-specific probe, adding ligase; and synthesizing a covalent bond between the probes.
The present invention includes and provides a method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising annealing a SNP-specific probe ending with a nucleotide
complementary to a nucleotide at a Group A SNP or Group B SNP to template DNA from the subject, wherein the SNP-specific probe further comprises a sequence complementary to sequence on the other side of the SNP site, adding ligase, synthesizing a covalent bond between the ends of the probe, and amplifying the ligated probe.
The present invention further includes a method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising cleaving a covalent bond at a Group A SNP or Group B SNP that is recognized by a restriction enzyme.
The present invention includes and provides a method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising annealing an invader probe that is fully complementary to a Group A SNP or Group B SNP on just one side of the SNP site of DNA from a subject, annealing a second SNP-specific probe complementary to the SNP site and the other side of a Group A SNP or Group B SNP, the second SNP-specific probe further comprising a reporter label and a quencher label on opposite sides of the second SNP-specific probe, adding a cleavase enzyme, and cleaving the reporter or quencher from the second SNP-specific probe.
The present invention includes and provides a method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising annealing a SNP-specific primer that is fully complementary to a Group A SNP or a Group B SNP to template DNA from said subject, amplifying the template DNA, melting double-stranded template DNA into single-stranded DNA strands, running the single- stranded DNA on a gel under nondenaturing conditions, and identifying a genotype at the allele, wherein alleles with different genotypes have different mobilities.
The present invention also includes two or more oligonucleotides of about 10 to about 400 nucleotides that hybridize specifically to a sequence contained in a human target sequence, a complementary sequence of the human target sequence or RNA equivalent of the human target sequence, and where the two or more oligonucleotides are capable of determining the presence or absence of two or more improved response genotype(s) in the target sequence selected from one of the SNPs in Table 1 or Table 2, or a sequence selected from SEQ ID NOs: 1 to 293, SEQ ID NOs: 294 to 317, or SEQ ID NOs: 318 to 7046.
The present invention also includes and provides a kit comprising two or more oligonucleotides of about 10 to about 400 nucleotides that are capable of being used to determine the presence or absence of two or more improved response genotype(s) in a human target sequence selected from SEQ ID NOs: 1 to 293, SEQ ID NOs: 294 to 317, or SEQ ID NOs: 318 to 7046, and instructions on how to use the two or more oligonucleotides to determine the presence or absence of an improved response genotype in the human target sequence selected from a SNP in Table 1, Table 2, Table 3, or as provided below on pages 39 to 196. The present invention includes and provides a method of treating an inflammatory condition in a selected subject in need thereof, comprising administering to the selected subject an activated protein C, protein C, or an activator of protein C, in an amount effective to treat the inflammatory condition, wherein the selected subject has been determined to have an improved response genotype at a polymorphic site selected from the group consisting of the IRP SNPs or a polymorphic site in linkage disequilibrium therewith, and the improved response genotype indicates that the selected subject would benefit from treatment with activated protein C, protein C, or an activator of protein C.
The present invention also includes a method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising determining a genotype of the subject at a Group A SNP, a Group B SNP, or a Group A and a Group B SNP, where the determining is done using a sample of nucleic acid obtained from the subject and performing one or more of the following techniques: (a) restriction fragment length analysis; (b) nucleic acid sequencing; (c) micro- sequencing assay; (d) hybridization; (e) invader assay; (f) gene chip hybridization assays; (g) oligonucleotide ligation assay; (h) ligation-rolling circle amplification; (i) 5' nuclease assay; (j) polymerase proofreading methods; (k) allele-specific PCR; (1) matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectroscopy; (m) ligase chain reaction assay; (n) enzyme-amplified electronic transduction; and (o) single base pair extension assay, where an improved response genotype at a Group A, Group B, or Group A and Group B SNP is indicative of a subject having an improved response to treatment with activated protein C.
The present invention includes and provides a method of for predicting the benefit of treatment with an activated protein C, protein C, or an activator of protein C, comprising determining the genotype of the subject at a Group A or Group B SNP, wherein the determining is done using a sample of nucleic acid obtained from the subject, and performing one or more of the following techniques: (a) restriction fragment length analysis, (b) nucleic acid sequencing, (c) micro-sequencing assay, (d) hybridization, (e) invader assay, (f) gene chip hybridization assays, (g) oligonucleotide ligation assay, (h) ligation-rolling circle amplification, (i) 5' nuclease assay, (j) polymerase proofreading methods, (k) allele specific PCR, (1) matrix assisted laser desorption ionization time of flight (MALDI-TOF) mass spectroscopy, (m) ligase chain reaction assay, (n) enzyme-amplified electronic transduction, and (o) single base pair extension assay where an improved response genotype at a Group A SNP, a Group B SNP, or a Group A and a Group B SNP is indicative of a subject having an improved response to said treatment.
The present invention includes and provides a method of selecting a subject for the treatment of an inflammatory condition with an anti-inflammatory agent or an anti-coagulant agent, comprising the step of identifying a subject having an improved response genotype at a Group A SNP, a Group B SNP, or a Group A and a Group B SNP, wherein the identification of a subject with the improved response genotype is predictive of increased responsiveness to the treatment of the inflammatory condition with the anti-inflammatory agent or the anticoagulant agent.
The present invention includes and provides a method for the treatment of an inflammatory condition with an anti-inflammatory agent or an anti-coagulant agent, comprising identifying a subject having an improved response genotype at a Group A SNP, a Group B SNP, or a Group A and Group B SNP, and providing an anti-inflammatory agent or an anti-coagulant agent. The present invention includes and provides a method for increasing the likelihood of effectiveness of an activated protein C treatment, protein C treatment, or a protein C like compound treatment, the method comprising administering an inflammatory condition treating dose of an activated protein C, protein C or protein C like compound to a subject, wherein said subject is determined to have an improved response genotype at a Group A SNP, a Group B SNP, or a Group A and a Group B SNP.
The present invention includes and provides a method for identifying a subject with a decreased likelihood to respond to an anti-inflammatory agent or an anti-coagulant agent comprising determining a genotype of said subject at a polymorphic site, wherein said genotype is a non-response genotype and wherein said polymorphic site is a Group A SNP, a Group B SNP, or a Group A and a Group B SNP.
The present invention includes and provides a method of treating an inflammatory condition in a subject in need thereof, the method comprising administering to the subject an anti-inflammatory agent or an anti-coagulant agent, wherein said subject is determined to have an improved response genotype at a Group A SNP, a Group B SNP, a Group A and Group B SNP, or one or more polymorphic sites in linkage disequilibrium thereto.
The present invention includes and provides a method of selecting a subject for the treatment of an inflammatory condition with an anti-inflammatory agent or an anti-coagulant agent, comprising the step of identifying a subject having an improved response genotype a Group A SNP, a Group B SNP, a Group A and Group B SNP, or one or more polymorphic sites in linkage disequilibrium thereto, wherein the identification of a subject with the improved response genotype is predictive of increased responsiveness to the treatment of the inflammatory condition with the anti-inflammatory agent or the anti-coagulant agent.
The present invention includes and provides for a use of an anti-inflammatory agent or an anti-coagulant agent in the manufacture of a medicament for the treatment of an inflammatory condition, wherein the subjects treated are determined to have an improved response genotype at a Group A SNP, a Group B SNP, a Group A and Group B SNP, or one or more polymorphic sites in linkage disequilibrium thereto.
The present invention includes and provides for a use of an anti-inflammatory agent or an anti-coagulant agent in the manufacture of a medicament for the treatment of an inflammatory condition in a subset of subjects, wherein the subset of subjects have an improved response genotype at a Group A SNP, a Group B SNP, a Group A and Group B SNP, or one or more polymorphic sites in linkage disequilibrium thereto.
The present invention includes and provides a method of treating an inflammatory condition in a subject in need thereof, the method comprising administering to the subject a protein C or protein C like compound, wherein said subject is determined to have an improved response genotype at a Group A SNP, a Group B SNP, a Group A and Group B SNP, or one or more polymorphic sites in linkage disequilibrium thereto.
The present invention includes and provides a method for increasing likelihood of effectiveness of a protein C treatment or protein C like compound treatment, the method comprising administering an inflammatory condition treating dose of the protein C or protein C like compound to a subject, wherein said subject is determined to have an improved response genotype at a Group A SNP, a Group B SNP, a Group A and Group B SNP, or one or more polymorphic sites in linkage disequilibrium thereto.
The present invention includes and provides for a commercial package containing, as active pharmaceutical ingredient, a protein C or protein C like compound, together with instructions for its use for the curative or prophylactic treatment of an inflammatory condition in a subject, wherein the subject treated has an improved response genotype at a Group A SNP, a Group B SNP, a Group A and Group B SNP, or one or more polymorphic sites in linkage disequilibrium thereto. The present invention includes and provides for a method for identifying a subject having one or more improved response genotype(s), the method comprising determining a genotype of a subject at one or more polymorphic sites, wherein the genotype is indicative of the subject's response to an anti-inflammatory agent or an anti-coagulant agent, wherein the polymorphic site(s) are selected from one or more of a Group A SNP, a Group B SNP, a Group A and Group B SNP, or one or more polymorphic sites in linkage disequilibrium thereto.
The present invention includes and provides for a method for selecting a group of subjects for determining the efficacy of a candidate drug known or suspected of being useful for the treatment of an inflammatory condition, the method comprising determining a genotype at one or more of a Group A SNP, a Group B SNP, a Group A and Group B SNP, or one or more polymorphic sites in linkage disequilibrium thereto, wherein the genotype is indicative of the subject's response to the candidate drug and sorting subjects based on their genotype. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graph showing the absolute risk reduction (ARR) in mortality for subjects by rs4354185 genotype in PROWESS and the VASST/SPH replication cohort with bars indicating 95% confidence intervals.
Figure 2 is a graph showing the absolute risk reduction (ARR) in mortality for subjects by rs 1042327 genotype in PROWESS and the VASST/SPH replication cohort with bars indicating 95% confidence intervals.
Figure 3 is a graph showing the absolute risk reduction (ARR) in mortality for subjects by rs684923 genotype in PROWESS and the VASST/SPH replication cohort with bars indicating 95% confidence intervals.
Figure 4 is a graph showing the absolute risk reduction (ARR) in mortality for subjects by rs3751501 genotype in PROWESS and the VASST/SPH replication cohort with bars indicating 95% confidence intervals.
Figure 5 is a graph showing the absolute risk reduction (ARR) in mortality for subjects by rs3179969 genotype in PROWESS and the VASST/SPH replication cohort with bars indicating 95% confidence intervals.
Figure 6 is a graph showing the absolute risk reduction (ARR) in mortality for subjects by rs640098 genotype in PROWESS and the VASST/SPH replication cohort with bars indicating 95% confidence intervals. Figure 7 is a graph showing the absolute risk reduction (ARR) in mortality for subjects by combined genotype with bars indicating 95% confidence intervals in the VASST/SPH replication cohort. Improved response genotypes (IRG) include (rs684923AA and/or rs4354185AA). Non-response genotypes (NRG) include (rs684923AG and rs4354185AG), (rs684923AG and rs4354185GG), (rs684923GG and rs4354185AG), and (rs684923GG and rs4354185GG).
Figure 8 is a graph showing the absolute risk reduction (ARR) in mortality for subjects by combined genotype with bars indicating 95% confidence intervals in the VASST/SPH replication cohort. Improved response genotypes (IRG) include (rs684923AA and/or rsl042327AA). Non-response genotypes (NRG) include (rs684923AG and rsl042327AG), (rs684923AG and rsl042327GG), (rs684923GG and rsl042327AG), and (rs684923GG and rsl042327GG).
Figure 9 is a graph showing the absolute risk reduction (ARR) in mortality for subjects by combined genotype with bars indicating 95% confidence intervals in the VASST/SPH replication cohort. Improved response genotypes (IRG) include (rs684923AA and/or rs3751501 AA) and (rs684923AA and/or rs3751501 AG). Non-response genotypes include (rs684923AG and rs3751501GG) and (rs684923GG and rs3751501GG).
Figure 10 is a graph showing the absolute risk reduction (ARR) in mortality for subjects by combined genotype with bars indicating 95% confidence intervals in the VASST/SPH replication cohort. Improved response genotypes (IRG) include (rs3179969AA and/or rs640098AA). Non-response genotypes include (rs3179969AG and rs640098AG), (rs3179969AG and rs640098GG), (rs3179969GG and rs640098AG), and (rs3179969GG and rs640098GG). DETAILED DESCRIPTION OF THE INVENTION
The present invention includes and provides a method of identifying a subject having an improved response to a treatment with an anti-inflammatory agent or an anti-coagulant agent, for example, activated protein C, protein C, or an activator of protein C, comprising determining a genotype at a Group A SNP of Table 1, a Group B SNP in linkage
disequilibrium with a Group A SNP, or a Group A and a Group B SNP, where an improved response genotype at a Group A, Group B, or Group A and Group B SNP is indicative of a subject having a phenotype of an improved response to a treatment with activated protein C. As used herein, the use of the term "a SNP" includes a single SNP and one or more SNPs. The present invention includes and provides a method of identifying a subject having an improved response to a treatment with an anti-inflammatory agent or an anti-coagulant agent, for example, activated protein C, protein C or an activator of protein C, comprising determining a genotype at a Group A SNP of Table 1, a Group B SNP in linkage
disequilibrium with a Group A SNP, or a Group A and a Group B SNP, where an improved response genotype at a Group A, Group B, or Group A and Group B SNP is indicative of a subject having a phenotype of an improved response to a treatment with activated protein C.
The present invention provides methods to identify a subject with an improved response to a treatment with an anti-inflammatory agent or an anti-coagulant agent, for example, activated protein C, protein C, or an activator of protein C, by determining a genotype for that trait.
The present invention provides methods that identify those who have an improved response to a treatment with an anti-inflammatory agent or an anti-coagulant agent, for example, activated protein C, protein C, or an activator of protein C, where an improved response subsequent to administrationis selected from the group consisting of an increased likelihood of survival, a reduced likelihood of organ damage or organ dysfunction, an improvement measured by an Acute Physiology and Chronic Health Evaluation II (APACHE II) score (see, Knaus et ah, "APACHE II: a severity of disease classification system," Critical Care Medicine, 13(10):% 18-29 (1985)); an increase in days alive; an increase in days free of pressors; an increase in days free of inotropes; a reduced systemic dysfunction
(cardiovascular, respiratory, ventilation, CNS, coagulation [INR> 1.5], renal and/or hepatic); an increase in the number of Organ Failure Free (OFF) days for one or more organ systems; a decrease in organ dysfunction; decreased hypotension and acidemia; a decrease in clinically important bleeding; and a decrease in adverse bleeding.
Indicia of an improved response to, or benefit from treatment with, an antiinflammatory agent or anti-coagulant agent such as activated protein C may include, without limitation, any of the following:
(a) survival benefit, including increased period of survival, increased survival during hospital stay, and increased survival over a period ranging from 28 to 90 days post- treatment;
(b) renal benefit, including days alive and free of renal dysfunction (using Brussels,
SOFA, or other scores), days alive and free of renal support, days alive and free of renal failure, prevention of need for renal support (hemodialysis, peritoneal dialysis, continuous renal replacement therapy (CRRT)), and reversal of renal dysfunction; (c) pulmonary benefit, including days alive and free of pulmonary dysfunction (using Brussels, SOFA, or other scores), and days alive and free of ventilation; days alive and free of acute lung injury;
(d) cardiovascular benefit, including days alive and free of cardiovascular dysfunction (using Brussels, SOFA, or other scores), days alive and free of vasopressors, days alive and free of renal dysfunction (using Brussels, SOFA, or other scores), and days alive and free of inotropic agents; and
(e) central nervous system benefit, including days alive and free of neurologic
dysfunction (using Brussels, SOFA, or other scores), reversal of stroke, reversal of cerebral vascular accident (CVA), prevention of stroke, prevention of cerebrovascular accident, reversal of cerebral ischemic event, reversal of transient ischemic event (TIA), prevention of cerebral ischemic event, and prevention of transient ischemic event. Table 1: Single Nucleotide Polymorphisms (SNPs) Associated With Response to
Treatment with Activated Protein C (Group A SNPs)
Figure imgf000015_0001
RSII) CHR Coordinate Gene IRP NR
(GRCh37.p5) Model Model rsl2327456 18 1485613 METTL4/C18orf2 AT TT AA rsl2335840 9 12671341 1 LHX2/DENND 1 A cc CT TT rsl2436579 14 60983087 SIX6/LOC100287070 AC CC AA rs 12494795 3 1 15687191 LSAMP CC CT TT rsl2513381 4 1 15151872 UGT8/A SJ AA GG AG rsl2529871 6 67995171 LOC100289348/LOC100289683 GT TT GG rsl2573176 10 18996761 LOC100130846/ARL5B AC AA CC rsl2618741 2 1 15118072 LOC440900/DPP10 CC CT TT rsl265140 8 103201058 RRM2B/NCALD CG CC GG rsl266382 1 236682164 LOC100287902/LGALS8 CT CC TT rsl2680523 8 1 14139597 CSMD3 CT CC TT rsl2918570 16 58268436 CSNK2 A2/CCDC 1 13 CT CC TT rs 1294227 1 233520845 KIAA1804 CC TT CT rsl2951391 17 69911582 LOC124685/SOX9 CT CC TT rsl3153368 5 1 19017509 F AM 170 A/PR 16 CC TT CT rsl3190448 5 65936799 MAST4/LOC 100129571 AA AC CC rsl3247490 7 361 15303 EEPD1/SEPT7 AG AA GG rsl3250662 8 64072039 YTHDF3/TTPA CT TT CC rsl3273073 8 23584226 NKX2-6/LOC100288985 GG TT GT rsl348181 6 50239686 TF AP2D/DEFB 1 12 AA AG GG rsl355597 20 51874769 TSHZ2 CC CT TT rs 1373649 4 9589271 1 BMPR1B AG AA GG rsl41 1820 9 1 19026907 PAPPA CC CT TT rsl478842 3 35152160 LOC 100130503/PDCD6IP AA AG GG rsl560582 2 2221071 15 SLC4A3/EPHA4 AA AG GG rsl560941 4 154378744 MND1/KIAA0922 AA GG AG rsl605461 2 189556081 DIRC1/GULP1 AG AA GG rsl667223 18 29136399 TTR/DSG2 AA CC AG rsl6953047 16 54130170 FTO GT GG TT rs 17014760 4 130340880 LOC100132483/C4orG3 AA GG AG rsl71 14618 14 44443127 LRFN5/FSCB CC CT TT rsl7151969 8 10301469 MSRA/LOC346702 AA CC AC rsl 7172693 7 46430673 LOC100287349/TNS3 CC CT TT rsl7209998 5 65940678 MAST4/LOC 100129571 CC CT TT rsl7278159 5 66012846 LOC100129571/MAST4 CT TT CC rsl 74948 7 29889233 WIPF3/LOC100289602 AG AA GG rsl74957 7 29910227 WIPF3/LOC100289602 AG AA GG rsl7507051 1 83271 130 TTLL7/LPHN2 CC CT TT rsl7781459 18 57564265 CCBE1/PMAIP1 AG GG AA rsl7839997 6 30339293 RPP21/HLA-E AA AC CC rsl 823790 2 181277132 LOC729009/CWC22 AA AG AA rsl 897833 5 896491 18 CETN3/MEF2C GT GG TT rsl 915279 1 239075714 LOC339535/CHRM3 AG AA GG rs2024408 7 38432937 AMPH CT TT CC rs2027363 9 73252653 TRPM3 AA GG AG rs2048070 4 1 1 188974 CLNK/LOC643446 GG AA AG rs2069643 5 75919662 IQGAP2/F2RL2 AG AA GG rs2076977 1 30574158 MATN1/LOC100288450 CT TT CC rs21 10167 12 5734319 AN02 AA GG AG rs2159688 7 31756362 PDElC/C7orfl6 AA AG GG rs2170169 1 38408164 INPP5B AG GG AA rs2178032 3 74860393 CNTN3/FAM86D CC TT CT rs2240660 19 32535207 TSHZ3/ZNF507 CC TT CT rs2246277 17 74081345 EXOC7 CC TT CT rs227397 14 70407769 SMOC1 CC TT CT rs2280665 4 186185293 SNX25 AA GG AG RSII) CHR Coordinate Gene IRP NR (GRCh37.p5) Model Model rs2310160 4 186190294 SNX25 CC TT CT rs2322784 17 12969292 ELAC2/LOC100287710 CT CC TT rs2341551 6 149814762 ZC3H12D/PPIL4 AG AA GG rs2394824 7 97739317 LMTK2 AA AG GG rs2501976 6 49370984 C6orfl38/MUT CT TT CC rs2531894 17 26173945 NOS2/LOC201229 AA AG GG rs2598414 17 74067099 SRP68 CC TT CT rs2653814 9 9142361 1 LOC286238/C9orf47 GT GG TT rs2694418 12 105038670 CHST1 1 TT GG GT rs2695027 7 18631680 HDAC9 AA GG AG rs2716555 16 72628133 LOC441506 LOC401859 GG AA AG rs2716601 16 74076252 LOC100288121/LOC401859 AA AG GG rs2721952 8 1 16645056 TRPS1 CT CC TT rs2728981 3 22253194 ZNF385D/UBE2E2 AA AG GG rs2729140 3 1 128796 CHL1/CNTN6 AG AA GG rs2729547 7 1 1 1817732 DOCK4 CC TT CT rs2829523 21 26414531 NC AM2/NCRN A00158 AC CC AA rs2942917 1 195778671 CDC73/KCNT2 AA AG GG rs310244 1 65305877 JAK1 AG AA GG rs31 18050 1 58219167 DAB1/LOC100288923 CT TT CC rs3130454 6 31 108485 PSO S1C1/CCHC 1 AG AA GG rs321224 9 20221607 SLC24A2/MLLT3 CC TT CT rs359447 5 173271 163 CPEB4/BOD1 CT CC TT rs3813026 17 76123528 TMC6 AA AG GG rs3816253 15 78458485 IDH3A CC CT TT rs3847794 12 94528825 LOC441644/LOC 100287069 AG AA GG rs3963484 16 6931014 A2BP1 AA AG GG rs4140512 22 41032863 MKL1/MCHR1 AA AG GG rs4237265 9 76944002 ANXA1/LOC10013091 1 CT CC TT rs426357 10 17356447 LOC100287578/ST8SIA6 AG AA GG rs4322073 9 73250037 TRPM3 CC TT CT rs4331850 5 65923124 LOC100129571/MAST4 AA AG GG rs436961 1 15 35957584 LOC100288892/ATPBD4 AA GG AG rs4525972 4 19492256 SLIT2/LCORL AG AA GG rs4553010 9 13301 1232 LOC100289200/FREQ AG AA GG rs4595752 15 27701578 GABRG3 GT GG TT rs4608848 4 187010104 TLR3/FAM 149A CC CT TT rs471814 1 1 1 19794509 TRIM29/PVRL1 AA AG GG rs4729408 7 97772658 LMTK2 CT CC TT rs4876024 8 251 1536 LOC100286951/CSMD1 CT CC TT rs4952903 2 48254907 FOXN2/FBX01 1 GT TT GG rs4975300 4 129160316 LARP2/PGRMC2 CC CT TT rs530461 20 48467716 SLC9A8 AG AA GG rs589258 13 94807356 GPC6 CT CC TT rs6012750 20 48430680 SLC9A8 AG AA GG rs61 1003 1 1 69445284 CCND1/MYEOV AA AC CC rs626545 10 131780831 LOC387723/EBF3 GG AA AG rs6446731 4 3284751 RGS12/C4orf44 AG AA GG rs6482910 10 133367723 FLJ46300/TCERG 1 L CC TT CT rs6489851 12 1 13128754 PTPN1 1/RPH3A CT CC TT rs651844 1 108079073 VAV3/NTNG1 CT CC TT rs6549946 3 29517861 RBMS3 AA GG AG rs6713126 2 129914893 LOC 100130549/LOC 151 121 TT CC CT rs6780177 3 21647818 ZNF385D CT CC TT rs6864 10 70776594 KIAA1279 AC AA CC rs6893958 5 6842842 POLS/LOC442132 AA AG GG RSII) CHR Coordinate Gene IRP NR (GRCh37.p5) Model Model rs6896102 5 65961205 LOC100129571/MAST4 GG GT TT rs6909151 6 1 10288776 FIG4/GP 6 AG GG AA rs6918854 6 26577924 ABT1/HMGN4 AA GG AG rs6922979 6 99627975 C6orfl68/FBXL4 AA GG AG rs6925087 6 26592853 ABT1/HMGN4 TT AA AT rs6941022 6 26553531 HMGN4/ABT1 TT CC CT rs6953258 7 94375808 PEG 10/PPP 1 9 A CC CT TT rs6972943 7 89544313 ZNF 804B/DP Y 19L2P4 AG AA GG rs6977578 7 8532519 NXPH1 CC CT TT rs6981251 8 120873916 DEPDC6/DSCC 1 AA AG GG rs6987100 8 120875221 DEPDC6/DSCC 1 AA AG GG rs71 10072 1 1 26661690 AN03 CC CT TT rs712001 1 1 1 98953367 CNTN5 TT GG GT rs7134223 12 73854918 TRHDE/LOC552889 TT GG GT rs7292804 22 41047556 MKL1/MCHR1 GG GT TT rs7305954 12 48403530 COL2A1/LOC7281 14 CC TT CT rs7409 17 74035543 SRP68 CC TT CT rs7425164 2 16784998 FAM49A CC CT TT rs7444603 5 53939221 SNX18/LOC727930 AA CC AC rs7523607 1 242767678 PLD5/LOC100289254 AA CC AC rs7544877 1 106807637 LOC100287317/LOC126987 CT TT CC rs7551773 1 239060960 CHRM3/LOC339535 AG GG AA rs7572996 2 220269475 DNPEP/LOC100288941 AG AA GG rs7582779 2 80869195 CTNNA2 AG GG AA rs7617493 3 3080200 CNTN4 CT CC TT rs7641222 3 65479068 MAGI1 AC AA CC rs7673752 4 95877680 BMPR1B AC AA CC rs7702195 5 2089221 IRX4/IRX2 CT CC TT rs7795499 7 38268395 STARD3NL CC TT CT rs7815122 8 120869022 DSCC1/DEPDC6 GG GT TT rs7867693 9 133003804 FREQ/LOC100289200 AG AA GG rs7970821 12 10426987 GAB ARAPL 1 /KLRD 1 CC TT CT rs7974223 12 105048460 CHST1 1 AA AG GG rs7979573 12 59886104 SLC16A7/LRIG3 AG GG AA rs7986188 13 23625664 SGCG/LOC646201 AA GG AG rs8028880 15 56019653 PRTG CC CT TT rs8041979 15 50163854 ATP8B4 AG AA GG rs835481 12 105048914 CHST1 1 CC CT TT rs922902 2 48372254 FBXOH/FOXN2 CG GG CC rs9291224 4 42827373 GRXCR1/ATP8A1 CC TT CT rs9296272 6 38940282 DNAH8 CC TT CT rs9372243 6 1 10290740 FIG4/GPR6 AG GG AA rs9373836 6 106616379 LOC100287304/ATG5 TT CC CT rs9460540 6 20648762 CDKAL1 AG GG AA rs9554684 13 101040056 PCCA CT CC TT rs9587280 13 107682425 LOC390424/FAM155A CT TT CC rs958738 6 1 16470561 NT5DC1/COL10A1 AA GG AG rs966775 5 174763322 MSX2/DRD1 AA AG GG rs9815663 3 3614887 LOC100130207/CRBN CT TT CC rs993691 3 140120742 CLSTN2 CC TT CT rs9962772 18 56151 138 ALPK2 AC CC AA rsl238061 1 9 72648665 MAMDC2/C9orfl35 CC CT TT rsl2423283 12 74592708 TRHDE/LOC552889 TT CC CT rsl 813758 20 51518287 ZFP64/TSHZ2 GT GG TT rs2665981 17 7408931 1 LOC100131436/EXOC7 AA GG AG rsl0165340 2 173327168 ITGA6/LOC100287375 CT CC TT RSII) CHR Coordinate Gene IRP NR (GRCh37.p5) Model Model rs 1042277 7 20418926 ITGB8 CC CT TT rsl0486391 7 20376018 ITGB8 GG AA AG rsl0812532 9 27197282 TEK GG GT TT TG rsl l585501 1 237797452 Y 2 AC AA CC rsl 1645653 16 31312855 ITGAM CC TT CT rs 1421940 5 52306013 ITGA2 AA AC CC rs1445943 5 52342409 ITGA2 AA CC AC rsl457238 2 160985462 ITGB6 AA AG GG rsl53141 5 52304996 ITGA2 GG AA AG rsl7318470 15 68616610 ITGA1 1 CT CC TT rsl991013 5 52359934 ITGA2 TT CC CT rs2222202 1 206945381 IL10 AA AG GG rs2257096 1 237703401 RYR2 GG AA AG rs2515481 8 6390027 ANGPT2 GG AA AG rs2756901 9 27218053 TEK CC CT TT rs2916755 8 6369350 ANGPT2 AA AG GG rs3024496 1 206941864 IL10 GG AA AG rs3176876 1 101200608 VCAM1 GG AA AG rs3176877 1 101203395 VCAM1 AA AT TT rs3212435 5 52337326 ITGA2 TT GG GT rs3212439 5 52337783 ITGA2 TT CC CT rs3212461 5 52341 1 10 ITGA2 GG TT GT rs3212464 5 52341512 ITGA2 AA GG AG rs3212481 5 52343802 ITGA2 CC CT TT rs3212640 5 52383718 ITGA2 CC CG GG rs3733138 3 37560708 ITGA9 AG AA GG rs3768777 2 187456121 ITGAV GG AA AG rs3917019 1 101202354 VCAM1 AA AG GG rs4777049 15 68695448 ITGA1 1 CC CT TT rs4941 183 18 60802931 LOC100287255/BCL2 GG AA AG rs4987821 18 60813215 LOC100287255/BCL2 CT CC TT rs61 19410 20 32442607 CHMP4B/RALY CT CC TT rs641 153 6 31914180 CFB AG AA GG rs6755175 2 173320520 LOC100287375/ITGA6 AG AA GG rs7032817 9 27133385 TEK TT CC CT rsl0230573 7 80141069 GNAT 3 AA AG GG rsl042327 6 170878793 TBP TT CC CT rsl0950521 7 14429350 DGKB CC CT TT rsl l6187 17 64497737 PRKCA AA AG GG rsl258236 10 50916484 C10orf53 AG AA GG rsl363560 5 167645888 ODZ2 CC CT TT rsl 37794 22 44079680 EFCAB6 AA AG GG rsl386440 8 32177531 NRG1 AA AG GG rsl563632 17 18220770 SMCR8 GG AA AG rsl7395296 22 26689105 SEZ6L AA AG GG rsl7724627 20 36376580 CTNNBL1 CC CT TT rsl 805100 8 76476396 HNF4G AA AG GG rs2016224 3 88041650 HTR1F GG AA AG rs2020860 1 171 162583 FM02 CT CC TT rs2073619 16 75327916 CFDP1 AG AA GG rs2073721 6 31 129616 TCF19 AG AA GG rs2276932 4 148984321 ARHGAP10 AG AA GG rs2827845 21 24464910 NC AM2/NCRN AOO 158 AG AA GG rs2941483 8 76478616 HNF4G AA AG GG rs2989946 1 227178948 CDC42BPA AG AA GG rs3746766 20 61519988 DIDOl GG AA AG RSII) CHR Coordinate Gene IRP NR
(GRCh37.p5) Model Model
rs3848668 20 62293272 TEL1 AG AA GG
rs397250 1 1 9737574 SWAP70 GG AA AG
rs4149338 9 107545903 ABCA1 AA AG GG
rs4267943 6 49439805 CENPQ AA AG GG
rs4354185 6 1 10301661 GPR6 AA AG GG
rs4371530 3 174951756 NAALADL2 TT CC CT
rs4715631 6 56417545 DST TT CC CT
rs4757548 1 1 17596313 OTOG AA AG GG
rs5847 1 1 57319339 UBE2L6 TT CC CT
rs71 1 173 17 3800995 P2RX1 CC CT TT
rs7535528 1 2444414 PANK4 AA AG GG
rs7610425 3 149485293 C3orfl6 CC CT TT
rs7861460 9 101282313 GABBR2 GG GT TT
rs7940667 1 1 1 19510644 PVRL1 AC AA CC
rs7992 6 31630241 BAT4 TT CC CT
rs8128 1 1 15110683 BCAS2 AA AC CC
rs397686 1 1 9706221 SWAP70 CC AA AC
rs4936280 1 1 1 13075615 TMPRSS5 TT CC CT
rs8878 4 76942300 CXCL10 AA AG GG
rs684923 1 237814783 RYR2 TT CC CT
rs640098 1 1 128648966 FLU AA AG GG
rs3751501 14 23549285 ACINI AA AG GG
rs3179969 14 88862529 SPATA7 AA AG GG
rsl 1 159859 14 89027891 ZC3H14/PTPN21 GG GC CC
rs 12436642 14 89025376 PTPN21/ZC3H14 AA AG GG
rsl2436982 14 89156206 EML5 AA AG GG
rsl342836 1 237805965 RYR2 GG AA AG
rs1344747 14 89014435 PTPN21 AA AT TT
rsl7188228 14 89205265 EML5 CC CT TT
rsl950806 14 89240756 EML5 TT CC CT
rs2274737 14 88935651 PTPN21 CC CT TT
rs3742484 14 23566474 C14orfl l9 AT TT AA
rs3742486 14 23568376 C14orfl l9/LOC100128908 AG AA GG
rs3783889 14 88941981 PTPN21 TT AA AT
rs3814855 14 88933360 PTPN21 AA AG GG
rs61977053 14 88847220 SPATA7/LOC100287861 AA AC CC
rs61984684 14 89025448 ZC3H14/PTPN21 CC CT TT
rs625006 1 237813126 RYR2 GG AA AG
rs8017689 14 88949786 PTPN21 CC CT TT
rs8020072 14 89180676 EML5 CC CT TT
rs930181 14 89018708 PTPN21 TT CC CT
An improved response genotype is indicated as the genotype on both chromosomes of a SNP. An improved response phenotype or non-response phenotype may also be indicated by the reverse complement of the SNP allele. Table 2: Selected Improved Response Genotypes and Non-Response Genotypes
An improved response genotype is indicated as the genotype on both chromosomes of a SNP. An improved response phenotype or non-response phenotype may also be indicated by the reverse complement of the SNP allele.
Figure imgf000021_0001
Table 3: Improved Response and Non-Response Genotype Combinations
Figure imgf000021_0002
rs684923AA and rs4354185AG
rs684923AG and rs4354185AG rs684923AA and rs4354185GG
rs684923 and rs684923AG and rs4354185GG
rs684923AG and rs4354185AA
rs4354185 rs684923GG and rs4354185AG
rs684923GG and rs4354185AA
rs684923GG and rs4354185GG rs684923AA and rs4354185AA rs684923AA and rsl042327AG
rs684923AG and rsl042327AG rs684923AA and rsl042327GG
rs684923 and rs684923AG and rsl042327GG rs684923AG and rsl042327AA
rsl042327 rs684923GG and rsl042327AG rs684923GG and rsl042327AA
rs684923GG and rsl042327GG rs684923AA and rsl042327AA
rs684923AA and rs3751501AG
rs684923AA and rs3751501GG
rs684923AG and rs3751501AA
rs684923 and
rs684923GG and rs3751501AA rs684923AG and rs3751501GG rs3751501
rs684923AA and rs3751501AA rs684923GG and rs3751501GG rs684923GG and rs3751501AG
rs684923AG and rs3751501AG
rs3179969AA and rs640098AG rs3179969AG and rs640098AG rs3179969AA and rs640098GG rs3179969AG and rs640098GG rs3179969 and
rs3179969AG and rs640098AA rs3179969GG and rs640098AG rs640098
rs3179969GG and rs640098AA rs3179969GG and rs640098GG rs3179969AA and rs640098AA
The sequence listing provides the sequence of the SNPs set forth in Tables 1 and 2 at SEQ ID NOs: l to 293 and at SEQ ID NOs: 294 to 317. Sequences corresponding to the Group B SNPs are set forth in SEQ ID NOs: 318 to 7046.
An "improved response genotype" (IRG) or improved response polymorphic variant as used herein refers to an allelic variant or genotype at a polymorphic site described herein or a polymorphic site in linkage disequilibrium with a described polymorphic site as being predictive of a subject's increased likelihood of survival or improved condition in response to treatment with an anti-inflammatory agent or an anti-coagulant agent or a reduction in serious adverse events or adverse events in response to treatment with an anti-inflammatory agent or an anti-coagulant agent as described herein, for example, with an activated protein C. An IRG may be selected from a genotype selected from rs684923 (AA), rs 10822315 (GG), rs8028880 (GG), rs958738 (AA GG), rsl2380611 (GG), rsl2529871 (AA), rs6925087 (TT), rsl7781459 (AG GG), rs4525972 (AG), rs7572996 (AG), rs3179969 (AA), rs640098 (AA), rs4371530 (AA), rs2016224 (GG), rs4936280 (AA), rs3751501 (AA AG), rs4354185 (AA), rs7535528 (AA), rs7940667 (AC AA), rs 1042327 (AA), rs2989946 (CT), rs2073721 (AG), rsl805100 (AA), or rs8128 (TT) (see, Table 2).
An "Improved Response Genotype Combination" (IRGC) as used herein refers to allelic variants at more than one polymorphic site described herein or polymorphic sites in linkage disequilibrium with a described polymorphic site, wherein the genotype combination(s) are predictive of a subject's increased likelihood of survival or improved condition in response to treatment with an anti-inflammatory agent or an anti-coagulant agent or a reduction in serious adverse events or adverse events in response to treatment with an anti-inflammatory agent or an anti-coagulant agent as described herein, for example, with an activated protein C. An IRGC may be selected from a genotype selected from rs684923 (AA) and rs4354185 (AG), rs684923 (AA) and rs4354185 (GG), rs684923 (AG) and rs4354185 (AA), rs684923 (GG) and rs4354185 (AA), rs684923 (AA) and rs4354185 (AA), rs684923 (AA) and rs 1042327 (AG), rs684923 (AA) and rs 1042327 (GG), rs684923 (AG) and rsl042327 (AA), rs684923 (GG) and rsl042327 (AA), rs684923 (AA) and rsl042327 (AA), rs684923 (AA) and rs3751501 (AG), rs684923 (AA) and rs3751501 (GG), rs684923 (AG) and rs3751501 (AA), rs684923 (GG) and rs3751501 (AA), rs684923 (AA) and rs3751501 (AA), rs684923 (GG) and rs3751501 (AG), rs684923 (AG) and rs3751501 (AG), rs3179969 (AA) and rs640098 (AG), rs3179969 (AA) and rs640098 (GG), rs3179969 (AG) and rs640098 (AA), rs3179969 (GG) and rs640098 (AA), and rs3179969 (AA) or rs640098 (AA) (see, Table 3).
A "non-response genotype" (NRG) as used herein refers to an allelic variant or genotype at a polymorphic site described herein or a polymorphic site in linkage
disequilibrium with a described polymorphic site as being predictive of a subject's decreased likelihood of survival or a reduced survival prognosis in response to treatment with an anti- inflammatory agent or an anti-coagulant agent, such as activated protein C. A NRG may be selected from a genotype selected from rs684923 (AG/GG), rsl0822315 (AG/AA), rs8028880 (GA/GG), rs958738 (A/G), rsl2380611 (AG/AA), rsl2529871 (AC/CC), rs6925087 (TA AA), rsl 7781459 (AA), rs4525972 (AA GG), rs7572996 (AA/GG), rs3179969 (AG/GG), rs640098 (AG/GG), rs4371530 (AG/GG), rs2016224 (GA/AA), rs4936280 (AG/GG), rs3751501 (GG), rs4354185 (AG/GG), rs7535528 (AG/GG), rs7940667 (CC), rsl042327 (GA GG), rs2989946 (CC/TT), rs2073721 (AA/GG), rsl805100 (AG/GG), or rs8128 (TG/GG) (see, Table 2).
A "non-response genotype combination" (NRGC) as used herein refers to allelic variants at more than one polymorphic site described herein or polymorphic sites in linkage disequilibrium with one or more of the described polymorphic sites, wherein the genotype combination(s) are predictive of an absence of a subject's increased likelihood of survival or improved condition in response to treatment with an anti-inflammatory agent or an anticoagulant agent or a reduction in serious adverse events or adverse events in response to treatment with an anti-inflammatory agent or an anti-coagulant agent as described herein, for example, with an activated protein C. A NRGC may be selected from a genotype combination selected from rs684923 (AG) and rs4354185 (AG), rs684923 (AG) and rs4354185 (GG), rs684923 (GG) and rs4354185 (AG), rs684923 (GG) and rs4354185 (GG), rs684923 (AG) and rs 1042327 (AG), rs684923 (AG) and rs 1042327 (GG), rs684923 (GG) and rsl042327 (AG), rs684923 (GG) and rsl042327 (GG), rs684923 (AG) and rs3751501 (GG), rs684923 (GG) and rs3751501 (GG), rs3179969 (AG) and rs640098 (AG), rs3179969 (AG) and rs640098 (GG), rs3179969 (GG) and rs640098 (AG), or rs3179969 (GG) and rs640098 (GG).
A subject who has a non-response genotype or "non-response genotype combination" will, more likely than not, fail to benefit from treatment with an anti-inflammatory agent or an anti-coagulant agent, for example, activated protein C, protein C, or an activator of protein C.
A subject with an improved response genotype or an improved response genotype combination is a person who can, more likely than not, benefit from treatment with an anti- inflammatory agent or an anti-coagulant agent, for example, activated protein C, protein C or an activator or protein C.
A subject can have an inflammatory condition. An inflammatory condition can be any condition associated with inflammation. For example, the inflammatory condition may be associated with the injuries, diseases, or conditions selected from the group including: severe sepsis; sepsis; septicemia; pneumonia; septic shock; systemic inflammatory response syndrome (SIRS); Acute Respiratory Distress Syndrome (ARDS); acute lung injury;
aspiration pneumonitis; infection; pancreatitis; bacteremia; peritonitis; abdominal abscess; inflammation due to trauma; inflammation due to surgery; chronic inflammatory disease; ischemia; ischemia-reperfusion injury of an organ or tissue; tissue damage due to disease; tissue damage due to chemotherapy or radiotherapy; reactions to ingested, inhaled, infused, injected, or delivered substances; glomerulonephritis; bowel infection; opportunistic infections; major surgery or dialysis; immunocompromised immune system;
immunosuppressive agents; HIV/ AIDS; suspected endocarditis; fever; fever of unknown origin; cystic fibrosis; diabetes mellitus; chronic renal failure; acute renal failure; acute kidney injury (AKI); oliguria; acute renal dysfunction; glomerulo-nephritis; interstitial- nephritis; acute tubular necrosis (ATN); oliguric ATN; non-oliguric ATN; bronchiectasis; chronic obstructive lung disease; chronic bronchitis; emphysema; asthma; febrile
neutropenia; meningitis; septic arthritis; urinary tract infection; necrotizing fasciitis; other suspected Group A streptococcus infections; splenectomy; recurrent or suspected enterococcus infection; other medical and surgical conditions associated with increased risk of infection; Gram positive sepsis; Gram negative sepsis; culture negative sepsis; fungal sepsis; meningococcemia; post-pump syndrome; cardiac stun syndrome; myocardial infarction; stroke; congestive heart failure; cardiogenic shock; post-cardiopulmonary bypass low cardiac output syndrome; low cardiac output syndrome post-myocardial infarction;
disseminated intravascular coagulation (DIC); sepsis-induced coagulopathy; hepatitis;
epiglottitis; E. coli 0157:H7; malaria; gas gangrene; toxic shock syndrome; pre-eclampsia; eclampsia; HELLP syndrome; mycobacterial tuberculosis; Pneumocystis carinii pneumonia; Leishmaniasis; hemolytic uremic syndrome/thrombotic thrombocytopenic purpura; Dengue hemorrhagic fever; pelvic inflammatory disease; Legionella; Lyme disease; Influenza A; Epstein-Barr virus; encephalitis; inflammatory diseases and autoimmunity including
Rheumatoid arthritis, osteoarthritis, progressive systemic sclerosis, and systemic lupus erythematosus; inflammatory bowel disease; idiopathic pulmonary fibrosis; sarcoidosis; hypersensitivity pneumonitis; systemic vasculitis; Wegener's granulomatosis; transplants including heart, liver, lung, kidney, and bone marrow; graft- versus-host disease; transplant rejection; sickle cell anemia; nephrotic syndrome; toxicity of agents such as OKT3; cytokine therapy; hepatorental syndrome (HRS); and cirrhosis. In one aspect, the treatment is the treatment of the inflammation symptoms.
In one aspect, the inflammatory condition may be selected from SIRS, severe sepsis, sepsis, septic shock, cardiogenic shock and acute renal failure. In another aspect, the inflammatory condition may be selected from SIRS, severe sepsis, sepsis, and septic shock. In one aspect, the inflammatory condition may be selected from severe sepsis and septic shock. In yet another aspect, the inflammatory condition may be selected from cardiogenic shock and acute renal failure. In an aspect, the inflammatory condition may be severe sepsis. In another aspect, a condition can be any condition that can be treated with a therapeutic agent capable of increasing protein C levels or activated protein C levels, for example, by activated protein C.
A "systemic inflammatory response syndrome" or (SIRS) is defined as including both septic {i.e., sepsis or septic shock) and non-septic systemic inflammatory response {i.e., post operative). "SIRS" is further defined according to ACCP (American College of Chest Physicians) guidelines as the presence of two or more of A) temperature > 38°C or < 36°C, B) heart rate > 90 beats per minute, C) respiratory rate > 20 breaths per minute or the need for mechanical ventilation, and D) white blood cell count > 12,000 per mm 3 or < 4,000 mm 3. In the following description, the presence of two, three, or four of the "SIRS" criteria were scored each day over the 28-day observation period.
"Sepsis" is defined as the presence of at least two "SIRS" criteria and known or suspected source of infection.
"Severe sepsis" is defined as sepsis plus one new organ dysfunction by Brussels criteria or by the definition described in the PROWESS study (Bernard et al., supra).
"Septic shock" is defined as severe sepsis with multiple organ dysfunctions by Brussels criteria or by the definition described in the PROWESS study (Bernard et al., supra).
One aspect of the invention may involve the identification of subjects or the selection of subjects that are either at risk of developing an inflammatory condition or the identification of subjects who already have an inflammatory condition. For example, subjects who have undergone major surgery or are scheduled for or contemplating major surgery may be considered as being at risk of developing an inflammatory condition. Furthermore, subjects may be determined as having an inflammatory condition using diagnostic methods and clinical evaluations known in the medical arts.
Any of the diagnostic and therapeutic methods can include the step of further assessing subject outcome or prognosis and this may be accomplished by various methods. For Example, an "APACHE Π" score is defined as Acute Physiology And Chronic Health Evaluation and can be calculated on a daily basis from raw clinical and laboratory variables. See, Knaus et al., supra; see also, Vincent et al. ( "Scoring systems for assessing organ dysfunction and survival," Critical Care Clinics, 7(5:353-366 (2000)). The maximum possible APACHE II score is 71, and high scores have been well correlated with mortality. The APACHE II score has been widely used to stratify and compare various groups of critically ill subjects, including subjects with sepsis, by severity of illness on entry into clinical trials. The criteria or indication for administering activated protein C (XIGRIS™ - drotrecogin alfa (activated)) in the United States is an APACHE II score of > 25. In Europe, the criteria or indication for administering activated protein C is an APACHE II score of > 25 or 2 organ system failures.
Organ dysfunction may be measured, for example, using the Brussels score (Bernard,
"The Brussels Score," Sepsis, 1(1) Ά3-44 (1997)), the Sepsis-related Organ Failure
Assessment (SOFA) score (Vincent, "Organ dysfunction as an Outcome Measure: The Sofa Score," Sepsis, l(l):53-54 (1997)), and the Multiple Organ Dysfunction Score (MODS) (Marshall, "The Multiple Organ Dysfunction (MOD) Score," Sepsis, l(l)A9-52 (1997)). Bleeding is the most common serious adverse reaction experienced by patients receiving activated protein C (e.g., Xigris™). An improved response may include a decrease in adverse bleeding.
A "Brussels score" score is a method for evaluating organ dysfunction as compared to a baseline. If the Brussels score is 0 (i.e., moderate, severe, or extreme), then organ failure was recorded as present on that particular day. To correct for deaths during the observation period, days alive and free of organ failure (DAF) can be calculated. For example, acute lung injury can be calculated as follows. Acute lung injury is defined as present when a subject meets all of these four criteria: 1) need for mechanical ventilation; 2) bilateral pulmonary infiltrates on chest X-ray consistent with acute lung injury; 3) Pa02/Fi02 ratio is less than 300 mmHg; and 4) no clinical evidence of congestive heart failure or if a pulmonary artery catheter is in place for clinical purposes, a pulmonary capillary wedge pressure less than 18 mm Hg. The severity of acute lung injury can be assessed by measuring days alive and free of acute lung injury over a 28-day observation period. Acute lung injury is recorded as present on each day that the person has moderate, severe, or extreme dysfunction as defined in the Brussels score. Days alive and free of acute lung injury can be calculated as the number of days after onset of acute lung injury that a subject is alive and free of acute lung injury over a defined observation period (28 days). Thus, in an aspect, a lower score for days alive and free of acute lung injury indicates more severe acute lung injury. Days alive and free of acute lung injury can be preferable to the simple presence or absence of acute lung injury, because acute lung injury has a high acute mortality and early death (within 28 days) precludes calculation of the presence or absence of acute lung injury in dead subjects. In an aspect, the cardiovascular, renal, neurologic, hepatic, and coagulation dysfunction can be similarly defined as present on each day that the subject had moderate, severe, or extreme dysfunction as defined by the Brussels score. In another aspect, days alive and free of steroids can be days that a person is alive and is not being treated with exogenous
corticosteroids (e.g., hydrocortisone, prednisone, methylprednisolone). In another aspect, days alive and free of pressors can be days that a person is alive and not being treated with intravenous vasopressors (e.g., dopamine, norepinephrine, epinephrine or phenylephrine). In another aspect, days alive and free of an International Normalized Ratio (INR) > 1.5 can be days that a person is alive and does not have an INR > 1.5.
Table 4: Brussels Organ Dysfunction Scoring System
ORGANS Free of Organ Dysfunction Clinically Significant Organ Dysfunction Normal Mild Moderate Severe Extreme
DAF ORGAN 1 0
DYSFUNCTION
SCORE
Cardiovascular >90 <90 <90 <90 plus <90 plus
Systolic BP Responsive to Unresponsive to pH <7.3 pH <7.2 (mmHg) fluid fluid
Pulmonary >400 400-301 300-201 200-101 <100
Pao2 Fi02 (mmHg) Acute lung injury ARDS Severe ARDS
Renal <1.5 1.5-1.9 2.0-3.4 3.5-4.9 >5.0
Creatinine (mg/dL)
Hepatic <1.2 1.2-1.9 2.0-5.9 6.0-11.9 >12
Bilirubin (mg/dL)
Hematologic >120 120-81 80-51 50-21 <20
Platelets (xl05/mm3)
Neurologic 15 14-13 12-10 9-6 <5
(Glasgow Coma
Score)
Round Table Conference on Clinical Trials for the Treatment of Sepsis
Brussels, March 12-14, 1994.
It is understood that such tests or steps can be before, concurrent, or after any other step described herein.
The present invention provides markers that allow for the determination of the effectiveness of treatments with an anti-inflammatory agent or an anti-coagulant agent. In an aspect, the present invention provides markers that allow for the determination of the effectiveness of treatments directed at increasing protein C levels and /or activated protein C levels. Such markers can be effective for determining the effectiveness of any therapeutic agent capable of increasing protein C levels and/or activated protein C levels and any disease or indication associated with the need to increase such levels. Examples of such diseases and conditions are both provided and known in the art.
In an aspect of the present invention, a subject may have already provided a biological sample for other purposes or may have even had their genetic sequence determined in whole or in part and stored for future use. Genetic sequence information may be obtained in numerous different ways and may involve the collection of a biological sample that contains genetic material, particularly genetic material containing the sequence or sequences of interest. "Genetic material" includes any nucleic acid and can be a deoxyribonucleotide or ribonucleotide polymer in either single or double-stranded form. Many methods are known in the art for collecting biological samples and extracting genetic material from those samples. Genetic material can be extracted from blood, tissue, hair, and other biological material. There are many methods known to isolate DNA and RNA from biological material.
Typically, DNA may be isolated from a biological sample when first the sample is lysed and then the DNA is separated from the lysate according to any one of a variety of multi-step protocols, which can take varying lengths of time. DNA isolation methods may involve the use of phenol (Sambrook et al, "Molecular Cloning," Vol. 2, pp. 9.14-9.23, Cold Spring Harbor Laboratory Press (1989), and Ausubel et al, "Current Protocols in Molecular Biology," Vol. 1, pp. 2.2.1-2.4.5, John Wiley & Sons, Inc. (1994)). Typically, a biological sample is lysed in a detergent solution and the protein component of the lysate is digested with proteinase for 12-18 hours. Next, the lysate is extracted with phenol to remove most of the cellular components, and the remaining aqueous phase is processed further to isolate DNA. In another method, described in Van Ness et al. (U.S. Pat. 5,130,423), non-corrosive phenol derivatives are used for the isolation of nucleic acids. The resulting preparation is a mix of RNA and DNA.
Other methods for DNA isolation utilize non-corrosive chaotropic agents. These methods, which are based on the use of guanidine salts, urea and sodium iodide, involve lysis of a biological sample in a chaotropic aqueous solution and subsequent precipitation of the crude DNA fraction with a lower alcohol. The final purification of the precipitated, crude DNA fraction can be achieved by any one of several methods, including column
chromatography (Analects (1994), Vol. 22, No. 4, Pharmacia Biotech), or exposure of the crude DNA to a polyanion-containing protein as described in Koller (U.S. Pat. 5,128,247).
Yet another method of DNA isolation, which is described by Botwell {Anal.
Biochem., 162:463-465 (1987)) involves lysing cells in 6M guanidine hydrochloride, precipitating DNA from the lysate at acid pH by adding 2.5 volumes of ethanol, and washing the DNA with ethanol.
Numerous other methods are known in the art to isolate both RNA and DNA, such as the one described by Chomczynski (U.S. Pat. 5,945,515), whereby genetic material can be extracted efficiently in as little as twenty minutes. Evans et al. (U.S. Pat. 5,989,431) describe methods for isolating DNA using a hollow membrane filter.
Nucleic acid samples can be obtained and genotyped by methods known in the art. For example, a neighboring sequence can be used to design SNP detection reagents such as oligonucleotide probes, which may optionally be implemented in a kit format. Exemplary SNP genotyping methods are described in Chen et al., "Single nucleotide polymorphism genotyping: biochemistry, protocol, cost and throughput," Pharmacogenomics J. , 3(2):ΊΊ-96 (2003); Kwok et al, "Detection of single nucleotide polymorphisms," Curr. Issues Mol. Biol, 5 (2) :43-60 (2003); Shi, "Technologies for individual genotyping: detection of genetic polymorphisms in drug targets and disease genes," Am. J. Pharmacogenomics, 2(3): 197-205 (2002); and Kwok, "Methods for genotyping single nucleotide polymorphisms," Annu. Rev. Genomics Hum. Genet., 2:235-58 (2001). Exemplary techniques for high-throughput SNP genotyping are described in Marnellos, "High-throughput SNP analysis for genetic association studies," Curr. Opin. Drug Discov. Devel, 6(3) :317-21 (2003). Another method is the chain termination method of sequencing commonly known as Sanger sequencing (Sanger et al., "DNA sequencing with chain-terminating inhibitors," Proc. Natl. Acad. Sci. USA, 74(12) :5463-7 (1977)). Hybridization methods for the identification of single nucleotide polymorphisms or other mutations involving few nucleotides are described in U.S. Patent Nos. 6,270,961, 6,025,136, and 6,872,530. A template-directed dye -terminator incorporation of a fluorescent polarization methods is described by Freeman et al. (
"Template-directed dye -terminator incorporation with fluorescence polarization detection for analysis of single nucleotide polymorphisms implicated in sepsis," J. Mol. Diagn., 4(4):209- 15 (2002)). In another aspect, microsphere based tag-it high throughput genotyping arrays may be used (Bortolin et al., "Analytical validation of the tag-it high-throughput
microsphere -based universal array genotyping platform: application to the multiplex detection of a panel of thrombophilia-associated single-nucleotide polymorphisms," Clin Chem., 50(11) 2028-36 (2004)). Ligation-Rolling Circle Amplification (L-RCA) has also been successfully used for genotyping single nucleotide polymorphisms as described in Qi et al. ( "L-RCA (ligation-rolling circle amplification): a general method for genotyping of single nucleotide polymorphisms (SNPs)," Nucleic Acids Res., 29(22):Έ\ \β (2001)). A 5' nuclease assay has also been successfully used for genotyping single nucleotide
polymorphisms (Aydin et al. "Efficient and cost-effective single nucleotide polymorphism detection with different fluorescent applications," Biotechniques, 31 (4) :920-2, 924, 926-8 (2001)). Gene chip technologies are also known for single nucleotide polymorphism discrimination whereby numerous polymorphisms may be tested simultaneously on a single array (EP 1120646 and Gilles et al., "Single nucleotide polymorphic discrimination by an electronic dot blot assay on semiconductor microchips," Nat. Biotechnol., 17(4) 365-70 (1999)). Matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectroscopy is also useful in SNP genotyping (Haff et al., "Multiplex genotyping of PCR products with MassTag-labeled primers," Nucleic Acids Res., 25(18) :3 '49-50 (1997), Haff et al., "Single-nucleotide polymorphism identification assays using a thermostable DNA polymerase and delayed extraction MALDI-TOF mass spectrometry," Genome Res.,
7(¾):378-88 (1997); Sun et al., "A new MALDI-TOF based mini-sequencing assay for genotyping of SNPS," Nucleic Acids Res., 28(12) Έ6& (2000); Braun et al. , "Detecting CFTR gene mutations by using primer oligo base extension and mass spectrometry," Clin Chem., 43 (7) : 1151 -8 (1997)). Additional techniques useful for determining the genotype of SNPs of the present invention include the methods disclosed in Eid et al, "Real-time DNA
sequencing from single polymerase molecules," Science, 323(5910) \33-% (2009), Rothberg et al, "An integrated semiconductor device enabling non-optical genome sequencing," Nature, 475(7356) :348-52 (2011), Clarke et al, "Continuous base identification for single- molecule nanopore DNA sequencing," Nat Nanotechnol, 4(4) 265-70 (2009), Garaj et al., "Graphene as a subnanometre trans-electrode membrane," Nature, 467(7312) : 190-3 (2010), Harris TD. et al, "Single-molecule DNA sequencing of a viral genome," Science,
320(5872):106-9 (2008), McKernan et al, "Sequence and structural variation in a human genome uncovered by short-read, massively parallel ligation sequencing using two-base encoding," Genome Res., 19(9) 1527-41 (2009), Drmanac et al, "Human genome sequencing using unchained base reads on self-assembling DNA nanoarrays," Science, 327(5961) 7%-%1 (2010), Shendure et al, "Accurate multiplex polony sequencing of an evolved bacterial genome," Science, 309(5741) \728-32 (2005), Ju et al, "Four-color DNA sequencing by synthesis using cleavable fluorescent nucleotide reversible terminators," Proc Natl Acad Sci USA., 103(52) 19635-40 (2006), Tanaka et al, "Partial sequencing of a single DNA molecule with a scanning tunnelling microscope," Nat Nanotechnol, 4(8) :518-22 (2009), Das et al, "Single molecule linear analysis of DNA in nano-channel labeled with sequence specific fluorescent probes," Nucleic Acids Res.,
Figure imgf000031_0001
(2010), Ronaghi, "Real-time DNA sequencing using detection of pyrophosphate release," Anal Biochem., 242(l) %4-9 (1996), and Braslavsky et al, "Sequence information can be obtained from single DNA molecules," Proc Natl Acad Sci USA., 100(7) 3960-4 (2003). Additional methods for sequencing and determining the genotype according to the methods of the present invention may be found, for example, in Shendure et al, "Overview of DNA sequencing strategies," Curr Protoc Mol Biol, Chapter 7:Unit7.1. (2011) and Slatko et al, '"First generation' automated DNA sequencing technology," Curr Protoc Mol Biol, Chapter 7:Unit7.2 (2011).
Common SNP genotyping methods include, but are not limited to, TaqMan™ assays, molecular beacon assays, nucleic acid arrays, allele-specific primer extension, allele-specific PCR, arrayed primer extension, homogeneous primer extension assays, primer extension with detection by mass spectrometry, multiplex primer extension sorted on genetic arrays, ligation with rolling circle amplification, homogeneous ligation, OLA (U.S. Pat. No. 4,988,167), multiplex ligation reaction sorted on genetic arrays, restriction-fragment length
polymorphism, single base extension-tag assays, and the Invader assay. {See, also Kim et al, "SNP genotyping: technologies and biomedical applications," Annu Rev Biomed Eng., :289-320 (2007)). Such methods may be used in combination with detection mechanisms such as, for example, luminescence or chemiluminescence detection, fiuorescence detection, time-resolved fiuorescence detection, fluorescence resonance energy transfer, fiuorescence polarization, mass spectrometry, and electrical detection.
In another aspect of the invention, large scale sequencing methods may be used to identify single nucleotide polymorphisms. Such methods include, but are not limited to, massively parallel signature sequencing (MPSS) (Reinartz et al, "Massively parallel signature sequencing (MPSS) as a tool for in-depth quantitative gene expression profiling in all organisms," Brief Fund. Genomic Proteomic, 7(7^:95-104 (2002)). In another aspect, pyrosequencing techniques may be used for SNP genotyping (Ronaghi et al,
"Pyrosequencing for SNP genotyping," Methods Mol. Biol, 272:189-95 (2003)). In another aspect, SNPs may be identified using whole genome resequencing (Bentley, "Whole-genome re-sequencing," Curr. Opin. Genet. Dev., 16(6):545-52 (2006), Zhao et al, "Advances in Whole Genome Sequencing Technology," Curr. Pharm. BiotechnoL, 720:293-305 (2011) and Next Generation Genome Sequencing: Towards Personalized Medicine, Michal Janitz, ed., Wiley (2008)). In another aspect, sequencing and SNP identification may be
accomplished using parallel pooled ligation 'Bar-seq methods (Smith et al, "Highly- multiplexed barcode sequencing: an efficient method for parallel analysis of pooled samples," Nucleic Acids Res., 38(13):E 2 (2010)).
In one aspect of the invention, samples may be genotyped using a two-step detection process. Using 50-mer probes designed to selectively hybridize to the loci of interest that stop one base before the interrogated marker, specificity is conferred by enzymatic single- base extension to incorporate a labeled nucleotide. Subsequent dual-color fluorescent staining allows the labeled nucleotide to be detected by both color and signal intensity. For genotyping assays using, for example, red and green fluorescent labels, the red and green color signals specify each allele, where homozygotes are indicated by red/red or green/green signals, and heterozygotes are indicated by red/green (yellow) signals. Shen et al, "High- throughput SNP genotyping on universal bead arrays," Mutat. Res., 575(7-2^:70-82 (2005).
Various methods for detecting genotypes include, but are not limited to, methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA duplexes (Myers et al, Science, 230: 1242 (1985); Cotton et al, PNAS, 55:4397 (1988); and Saleeba et al., Meth. Enzymol, 277:286-295 (1992)), comparison of the electrophoretic mobility of variant and wild-type nucleic acid molecules (Orita et al, PNAS, 86:2166 (1989); Cotton et al., Mutat. Res., 255: 125-144 (1993); and Hayashi et al., Genet. Anal. Tech. AppL, 9:11-19 (1992)), and assaying the movement of polymorphic or wild-type fragments in polyacrylamide gels containing a gradient of denaturant using denaturing gradient gel electrophoresis (DGGE) (Myers et al, Nature, 373:495 (1985)). Sequence variations at specific locations can also be assessed by nuclease protection assays, such as R ase and SI protection, or chemical cleavage methods.
Any marker that is in linkage disequilibrium or linked with the trait can be used to provide a correlation, for example, r . In an aspect, the marker is a nucleic acid sequence correlated with an improved response to a treatment with activated protein C. As used herein, a marker is a sequence or sequences that can be used to track inheritance.
Traditionally, a marker referred to a phenotypic marker, which could be followed in progeny generations. In an aspect, markers include nucleic acid sequence based markers that may or may not have a phenotypic consequence. In another aspect, a nucleic acid sequence marker, or genetic marker can be, but does not have to be, associated with a known location on a chromosome. A marker not only provides for the identification of the marker itself, but also for the presence of any sequences, loci or genes that may be linked nearby. Any nucleic acid sequence may be used as a marker, provided it is sufficiently different from other sequences so as to be distinguished from other sequences.
A marker can be linked to a trait. Two or more loci which remain associated with each other in progeny generations at a frequency that is greater than random 50:50 proportions are said to be linked. The tendency of loci to remain associated is referred to a linkage.
In general, the term "linkage," as used in population genetics, refers to the co- inheritance of two or more nonallelic genes or sequences due to the close proximity of the loci on the same chromosome, where after meiosis they remain associated more often than the 50% expected for unlinked genes. However, during meiosis, a physical crossing between individual chromatids may result in recombination(s). "Recombination" generally occurs between large segments of DNA, whereby contiguous stretches of DNA and genes are likely to be moved together in the recombination event (crossover). Conversely, regions of the DNA that are far apart on a given chromosome are more likely to become separated during the process of crossing-over than regions of the DNA that are close together. Polymorphic molecular markers, like SNPs, are often useful in tracking meiotic recombination events as positional markers on chromosomes. The pattern of a set of markers along a chromosome is referred to as a "Haplotype." Accordingly, groups of alleles on the same small chromosomal segment tend to be transmitted together. Haplotypes along a given segment of a chromosome are generally transmitted to progeny together unless there has been a recombination event. Absent a recombination event, haplotypes can be treated as alleles at a single highly polymorphic locus for mapping.
As used herein "haplotype" is a set of alleles of closely linked loci on a chromosome that tend to be inherited together. Such allele sets occur in patterns, which are called haplotypes. Accordingly, a specific SNP or other polymorphism allele at one SNP site is often associated with a specific SNP or other polymorphism allele at a nearby second SNP site or other polymorphism site. When this occurs, the two SNPs or other polymorphisms are said to be in LD because the two SNPs or other polymorphisms are not just randomly associated (i.e., in linkage equilibrium).
A "clade" is a group of haplotypes that are closely related phylo genetically. For example, if haplotypes are displayed on a phylogenetic (evolutionary) tree, a clade includes all haplotypes contained within the same branch.
Furthermore, the preferential occurrence of a disease gene in association with specific alleles of linked markers, such as SNPs or other polymorphisms, is called "Linkage
Disequilibrium" (LD). This sort of disequilibrium generally implies that most of the disease chromosomes carry the same mutation and the markers being tested are relatively close to the disease gene(s).
A marker can exhibit "linkage disequilibrium" with a trait. Linkage disequilibrium refers to the "preferential association of a particular allele, for example, a mutant allele for a disease with a specific allele at a nearby locus more frequently than expected by chance" and implies that alleles at separate loci are inherited as a single unit (Gelehrter, T.D., Collins, F.S. (1990). Principles of Medical Genetics. Baltimore: Williams & Wilkens).
As used herein "linkage disequilibrium" (LD) is the occurrence in a population of certain combinations of linked alleles in greater proportion than expected from the allele frequencies at the loci. For example, the preferential or increased frequency of occurrence of a trait in association with specific alleles of linked markers, such as SNPs, or between specific alleles of linked markers, are considered to be in LD. This sort of disequilibrium generally implies that most of the disease chromosomes carry the same mutation and that the markers being tested are relatively close to the disease gene(s). Accordingly, if the genotype of a first locus is in LD with a second locus (or third locus, etc.), the determination of the allele at only one locus would necessarily provide the identity of the allele at the other locus. When evaluating loci for LD, those sites within a given population having a high degree of linkage disequilibrium (i.e., an absolute value for r > 0.5) are potentially useful in predicting the identity of an allele of interest (i.e., associated with the condition of interest). A high degree of linkage disequilibrium may be represented by an absolute value for r > 0.6.
Alternatively, a high degree of linkage disequilibrium may be represented by an absolute
2 2
value for r > 0.7 or by an absolute value for r > 0.8. Additionally, a high degree of linkage disequilibrium may be represented by an absolute value for r > 0.85 or by an absolute value for r > 0.9. Accordingly, two SNPs that have a high degree of LD may be equally useful in determining the identity of the allele of interest or disease allele. Therefore, we may assume that knowing the identity of the allele at one SNP may be representative of the allele identity at another SNP in LD. Accordingly, the determination of the genotype of a single locus can provide the identity of the genotype of any locus in LD therewith and the higher the degree of linkage disequilibrium the more likely that two SNPs may be used interchangeably. For example, where the genotype of SNP rs7242 is 'G', the genotype of SNP rsl 1178 in linkage diseqilibrium is 'C. Similarly, when the genotype of rs7242 is 'T', the genotype of rsl 1178 is 'T'. Accordingly, the determination of the genotype at by rs7242 will provide the identity of the genotype at rsl 1178 or any other locus in "linkage disequilibrium" therewith.
Particularly, where such a locus is has a high degree of linkage disequilibrium thereto.
LD is useful for genotype-phenotype association studies. For example, if a specific allele at one SNP site (e.g., "A") is the cause of a specific clinical outcome (e.g., call this clinical outcome "B") in a genetic association study then, by mathematical inference, any SNP (e.g., "C") which is in significant LD with the first SNP, will show some degree of association with the clinical outcome. That is, if A is associated (~) with B, i.e., A~B and C~A, then it follows that C~B. Of course, the SNP that will be most closely associated with the specific clinical outcome, B, is the causal SNP - the genetic variation that is
mechanistically responsible for the clinical outcome. Thus, the degree of association between any SNP, C, and clinical outcome will depend on LD between A and C.
Until the mechanism underlying the genetic contribution to a specific clinical outcome is fully understood, LD helps identify potential candidate causal SNPs and also helps identify a range of SNPs that may be clinically useful for prognosis of clinical outcome or of treatment effect. If one SNP within a gene is found to be associated with a specific clinical outcome, then other SNPs in LD will also have some degree of association and therefore some degree of prognostic usefulness. Linkage disequilibrium is a non-random association of alleles at two or more loci, not necessarily on the same chromosome. The non-random association of alleles may occur either within an individual chromosome or among two or more chromosomes. Linkage disequilibrium includes the association of two or more loci on a chromosome with limited recombination between them termed 'linkage', but linkage disequilibrium is a broader term. Linkage disequilibrium refers to co -inheritance of at least two alleles in a population at frequencies greater than, or less than, would be expected from a random formation of haplotypes of those alleles based on their frequencies in that same population.
In another aspect, linkage disequilibrium can be determined according to Johnson et al, "SNAP: A Web-Based Tool for Identification and Annotation of Proxy SNPs Using HapMap," Bioinformatics, 24 (2 '4) :2938-2939 (2008), using SNAP Version 2.2 (Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142). Default parameters are applied. Genotyping is carried out using the Illumina® Human lM-Duo BeadChip (Illumina, 9885 Towne Centre Drive, San Diego, CA 92121). In an aspect, the absolute value of r > 0.50, r2 > 0.60, r2 > 0.70, r2 > 0.75, r2 > 0.80, r2 > 0.85, r2 > 0.90, r2 > 0.95, r2 > 0.98, or r2 > 0.99. The deviation of the observed frequency of a haplotype from the expected is a quantity called the linkage disequilibrium and is commonly denoted by a capital D. The correlation coefficient between pairs of loci, denoted as r, where r = D/sqrt(/?//¾ /<¾)- See, Robbins, "Some applications of mathematics to breeding problems III," Genetics, J(¾):375-389 (1918). One of skill in the art understands that r is a useful measure of LD. See, VanLiere et al.
"Mathematical properties of the r2 measure of linkage disequilibrium," Theor Popul Biol., 74(1) 130-137 (2008); Hill et al., "Linkage disequilibrium in finite populations," Theoretical and Applied Genetics, 35:226-231 (1968); Pritchard et al, "Linkage disequilibrium in humans: models and data," American Journal of Human Genetics, 69:1-14 (2001); Jorgenson et al. , "Coverage and power in genome -wide association studies," American Journal of Human Genetics, 75:884-888 (2006); Terwilliger et al., "An utter refutation of the
'Fundamental Theorem of the HapMap,'" European Journal of Human Genetics, 14:426-431 (2006); Carlson et al., "Selecting a maximally informative set of single-nucleotide
polymorphisms for association analyses using linkage disequilibrium," American Journal of Human Genetics, 74: 106-120 (2004); de Bakker et al., "Efficiency and power in genetic association studies," Nature Genetics, 57:1217-1223 (2005).
One example of a marker is a polymorphic marker. Polymorphisms can be used to determine the genotype of a subject. A "polymorphic site" or "polymorphism site" or "polymorphism" or "single nucleotide polymorphism site" (SNP site) or single nucleotide polymorphism" (SNP) as used herein is the locus or position with variation between allelic sequences. A "polymorphism" is the occurrence of two or more forms of a gene or position within a gene (allele), in a population, in such frequencies that the presence of the rarest of the forms cannot be explained by mutation alone. Preferred polymorphic sites have at least two alleles, each occurring at a frequency of greater than 1%, and more preferably greater than 10% or 20%, of a selected population. Polymorphic sites may be at known positions within a nucleic acid sequence. One of skill in the art would recognize that a given genotype may be equivalently indicated by the nucleotides present on one nucleic acid strand, or its reverse complement. Additional markers can be developed based on the disclosure and techniques known in the art. Polymorphisms may occur in coding regions and noncoding regions (for example, promoters, introns, or untranslated regions) of genes. Polymorphisms are not limited to polymorphisms found within genes. Polymorphisms may occur as a single nucleotide substitution or may involve an insertion or deletion.
A "single nucleotide polymorphism" (SNP) occurs at a polymorphic site occupied by a single nucleotide, which is the site of variation between allelic sequences. A SNP site is often preceded by and followed by highly conserved sequences of the allele (e.g., sequences that vary in less than 1/100 or 1/1000 members of the populations). While not limited by any biological mechanism, a single nucleotide polymorphism can arise due to substitution of one nucleotide for another at the polymorphic site. As used herein, such a substitution may be a transition or transversion. A "transition" is the replacement of one purine by another purine or one pyrimidine by another pyrimidine. A "transversion" is the replacement of a purine by a pyrimidine or vice versa. Single nucleotide polymorphisms can also arise from a deletion (represented by "-" or "del") of a nucleotide or an insertion (represented by "+" or "ins" or "I") of a nucleotide relative to a reference allele. Furthermore, a person of skill in the art would appreciate that an insertion or deletion within a given sequence could alter the relative position and therefore the position number of another polymorphism within the sequence providing additional markers for use. An insertion or deletion may involve the deletion or insertion of more than a single nucleotide at a given position. Such polymorphisms can also be referred to as SNPs as they can result from an insertion or deletion at a single site within a given sequence.
Any "polymorphic site" or "polymorphism site" or "polymorphism" or "single nucleotide polymorphism site" (SNP site) or "single nucleotide polymorphism" can be used that is in linkage disequilibrium or linked to the trait of interest, such as improved response to treatment with activated protein C. Based on such "polymorphic site" or "polymorphism site" or "polymorphism" or "single nucleotide polymorphism site" (SNP site) or "single nucleotide polymorphism," such subjects can be identified or grouped.
An "allele" is defined as any one or more alternative forms of a given gene. In a diploid cell or organism the members of an allelic pair (i.e., the two alleles of a given gene) occupy corresponding positions (loci) on a pair of homologous chromosomes and if these alleles are genetically identical, the cell or organism is said to be "homozygous," but if genetically different, the cell or organism is said to be "heterozygous" with respect to the particular gene.
A "gene" is an ordered sequence of nucleotides located in a particular position on a particular chromosome that encodes a specific functional product and may include untranslated and untranscribed sequences in proximity to the coding regions (5 ' and 3 ' to the coding sequence). Such non-coding sequences may contain regulatory sequences needed for transcription and translation of the sequence or introns, etc., or may not yet have any function attributed to them beyond the occurrence of the SNP of interest.
A "genotype" is defined as the genetic constitution of an organism, usually in respect to one gene or a few genes or a region of a gene relevant to a particular context (i.e., the genetic loci responsible for a particular phenotype).
A "phenotype" is defined as the observable characters of an organism.
SNPs of the present invention provide for the identification or selection for treatment of a subject in need thereof. In an aspect, a subject in need thereof can have a need for treatment of an inflammatory condition comprising the administration of an antiinflammatory agent or an anti-coagulent agent. In another aspect, a subject in need thereof can be selected or identified to have an improved response to treatment of an inflammatory condition comprising the administration of an anti-inflammatory agent or an anti-coagulent agent. In an aspect, a subject in need thereof can have a need for identification of an improved response to activated protein C in an amount effective to treat an inflammatory condition. In another aspect, a subject in need thereof can have a need for identifying a non- improved response to a treatment of an anti-inflammatory agent or an anti-coagulent agent, for example, activated protein C. In an aspect, a subject in need thereof can have a need for predicting the benefit of treatment with activated protein C, an anti-inflammatory agent, or an anti-coagulent agent.
SNPs of the present invention include, without limitation, those set forth in Tables 1 to 3 and SEQ ID NOs: 1 to 7046. Examples of SNPs associated with response to activated protein C, an anti-inflammatory agent, or an anti-coagulent agent are set forth in Table 1. Table 2 sets forth various SNPs that provide either associations with improved response or non-response to treatment with activated protein C, an anti-inflammatory agent, or an anti- coagulent agent. Table 3 sets forth various SNP combinations that provide either associations with improved response or non-response to treatment with activated protein C, an antiinflammatory agent, or an anti-coagulent agent. SEQ ID NOs: 318 to 7046 sets forth SNPs that exhibit linkage disequilibrium with a r of at least 0.8 with response to activated protein C, an anti-inflammatory agent, or an anti-coagulent agent and the genotypes are provided below on page 39 to page 196.
The flanking sequences for the SNPs of the invention listed in Table 1 are provided in SEQ ID NOs: 1 to 293. The position of the SNP within the sequence is indicated. It will be appreciated by a person of skill in the art that the numerical designations of the positions of polymorphisms within a sequence are relative to the specific sequence. Also, the same positions may be assigned different numerical designations depending on the way in which the sequence is numbered and the sequence chosen. Furthermore, sequence variations within the population, such as insertions or deletions, may change the relative position and subsequently the numerical designations of particular nucleotides at and around a
polymorphic site.
In one aspect, the polymorphism is the major allele. In another aspect, the
polymorphism is the minor allele. As used within a population, a major allele is the allele with the greatest frequency in a population. The minor allele, or alleles, are the alleles with the lowest frequency. Whether a SNP is the major or the minor allele depends on the population analyzed. Human populations, and human individuals vary, so SNPs may be found at both the individual and population level. The distribution of SNPs within human populations may vary so that what is a major allele in one population group may be a minor allele in a different population group. The population can be a geographic or suitable clinical sub-group. In one aspect, a population may be selected based on race, ethnicity, sex, or age. In another aspect, a population may be selected based on clinical subgroup such as failure of cardiovascular, respiratory, renal, hematologic, CNS, or hepatic organ.
In one aspect, the genotype is, or is in linkage disequilibrium with, a SNP that is associated with an improved response to activated protein C, including a Group A SNP of Table 1 (SEQ ID NOs: 1 to 293). In another aspect, the genotype is, or is in linkage disequilibrium with, a SNP that is associated with an improved response to activated protein C including rs684923 (AA), rsl0822315 (GG), rs8028880 (GG), rs958738 (AA GG), rsl2380611 (GG), rsl2529871 (AA), rs6925087 (TT), rsl7781459 (AG GG), rs4525972 (AG), rs7572996 (AG), rs3179969 (AA), rs640098 (AA), rs4371530 (AA), rs2016224 (GG), rs4936280 (AA), rs3751501 (AA AG), rs4354185 (AA), rs7535528 (AA), rs7940667 (AC AA), rsl042327 (AA), rs2989946 (CT), rs2073721 (AG), rsl805100 (AA), and rs8128 (TT), or combinations thereof (SEQ ID NOs: 294 to 317).
In another aspect, the genotype is, or is in linkage disequilibrium with, a SNP that is associated with a non-response to activated protein C including rs684923 (AG/GG), rsl0822315 (AG/AA), rs8028880 (GA/GG), rs958738 (A/G), rsl2380611 (AG/AA), rsl2529871 (AC/CC), rs6925087 (TA/AA), rsl7781459 (AA), rs4525972 (AA/GG), rs7572996 (AA/GG), rs3179969 (AG/GG), rs640098 (AG/GG), rs4371530 (AG/GG), rs2016224 (GA/AA), rs4936280 (AG/GG), rs3751501 (GG), rs4354185 (AG/GG), rs7535528 (AG/GG), rs7940667 (CC), rs 1042327 (GA/GG), rs2989946 (CC/TT), rs2073721 (AA/GG), rs 1805100 (AG/GG), and rs8128 (TG/GG), or combinations thereof In yet another aspect, the genotype is, or is in linkage disequilibrium with, a SNP that is associated with a non-response to activated protein C, including a Group A SNPs of Table 1 (SEQ ID NOs: 1 to 293).
In another aspect, an improved response may be associated with a pair of genotypes, or markers in linkage disequilibrium with pairs of genotypes, including the polymorphic sites rsl042327, rsl0822315, rsl2380611, rsl2529871, rsl7781459, rsl805100, rs2016224, rs2073721, rs2989946, rs3179969, rs3751501, rs4354185, rs4371530, rs4525972, rs4936280, rs640098, rs684923, rs6925087, rs7535528, rs7572996, rs7940667, rs8028880, rs8128, and rs958738. In a further aspect, the polymorphic sites may have the polymorphism pairs (rs684923AA and rs4354185AG), (rs684923AA and rs4354185GG), (rs684923AG and rs4354185AA), (rs684923GG and rs4354185AA), (rs684923AA and rs4354185AA), (rs684923AA and rsl042327AG), (rs684923AA and rsl042327GG), (rs684923AG and rsl042327AA), (rs684923GG and rsl042327AA), (rs684923AA and rsl042327AA), (rs684923AA and rs3751501AG), (rs684923AA and rs3751501GG), (rs684923AG and rs3751501AA), (rs684923GG and rs3751501AA), (rs684923AA and rs3751501AA), (rs684923GG and rs3751501AG), (rs684923AG and rs3751501AG), (rs3179969AA and rs640098 AG), (rs3179969AA and rs640098GG), (rs3179969AG and
rs640098AA), (rs3179969GG and rs640098AA), and (rs3179969AA and rs640098AA). In yet a further aspect, either member of a pair of polymorphic sites may be indicative of an improved response, including the polymorphism pairs: (rs684923AA or rs4354185AG), (rs684923AA or rs4354185GG), (rs684923AG or rs4354185AA), (rs684923GG or rs4354185AA), (rs684923AA or rs4354185AA), (rs684923AA or rsl042327AG),
(rs684923AA or rsl042327GG), (rs684923AG or rsl042327AA), (rs684923GG or rsl042327AA), (rs684923AA or rsl042327AA), (rs684923AA or rs3751501AG),
(rs684923AA or rs3751501GG), (rs684923AG or rs3751501AA), (rs684923GG or rs3751501AA), (rs684923AA or rs3751501AA), (rs684923GG or rs3751501AG),
(rs684923AG or rs3751501AG), (rs3179969AA or rs640098AG), (rs3179969AA or rs640098GG), (rs3179969AG or rs640098AA), (rs3179969GG or rs640098AA), and
(rs3179969AA or rs640098AA).
In an aspect of the present invention, an improved response may be associated with a genotype of a pair of Group A SNPs of Table 1 (SEQ ID NOs: 1 to 293). In an aspect, the pair of SNPs may have the genotype rs684923AA and rs4354185AG, rs684923AA and rs4354185GG, rs684923AG and rs4354185AA, rs684923GG and rs4354185AA, or rs684923AA and rs4354185AA. In another aspect, an improved response may be associated with the genotype pair rs684923AA and rsl042327AG, rs684923AA and rsl042327GG, rs684923AG and rsl042327AA, rs684923GG and rsl042327AA, or rs684923AA and rsl042327AA. In a further aspect, an improved response may be associated with the genotype pair rs684923AA and rs3751501AG, rs684923AA and rs3751501GG, rs684923AG and rs3751501AA, rs684923GG and rs3751501 AA, rs684923AA and rs3751501 AA, rs684923GG and rs3751501AG, or rs684923AG and rs3751501AG. In an aspect, an improved response may be associated with the genotype pair rs3179969AG and rs640098AA, rs3179969GG and rs640098AA, or rs3179969AA and rs640098AA. A person of ordinary skill in the art would understand that the SNP genotypes in linkage disequilibrium with the paired genotypes may be associated with an improved response.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 1000418 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 1000418 and having a genotype AA GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of a Group B SNP selected from the group consisting of rs923880(CC TT), rsl2760034(CC TT), rsl532306(AA CC), rsl532307(CC TT),
rs4268325(AA GG), rsl565785(AA GG), rsl565786(GG TT), rsl0429856(AA GG), rsl0914739(CC TT), rsl6835557(AA GG), rsl2729472(AA GG), rsl6835560(GG TT), rsl2741094(CC GG), rs6674055(CC TT), rsl000417(AA GG), rs2078248(CC GG), rsl2136254(CC TT), rsl0914742(CC TT), rsl2132063(CC TT), rs6425825(CC TT), rs6425826(CC TT), rsl2751162(AA CC), rs3795415(AA GG), and rs28445343(AA GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs3795421(AA TT), rsl2564170(CC GG), rs36000249(CC TT),
rs35673825(CC GG), rsl2030298(AA TT), rs28419044(AA GG), rs34150871(GG TT), rsl2132091(AA GG), rsl2135471(AA GG), and rsl493993(CC GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consistingln another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs3795419(AA CC), rs4233205(AA CC), rsl2046307(AA GG),
rsl6835523(CC GG), rsl2047859(CC TT), rsl2044678(AA GG), rsl2049021(AA GG), rsl0914737(CC TT), rs3816922(CC TT), rs3889480(CC TT), rsl0914738(CC TT), rs4653183(AA GG), rsl2739764(AA TT), and rsl2045011(CC TT). In an aspect, a Group B SNP may be found within -51167 and 12518 base pairs of SNP rs 1000418 located at 34008297 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within -21448 and 7922 base pairs of SNP rs 1000418. In an aspect, a Group B SNP may be found within -20519 and 9887 base pairs of SNP rs 1000418. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs 1000418.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 10026134 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 10026134 and having a genotype AA GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of a Group B SNP selected from the group consisting of rs28660347(CC TT), rs7657271(AA CC), rsl0440463(AA GG), and rs9990923(CC TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs 10471064(AA TT), rs427292(AA TT), rs28538140(CC TT), and
rs3113618(CC TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl398927(AA GG), rs298474(AA GG), rs425465(AA GG), rs4863550(AA GG), rsl513771(GG TT), rs7678098(CC TT), rs6842871(AA CC), rs6537379(AA GG), and rsl3108768(CC TT). In an aspect, a Group B SNP may be found within -18736 and 18349 base pairs of SNP rsl0026134 located at 139286794 of the human genome assembly GRCh37.2 sequence on chromosome 4. In an aspect, a Group B SNP may be found within -19976 and 6777 base pairs of SNP rsl0026134. In an aspect, a Group B SNP may be found within -18519 and -2016 base pairs of SNP rsl0026134. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl0026134.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl0165340 in the NCBI db SNP Build 134 located at 173327168 of the human genome assembly GRCh37.2 sequence on chromosome 2 and having a genotype CT.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl0230573 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 10230573 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl0226853(AA). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2030709(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl 107657(TT), rsl 107660(TT), and rs940541(AA). In an aspect, a Group B SNP may be found within 8949 and 9525 base pairs of SNP rsl0230573 located at 80141069 of the human genome assembly GRCh37.2 sequence on chromosome 7. In an aspect, a Group B SNP may be found within -195 base pairs of SNP rsl0230573. In an aspect, a Group B SNP may be found within -667 base pairs of SNP rsl 0230573. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 0230573.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 10275461 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 0275461 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs7790016(GG), rsl0260289(CC), rs6949580(TT), rs7797863(TT), rs 10951851(CC), rsl0275394(CC), rs58195829(AA), rsl0244546(TT), rsl580275(GG), rsl0261062(TT), rsl0231479(GG), and rsl0236600(GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl0480191(GG), rs7779303(GG), rsl 0244821(GG), rs62452697(GG), rs62452698(TT), and rs62452702(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs7794677(TT), rs7789988(CC), rsl0241906(TT),
rs4577872(TT), rs7802702(TT), rs6954936(CC), rsl551837(AA), rsl0280191(CC), rsl 157868(GG), and rs6959948(AA). In an aspect, a Group B SNP may be found within - 48130 and 868 base pairs of SNP rsl0275461 located at 46450230 of the human genome assembly GRCh37.2 sequence on chromosome 7. In an aspect, a Group B SNP may be found within -9556 and 62575 base pairs of SNP rsl0275461. In an aspect, a Group B SNP may be found within -12209 and 75382 base pairs of SNP rsl0275461. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 0275461.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 042277 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 042277 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl0215885(AA). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl2700186(CC), rs35527387(CC), and rs6968952(CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl0486391(GG), rsl7455533(CC), rsl 1765098(CC), rs3757727(CC), rs34134267(AA), rs2040732(TT), and rs3823974(CC). In an aspect, a Group B SNP may be found within -42908 and 23870 base pairs of SNP rs 1042277 located at 20418926 of the human genome assembly GRCh37.2 sequence on chromosome 7. In an aspect, a Group B SNP may be found within -2215 and 2564 base pairs of SNP rsl 042277. In an aspect, a Group B SNP may be found within 1244 base pairs of SNP rsl 042277. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl042277. In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 1042327 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 1042327 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs9460025(TT), rs9356597(GG), rsl474555(AA),
rs9366156(TT), rs6932721(CC), rs742348(GG), rs7742080(AA), rs2056970(CC), rs9356598(CC), rs2223473(AA), rs760909(AA), rs2076319(CC), rs9356663(TT), rs7758044(AA), rs7771229(AA), rs7760641(TT), rs6911104(GG), rs6940817(CC), rs6928833(TT), rs9348343(AA), rs3823298(GG), rs2076318(CC), rs2072916(TT), rs6937840(AA), rs8770(TT), rs960744(AA), rs2072917(AA), rs9295417(CC),
rs4140615(TT), rs4507568(TT), and rs2021899(GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs9366244(TT), rs2092027(AA), rs2092026(TT), rsl474554(GG), rs6919159(CC), rs9348344(AA), and rs4710734(CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2294183(CC), rs9295414(CC), rs6939854(GG),
rs9356658(CC), rs9356659(AA), rs9348277(TT), rs9460029(GG), rs9295416(CC), rs3823299(CC), rs9348278(AA), rs6456228(GG), rsl2207807(CC), rs756518(TT), rs6932750(TT), rs4579340(GG), rs6914744(AA), rs3778589(AA), rs3800236(AA), rsl2194821(AA), rs6456230(CC), rs7765023(AA), rs7745933(AA), and rs7775031(GG). In an aspect, a Group B SNP may be found within -70987 and 28941 base pairs of SNP rsl042327 located at 170878793 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within -49913 and 27622 base pairs of SNP rs 1042327. In an aspect, a Group B SNP may be found within -62075 and 27184 base pairs of SNP rs 1042327. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl042327.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl0486391 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 10486391 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs73086541(AA), rsl2700186(CC), and rs2040732(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl7455533(CC), rsl7364847(TT), rsl 7364861(AA), rs3757727(CC), rsl2700188(GG), rs35527387(CC), rsl0215885(AA), rs6968952(CC), rs3807947(GG), rs4473914(CC), and rsl0486393(CC). In an aspect, a Group B SNP may be found within 895 and 50279 base pairs of SNP rsl0486391 located at 20376018 of the human genome assembly GRCh37.2 sequence on chromosome 7. In an aspect, a Group B SNP may be found within 85 and 42116 base pairs of SNP rs 10486391. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 0486391.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl0500982 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 0500982 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl2281776(CT), rsl 1027978(CT), rsl 1027979(AC), rsl0767204(AG), rsl 1027980(AG), rsl2285639(CT), and rsl0834365(AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl0500981(CT), rsl2291835(AC), and rsl0767205(AC). In an aspect, a Group B SNP may be found within -5570 and 4395 base pairs of SNP rsl0500982 located at 24549045 of the human genome assembly GRCh37.2 sequence on chromosome 11. In an aspect, a Group B SNP may be found within 1531 and 3991 base pairs of SNP rs 10500982. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl0500982.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 0518784 in the NCBI db SNP Build 134 and having a genotype GT TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 0518784 and having a genotype GT TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl2913761(AA AC), rs2254624(AC CC),
rsl2914800(AG GG), rsl2905980(AA AG), rsl2905710(AG GG), rsl2910824(AA AG), rsl l639299(AG GG), rsl7237934(CG GG), rsl0518782(CC CT), rsl7237948(AG GG), rs35786535(AG GG), rsl0518783(CG GG), rsl7818801(GT TT), rsl875405(AA AG), rsl875404(CG GG), and rsl875403(CC CT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs34523293(CC CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs4774708(CG GG) and rsl501378(AT TT). In an aspect, a Group B SNP may be found within 9528 and 11964 base pairs of SNP rsl0518784 located at 55121519 of the human genome assembly GRCh37.2 sequence on chromosome 15. In an aspect, a Group B SNP may be found within -3382 base pairs of SNP rsl0518784. In an aspect, a Group B SNP may be found within -6818 and 472 base pairs of SNP rs 10518784. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs 10518784.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl0788160 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 10788160 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs4465316(AA), rsl2413648(AA), and rsl0886892(TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl 1199868(AA), rsl 1199869(GG), rsl0886886(GG), rsl 1199872(AA), rsl2761612(AA), rsl 1199874(AA), rsl0886887(TT), rsl0886888(CC), rs4468286(AA), rsl0886890(GG), rs34368402(CC), rsl 0788163(GG), rsl0886893(CC), rsl 1199879(CC), rsl l l99881(CC), rsl2415826(CC), rsl0788166(GG), rsl0886894(CC), rsl0886895(AA), rsl0886896(AA), rsl0886900(GG), rsl0886903(GG), and rsl2413088(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl2146156(CC), rsl2146366(TT), rs7915008(AA), rsl2220990(AA), rs4393247(AA), rs34634164(TT), rsl0886885(TT), rsl 1199871(AA), rs35634388(CC), rsl0886897(CC), rsl0886898(GG), rsl0886899(TT), rsl 0886901(CC), and rsl0886902(CC). In an aspect, a Group B SNP may be found within -9133 and 15715 base pairs of SNP rsl 0788160 located at 123033549 of the human genome assembly GRCh37.2 sequence on chromosome 10. In an aspect, a Group B SNP may be found within -5210 and 19179 base pairs of SNP rs 10788160. In an aspect, a Group B SNP may be found within 632 and 8078 base pairs of SNP rsl0788160. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl0788160.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl0812532 in the NCBI db SNP Build 134 and having a genotype GG GT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl0812532 and having a genotype GG GT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl0967766(AC CC), rs77951967(GT TT),
rs78110518(AG GG), rs79707567(CT TT), and rs80319101(CC CG). In an aspect, a Group B SNP may be found within range 1862 and 10766 base pairs of SNP rsl0812532 located at 27197282 of the human genome assembly GRCh37.2 sequence on chromosome 9. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl0812532.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 10817866 in the NCBI db SNP Build 134 and having a genotype CT TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 10817866 and having a genotype CT TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 0.9, including a Group B SNP selected from the group consisting of rsl411820(CC CT) and rs7851174(AG GG). In an aspect, a Group B SNP may be found within -169 and 3242 base pairs of SNP rs 10817866 located at 119027076 of the human genome assembly GRCh37.2 sequence on chromosome 9. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl0817866.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 10822315 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 10822315 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1, including a Group B SNP selected from the group consisting of rsl0822313(CC), rs2394097(CC), rsl 0822316(TT), and rs56023698(CC). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs3847332(TT), rsl 1817009(GG), rs2893962(GG), rs3999058(CC), rs2394090(GG), rsl0995915(TT), rsl0159914(AA), rs7922640(AA), and rsl0822314(CC). In an aspect, a Group B SNP may be found within -16539 and 3709 base pairs of SNP rsl0822315 located at 66333087 of the human genome assembly GRCh37.2 sequence on chromosome 10. In an aspect, a Group B SNP may be found within -13734 and -763 base pairs of SNP rs 10822315. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs 10822315.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl0849300 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 10849300 and having a genotype AA GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs4140862(AA CC), rs7133972(AA GG), rs728342(GG TT), and rs7969805(CC TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs3782588(AA CC), rs6489644(AA GG),
rs7486468(CC TT), rsl558777(CC TT), rsl0849302(AA GG), rsl0849303(CC TT), rs3782599(AA TT), rs2110167(AA GG), and rsl0774349(AA GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs7954629(CC TT), rsl074027(CC TT), rs2192190(GG TT), rs4930771(CC TT), rs7969693(AA CC), rsl0774350(CC TT), rs7972926(CC TT), rs4930772(AA GG), rs4930773(GG TT), and rs2361577(CC TT). In an aspect, a Group B SNP may be found within 14055 and 42894 base pairs of SNP rsl0849300 located at 5704168 of the human genome assembly GRCh37.2 sequence on chromosome 12. In an aspect, a Group B SNP may be found within -6611 and 32484 base pairs of SNP rs 10849300. In an aspect, a Group B SNP may be found within 716 and 8373 base pairs of SNP rs 10849300. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl0849300.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 10869665 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 10869665 and having a genotype CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl006280(CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl 1144675(CT), rs28712739(AG), rsl 3299419(AG), and rsl3297823(AG). In an aspect, a Group B SNP may be found within 377 and 9840 base pairs of SNP rsl0869665 located at 78518999 of the human genome assembly GRCh37.2 sequence on chromosome 9. In an aspect, a Group B SNP may be found within 10572 base pairs of SNP rsl0869665. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl0869665.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl0884100 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 0884100 and having a genotype CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 0.9, including a Group B SNP selected from the group consisting of rsl 0884091(CG), rsl 823713(CT), rsl0884096(AG), rsl 1192331(CT), rs7910908(CT), rsl332719(AG), rs4474369(AG), rsl418872(AG), rsl418871(CT), and rsl0884107(GT). In an aspect, a Group B SNP may be found within - 16468 and 12369 base pairs of SNP rsl0884100 located at 106891264 of the human genome assembly GRCh37.2 sequence on chromosome 10. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl0884100.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl0895944 in the NCBI db SNP Build 134 located at 106229906 of the human genome assembly GRCh37.2 sequence on chromosome 11 and having a genotype CT TT.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl0925783 in the NCBI db SNP Build 134 located at 239097333 of the human genome assembly GRCh37.2 sequence on chromosome 1 and having a genotype CC TT.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl0950521 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl0950521 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs4721334(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl7168132(AA) and rs2357958(AA). In an aspect, a Group B SNP may be found within 6096 and 7467 base pairs of SNP rs 10950521 located at 14429350 of the human genome assembly GRCh37.2 sequence on chromosome 7. In an aspect, a Group B SNP may be found within -2238 base pairs of SNP rsl0950521. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl0950521.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl0951131 in the NCBI db SNP Build 134 located at 3272526 of the human genome assembly GRCh37.2 sequence on chromosome 7 and having a genotype AA.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 10999122 in the NCBI db SNP Build 134 and having a genotype CT TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl0999122 and having a genotype CT TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs4746956(AA AG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs4746952(GG GT) and rs7901338(CC CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs7896632(CC CG), rsl0999124(CT TT), and rs7078541(AA AG). In an aspect, a Group B SNP may be found within -184 and 6354 base pairs of SNP rsl0999122 located at 71837875 of the human genome assembly GRCh37.2 sequence on chromosome 10. In an aspect, a Group B SNP may be found within 11406 and 12460 base pairs of SNP rsl0999122. In an aspect, a Group B SNP may be found within 12734 base pairs of SNP rs 10999122. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl0999122.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 1063674 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 1063674 and having a genotype AG. In another aspect, a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rs73039941(CT), rsl 1063669(GT), and rsl 1063673(CG). In an aspect, a Group B SNP may be found within -7809 and -1941 base pairs of SNP rsl 1063674 located at 5539134 of the human genome assembly GRCh37.2 sequence on chromosome 12. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 1063674.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 108255 in the NCBI db SNP Build 134 located at 77768463 of the human genome assembly GRCh37.2 sequence on chromosome 4 and having a genotype AA.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 1149155 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 1149155 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 1149156(AG), rsl 7072387(AC), and rsl 1617149(CT). In an aspect, a Group B SNP may be found within range 1688 and 13708 base pairs of SNP rsl 1149155 located at 80730953 of the human genome assembly GRCh37.2 sequence on chromosome 13. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl l l49155.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 1159859 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 1159859 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 1629164(GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs816069(CC), rs2778936(AA), rs7141608(TT), rs4904452(CC), rs7144432(GG), rs8017811(GG), rs4904454(TT), rsl344747(AA), rs7146241(TT), rs930181(TT), and rsl2436642(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs376698(GG), rs453112(AA), rsl627444(GG), rs845757(GG), rs845769(AA), rs2297129(GG), rs61542857(AA), rs7141363(AA), rs2274736(GG), rs28482235(TT), rsl0132554(CC), rs3783889(TT), rs2401751(AA), rs28711639(CC), rs8017689(TT), rs816072(TT), rsl864744(GG), rs28371093(AA), rsl0150594(AA), rs79681439(AA), rs816075(AA), rsl 152376(GG), rsl 152377(AA), rs2274735(GG), rs7142053(AA), rsl2050316(GG), rsl2437422(GG), rs2033418(CC), rsl0873392(TT), and rs3742681(CC). In an aspect, a Group B SNP may be found within -169661 and -6644 base pairs of SNP rsl 1159859 located at 89027891 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -60555 and -2515 base pairs of SNP rsl 1159859. In an aspect, a Group B SNP may be found within 3193 base pairs of SNP rsl 1159859. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 1159859.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 119642 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 119642 and having a genotype AA GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2919921 (AA TT), rs2583764(AA GG),
rs2465831(AA TT), and rs2953474(AA CC). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2717548(CC TT), rs2717543(CC TT), rs2717546(AA GG), rsl6906083(AA GG), rs2583762(AA TT), rs2717537(CC TT), and rsl 2677655 (AA GG). In an aspect, a Group B SNP may be found within -2147 and 5904 base pairs of SNP rsl 119642 located at 79664483 of the human genome assembly GRCh37.2 sequence on chromosome 8. In an aspect, a Group B SNP may be found within 6584 and 47843 base pairs of SNP rsl 119642. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 119642.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 1250131 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 1250131 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl435282(AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2250028(GT), rsl 1250130(AG), rs2249804(CG), and rs2736311(CT). In an aspect, a Group B SNP may be found within - 37586 and 995 base pairs of SNP rsl 1250131 located at 11251175 of the human genome assembly GRCh37.2 sequence on chromosome 8. In an aspect, a Group B SNP may be found within 530 base pairs of SNP rsl 1250131. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 1250131.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 1585501 in the NCBI db SNP Build 134 and having a genotype AC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 1585501 and having a genotype AC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs60659800(CT), rsl0925477(CT), and rsl 16234420(CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl 6832058(AG), rs41315858(AG), and rsl 11695681(GT). In an aspect, a Group B SNP may be found within -20550 and -18044 base pairs of SNP rsl 1585501 located at 237797452 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within -21767 and -923 base pairs of SNP rsl 1585501. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 1585501.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 16187 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 16187 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 1653643 (AA), rsl 1651708(AA), rs9908953(GG), rs8080727(CC), rsl980119(TT), rs9909097(TT), rs6504441(TT), and rs9303509(AA). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl005651(CC), rs990083(CC), rs990084(GG), rs228889(CC), rs228883(TT), rsl79275(CC), rs2109648(GG), rs2109649(TT), rs4791058(TT), rs228875(AA), rs2244497(CC), rs228876(CC), rs9896894(TT), and rs7225054(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs990082(AA), rsl72939(TT), rs59816(GG), rs8069465(AA), and rs9908167(AA). In an aspect, a Group B SNP may be found within -57730 and 35320 base pairs of SNP rsl 16187 located at 64497737 of the human genome assembly GRCh37.2 sequence on chromosome 17. In an aspect, a Group B SNP may be found within -59726 and 30144 base pairs of SNP rsl 16187. In an aspect, a Group B SNP may be found within 17994 and 33150 base pairs of SNP rs 116187. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 16187.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 1645653 in the NCBI db SNP Build 134 located at 31312855 of the human genome assembly GRCh37.2 sequence on chromosome 16 and having a genotype CC TT.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 164857 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 164857 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 164856(AA), rsl 164858(TT), rs2694419(TT), and rs2559643(AA). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2694418(TT). In an aspect, a Group B SNP may be found within -316 and 2217 base pairs of SNP rsl 164857 located at 105035739 of the human genome assembly GRCh37.2 sequence on chromosome 12. In an aspect, a Group B SNP may be found within 2931 base pairs of SNP rsl 164857. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 164857.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 1786372 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 1786372 and having a genotype CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs7464407(AT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs5025124(AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs4909605(CG), rs4909616(AG), rs4909617(GT), and rs4289761(AG). In an aspect, a
Group B SNP may be found within 5998 and 13770 base pairs of SNP rsl 1786372 located at 135492163 of the human genome assembly GRCh37.2 sequence on chromosome 8. In an aspect, a Group B SNP may be found within 2080 base pairs of SNP rsl 1786372. In an aspect, a Group B SNP may be found within -5155 base pairs of SNP rsl 1786372. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 1786372.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 1894266 in the NCBI db SNP Build 134 and having a genotype CT TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 1894266 and having a genotype CT TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl3010581(CC CG). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs4668163(CT TT) and rsl427387(AG GG). In an aspect, a Group B SNP may be found within -3150 base pairs of SNP rs 11894266 located at 170636642 of the human genome assembly GRCh37.2 sequence on chromosome 2. In an aspect, a Group B SNP may be found within 2428 and 3005 base pairs of SNP rsl 1894266. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 1894266.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 1984724 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 1984724 and having a genotype CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1, including a Group B SNP selected from the group consisting of rsl2675523(AG), rs7817251(CT), rs61239354(CT), rs55810383(AG), rs56077880(CT), rs59592387(AG), rsl0505202(AG), rsl 1995255(AG), rs72687658(AG), rs72687660(CT), rs72687663(AG), rsl6884440(AG), rsl6884442(CG), rs 10094251(CT), rs60488095(GT), rs60083181(AG), rs72687677(AG), rs72687683(AG), rs7012235(CT), rsl 1997737(CT), rs56191500(AG), rsl2678760(AT), rs72670712(CT), rs72670715(CT), rs72670719(CT), rsl0104117(CT), rs72670733(CT), rs7823590(CT), rs6993801(AC), rs72670739(AG), rs72670741(CT), rsl6884503(CT), rs72670750(AG), rsl6884505(CT), rs7460075(AG), rs72670754(AC), rs72670756(AG), rs59549863(CT), rsl2674571(CT), and rs72670769(CT). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl6884282(CT), rsl6884331(CT), rs3967800(CT), rs28470386(AG), rs4551388(AT), rsl2680523(CT), rsl0088226(CG), and rsl 1996690(AC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs28481615(CG), rsl0505197(CT), rs72682194(AG), rsl0093481(CT), rsl2678623(AT), rs28662129(AC), rsl2675765(CG), rs60838519(AG), rs59097425 (AG), rsl6884294(AT), rsl6884296(CT), rs59936026(CT), rsl6884324(AG), rs72685838(GT), rs28721970(AG), rs2204094(CT), rsl6884347(CT), rs72685859(CT), rs28694438(CT), rs28591225(AC), rs28696836(CT), rs28838615(CT), rsl0955648(CT), rs6985122(AT), rsl 7679991 (AT), rsl6884363(AC), rsl2681814(AG), rsl568552(CT), rsl522062(GT), rsl879739(AC), rsl879740(CT), rsl7606762(CT), rs6995851(CT), rs60648602(AG), rsl480445(AG), rsl480461(CT), rs56795694(CT), rsl2682363(AC), rs72670745(AG), rs72670752(CG), rs72670765(CT), rs72670767(AT), rs72670772(GT), rs 16884531(CT), rs4876512(CT), rsl6884568(CG), and rsl0505203(AG). In an aspect, a Group B SNP may be found within - 282098 and 135581 base pairs of SNP rsl 1984724 located at 114254109 of the human genome assembly GRCh37.2 sequence on chromosome 8. In an aspect, a Group B SNP may be found within -229033 and -63719 base pairs of SNP rsl 1984724. In an aspect, a Group B SNP may be found within -54310 and 96287 base pairs of SNP rsl 1984724. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 1984724.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 2025108 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 2025108 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs7535223(AG) and rsl2119492(AG). In an aspect, a Group B SNP may be found within range -11412 and -322 base pairs of SNP rsl 2025108 located at 210620492 of the human genome assembly GRCh37.2 sequence on chromosome 1. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs 12025108.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl2159200 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 12159200 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs4140512(AA), rs5995886(GG), rs6001990(AA),
rsl2627881(CC), rs7292804(GG), rs7293100(GG), rs7284768(TT), rsl2158399(GG), rs55775429(AA), rs55746155(AA), rs56203629(AA), rsl7002067(GG), rs733999(GG), rsl7002069(CC), rs6002000(GG), rs5995890(CC), rs73171013(GG), and rs8142396(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs73171007(AA), rs8141330(AA), rs56169543(GG), rs7284506(CC), and rs73171017(TT). In an aspect, a Group B SNP may be found within 7010 and 18762 base pairs of SNP rsl2159200 located at 41042091 of the human genome assembly GRCh37.2 sequence on chromosome 22. In an aspect, a Group B SNP may be found within -9228 and 10665 base pairs of SNP rs 12159200. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl2159200.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 12193402 in the NCBI db SNP Build 134 and having a genotype AA CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 12193402 and having a genotype AA CC. In another aspect, a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rsl2207474(AA GG). In an aspect, a Group B SNP may be found within 12137 base pairs of SNP rsl2193402 located at 52285832 of the human genome assembly GRCh37.2 sequence on chromosome 6. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl2193402.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 12317794 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl2317794 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl522129(AA). In an aspect, the Group B SNP may further include a Group B SNP. In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs67858040(TT) and rs4883508(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs66590102(CC), rs67176762(GG), rsl522130(CC), rsl2423283(TT), rsl 581403 (AA), rs66654091(AA), rsl 13065316(GG), and rsl608079(GG). In an aspect, a Group B SNP may be found within -24752 and 17113 base pairs of SNP rsl2317794 located at 74612263 of the human genome assembly GRCh37.2 sequence on chromosome 12. In an aspect, a Group B SNP may be found within 8528 and 9424 base pairs of SNP rsl2317794. In an aspect, a Group B SNP may be found within 10357 base pairs of SNP rsl 2317794. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 2317794.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl2327456 in the NCBI db SNP Build 134 and having a genotype AT TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl2327456 and having a genotype AT TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl2326639(CC CG), rsl2326978(CT TT), and rs75629917(GG GT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs66972705(AT TT). In an aspect, a Group B SNP may be found within -9257 base pairs of SNP rsl2327456 located at 1485613 of the human genome assembly GRCh37.2 sequence on chromosome 18. In an aspect, a Group B SNP may be found within 43 and 7346 base pairs of SNP rsl2327456. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl2327456.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl2335840 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 2335840 and having a genotype CC. In another aspect, a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rs7042625(CC), rs7037462(CC), and rs4838084(GG). In an aspect, a Group B SNP may be found within -5236 and 1864 base pairs of SNP rsl2335840 located at 126713411 of the human genome assembly GRCh37.2 sequence on chromosome 9. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl2335840.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 12380611 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 12380611 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl2555472(CC) and rsl2376586(AA). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl0868395(GG), rsl0868396(GG), and rs4484763(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8 selected from the group consisting of rsl0868350(AA). In an aspect, a Group B SNP may be found within -50063 base pairs of SNP rsl2380611 located at 72648665 of the human genome assembly GRCh37.2 sequence on chromosome 9. In an aspect, a Group B SNP may be found within -13405 and -9547 base pairs of SNP rs 12380611. In an aspect, a Group B SNP may be found within -5228 and -83 base pairs of SNP rs 12380611. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs 12380611.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 12423283 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl2423283 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1, including a Group B SNP selected from the group consisting of rs66590102(CC), rs67176762(GG), rsl522130(CC), rsl581403(AA), rs66654091(AA), and rsl 13065316(GG). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl608079(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of
rs79101905(CC), rsl522129(AA), and rs78006002(CC). In an aspect, a Group B SNP may be found within 23065 and 36959 base pairs of SNP rsl2423283 located at 74592708 of the human genome assembly GRCh37.2 sequence on chromosome 12. In an aspect, a Group B SNP may be found within 36668 base pairs of SNP rsl2423283. In an aspect, a Group B SNP may be found within -5197 and 20596 base pairs of SNP rsl2423283. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs 12423283.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl2436579 in the NCBI db SNP Build 134 and having a genotype AC CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl2436579 and having a genotype AC CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs 1254251(CC CT), rs932606(CT TT), rsl254252(GG GT), rsl254253(AA AG), rsl266416(CT TT), rs941716(AA AG), rsl033732(AA AG), rsl254257(CC CT), rsl254258(AA AG), rsl254259(CT TT), rsl254260(AA AG), rsl254262(CT TT), rsl254263(CC CT), rsl254264(AT TT), rsl254268(AG GG), rsl254271(CT TT), rsl254272(AA AG), rsl254274(AA AT), rsl254275(AC CC), rsl956874(AA AC), rsl313240(CC CT), rsl268616(AT TT), rsl254282(AG GG), rsl254283(AG GG), rsl254284(AG GG), rsl254285(CT TT), rs74448620(CT TT), rsl254290(AG GG), rsl254293(GT TT), rsl269982(GG GT), rsl262173(CC CT), rsl313244(CC CG), rsl314387(CC CT), rsl314343(GG GT), rsl313684(AA AC), rsl314620(AA AT), rsl313245(AA AT), rsl254299(AA AG), rsl254300(CC CG), rsl254301(CC CT), rsl254304(AA AC), rsl254305(AA AG), rsl254313(AA AT), rsl254314(CC CG), rsl254315(AA AG), rsl268618(AC CC), rsl268619(AA AG), rsl270509(AT TT), rsl254316(CT TT), rsl269027(AA AT), rsl254330(CC CT), and rsl 2878738(CC CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl 254261(GG GT), rsl254266(CT TT), rsl254269(AA AG), rsl313238(CT TT), rsl313239(AG GG), rs986418(CT TT), rsl271527(AA AG), rsl262172(GG GT), rsl254288(CC CG), rsl254297(CG GG), rsl254306(CT TT), rsl254319(AA AG), rsl254331(AG GG), rsl254333(AG GG), rsl254337(AT TT), rsl268620(CC CT), rs7155442(CT TT), rs7155448(CT TT), rsl0138913(CT TT), rsl2434902(GT TT), rsl 1158285(AG GG), rsl0133771(AG GG), rs8015263(CC CT), rsl018532(GT TT), rsl018533(CT TT), rs61991551(AG GG), and rs28543014(CC CT). In an aspect, a Group B SNP may be found within -145571 and 1917 base pairs of SNP rsl2436579 located at 60983087 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -164237 and -47806 base pairs of SNP rsl2436579. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl2436579.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl2436642 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 2436642 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs816069(CC), rs2778936(AA), rs7141608(TT),
rs4904452(CC), rs7144432(GG), rsl2437422(AA), rs8017811(GG), rs4904454(TT), rs2033418(CC), rsl0873392(CC), rsl344747(AA), rs7146241(TT) and rs930181(TT). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs376698(AA),
rs453112(AA), rsl627444(CC), rs845757(GG), rs2297129(GG), rs61542857(GG), rs7141363(TT), rs2274736(GG), rs28482235(AA), rsl0132554(TT), rs3783889(AA), rs2401751(AA), rs28711639(GG), rs8017689(CC), rs816072(TT), rsl864744(GG), rs28371093(CC), rsl0150594(GG), rs79681439(TT), rs816075(AA), rsl 152376(GG), rsl 152377(GG), rs2274735(GG), and rs7142053(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl2586714(CC), rsl028455(AA), rs865285(AA), rsl099698(CC), rs845758(CC), rs845769(AA),
rs7161660(CC), rsl288122(CC), rs879932(CC), rs7160717(CC), rsl 1845147(AA), rs7160471(TT), rs9323830(AA), rs7160647(TT), rs7143642(GG), rsl0143744(CC), rsl999177(GG), rsl999176(CC), rsl864746(GG), rsl864747(GG), rs7151164(TT), rsl2433026(TT), rsl0138139(GG), rsl0138002(TT), rsl0150311(CC), rsl0138309(TT), rsl 1847417(TT), rs3783885(TT), rsl 1159857(TT), rs4390529(CC), rs4301952(AA), rs4516145(TT), rs4594187(GG), rs4514599(GG), rs61975276(GG), rs61975277(CC), rs61975278(TT), rs61984675(AA), rs73317739(TT), rs28666030(GG), rs28493481(TT), rsl0150986(AA), rsl2050316(GG), rs4899955(CC), rs3742681(TT), and rsl 1629164(GG). In an aspect, a Group B SNP may be found within -198535 and 5708 base pairs of SNP rsl2436642 located at 89025376 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -167146 and -47438 base pairs of SNP rsl2436642. In an aspect, a Group B SNP may be found within -58040 and -6668 base pairs of SNP rsl2436642. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl2436642.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl2436982 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl2436982 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2274737(CC), rs2297128(CC), rs74074098(GG),
rsl2587528(GG), rsl864748(CC), rs59136503(AA), rsl998670(TT), rsl816372(GG), rs60878614(GG), rsl0143767(CC), rs76559451(CC), rsl 123421(GG), rs2004329(CC), rsl2436326(TT), rsl7203789(TT), rsl7798341(CC), rsl0134008(TT), rs891750(AA), rs891749(TT), rs61984683(CC), rs61984684(CC), rs61984708(CC), rs4635267(TT), rs56144430(AA), rsl7188046(TT), rs61984736(CC), rs8006652(TT), rsl2587200(GG), rsl2431548(TT), rs61984737(AA), rsl2586348(GG), rsl2434935(TT), rs61984746(TT), rsl 7260380(TT), rs58984912(AA), rsl7188207(GG), rs61986664(AA), rs61986665(CC), rs8018755(TT), rs8020072(CC), rsl7260408(GG), rsl2589982(GG), rs8021690(CC), rs61986669(AA), rsl2587598(CC), rs61986670(AA), rs61986671(GG), rsl7188228(CC), rs78077739(TT), rs 17260415 (GG), rs58655091(AA), rsl956406(CC), rs61983300(GG), rs78068036(CC), rsl 1159868(CC), rs61983303(CC), rs7157149(CC), rs2224333(TT), rsl2590826(GG), rs57889459(TT), rsl950806(TT), rs58550317(CC), rs61982733(TT), rs2145120(AA), and rsl2588535(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs79579293(GG), rs60310240(CC), rsl7772064(TT), rsl 7698817(CC), rsl2589467(CC), rsl2433464(GG), rs56987357(AA), rsl955599(TT), rsl955600(AA), rsl7772222(GG), rs7145588(AA), rs61977049(CC), rsl7772288(AA), rsl2587386(TT), rs61579615 (TT), rs60213984(AA), rs55722539(AA), rsl2589480(TT), rs61977058(CC), rs74071851(AA), rsl 1159856(GG), rsl7124652(GG), rs2295135(GG), rs61975260(CC), rsl7124700(TT), rs3814855(AA), rs77306894(GG), rs2274735(GG), rs7143853(GG), and rs57118463(CC). In an aspect, a Group B SNP may be found within -334138 and -24040 base pairs of SNP rsl2436982 located at 89156206 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -220555 and 92038 base pairs of SNP rs 12436982. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl2436982.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 12494795 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 12494795 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs72957734(AA), rs9869288(CC), rs59303243(GG), rs7650247(GG), rs9880684(CC), rs7610140(TT), rs7642705(CC), rs7642875(GG), rsl2486378(CC), rs7645780(GG), rs4330250(AA), rs73860537(GG), rs73860538(GG), rs57132467(CC), rs7636036(TT), rs72957757(AA), and rs72957759(GG). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs72957724(GG), rs60778976(TT), rs56767235(TT), rs4322999(TT), rs4373060(GG), rs4323000(TT), rs4318550(GG), rs4306851(CC), rs4306852(CC), rs4306853(CC), rsl6824357(GG), rs58048881(AA), rs57956951(CC), rs72957732(CC), rs4286427(AA), rs73860535(TT), rs7650067(GG), rsl2496680(CC), rsl2486101(CC), rs58845567(TT), rs61025769(GG), rs72957787(CC), and rs72957789(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs72957737(TT), rs7642612(GG), rsl2491832(TT), and rsl2491850(TT). In an aspect, a Group B SNP may be found within -762 and 9584 base pairs of SNP rsl2494795 located at 115687191 of the human genome assembly GRCh37.2 sequence on chromosome 3. In an aspect, a Group B SNP may be found within -2621 and 25021 base pairs of SNP rsl2494795. In an aspect, a Group B SNP may be found within - 800 and 10454 base pairs of SNP rs 12494795. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs 12494795.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl2513381 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl2513381 and having a genotype AA GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs3942964(CC TT), rs28409428(AA CC),
rsl497582(AA CC), rsl3128386(CC TT), rsl497593(CC TT), rs966882(CC GG), rs966884(AA CC), rsl l721528(AA CC), rs4348164(GG TT), rsl497596(GG TT), rs2173248(CC TT), rsl 1723923(AA GG), rs62307920(AA GG), rsl2503822(CC TT), rs2892641(AA TT), rs2388930(AA GG), and rsl 1732931(CC TT). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs6533753(AA GG), rs4834386(CC TT), rs4834387(CC TT), rsl 112496(AA GG), rsl0213347(CC TT), rsl2640805(CC TT), rsl0212727(AA GG), rs6841434(AA TT), rsl497597(AA GG), rsl603618(AA CC), rsl497595(CC TT), rs7672830(CC TT), rs2646653(CC TT), rs2646648(AA GG), rs4470706(CC TT), and rs4834391(CC TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs9993129(AA TT), rsl553063(AA CC), rs7673831(AA GG), rs7673694(CC TT), rs2036169(AA GG), rs2088414(AA GG), rs6533758(AA GG), rs9994892(CC TT), rsl0009761(AA TT), rs6818721(AA TT), rs6845056(GG TT), rsl0022474(CC TT), rs7673242(AA TT), rs4349665(AA GG), rsl603616(CC GG), rs7674230(CC GG), rs2388929(CC GG), rsl874672(AA GG), rsl497598(AA GG), rs7695066(GG TT), rs9683872(CC TT), rs9684478(AA GG), rs9884892(CC GG), rs9884464(AA GG), rs4437316(CC TT), rs4580712(CC TT), rs4410592(AA GG), rs6841300(CC TT), rs6841659(AA GG), rs6842032(AA GG), rs6842267(CC GG), rs6819384(CC TT), rs6842520(AA GG), rs6533761(GG TT), rs6533762(AA GG), rs4629528(CC TT), rs4582213(AA CC), rs4479779(AA GG), rs4640730(AA TT), rs4639145(AA CC), rs7441127(GG TT), rsl2508411(AA TT), rs28725209(CC TT), rsl2500754(AA CC), rsl2508477(AA GG), rsl0010486(GG TT), rs9998567(CC GG), rs4599484(AA GG), rs77424274(CC TT), rs966883(AA GG), rsl3110749(GG TT), rsl3135715(AA GG), rs4346715(CC TT), rs4624721(AA GG), rs4482843(AA GG), rs4298197(GG TT), rs4348163(AA TT), rs4272076(AA GG), rsl497594(AA CC), rsl 1723788(CC TT), rs62307919(CC GG), rs2892640(AA TT), rsl0516600(CC GG), rsl497603(GG TT), rs7672794(CC TT), rs9790751(CC TT), rsl3435657(CC TT), rsl3435248(CC TT), rsl304237(CC TT), rs2646655(AA GG), rsl603620(CC TT), rs996110(AA GG), rsl391184(CC TT), rs2725523(GG TT),
rs35092285(AA TT), rs6850513(CC TT), rs6533768(AA GG), and rsl3114496(AA GG). In an aspect, a Group B SNP may be found within -120621 and 37400 base pairs of SNP rsl2513381 located at 115151872 of the human genome assembly GRCh37.2 sequence on chromosome 4. In an aspect, a Group B SNP may be found within -137317 and 38146 base pairs of SNP rs 12513381. In an aspect, a Group B SNP may be found within -42507 and - 623 base pairs of SNP rsl2513381. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl2513381.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 12529871 in the NCBI db SNP Build 134 and having a genotype GT TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 12529871 and having a genotype GT TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs35492019(CC CG), rsl2525361(CT TT),
rs35996655(CC CT), rs67342855(GT TT), rsl2525205(AG GG), rs 13198645(AA AG), rsl3213561(CC CT), rs36010622(AG GG), rsl2530237(CT TT), rs34293995(CG GG), rs34321270(AA AG), rsl3215226(CC CT), rsl3195457(CG GG), rs961195(CT TT), rsl2525267(CC CT), rs2374153(CC CT), rs66833492(AG GG), rsl2525830(CC CT), rs34405066(AA AT), rsl380044(GT TT), rsl3215686(AG GG), rs35860855(AA AG), rsl841111(AA AG), rs35305959(AA AG), rs67648433(AA AC), rs35743657(AG GG), rs72881927(CT TT), rsl 12900503(AA AG), rs35513490(GT TT), rsl3210548(AG GG), rs34400080(CT TT), rs35424932(AG GG), rs67270926(AA AG), rsl6817(CG GG), rsl2529645(AA AT), rsl2527907(CT TT), rs72881954(GT TT), rs6937147(AA AT), rs6913908(AA AG), rsl3209495(AA AG), rsl 14260632(CC CT), rsl2525614(CC CT), rsl2524923(AT TT), rsl2526156(AA AG), rsl037748(AT TT), rsl458789(GT TT), rsl458790(GG GT), rsl2525977(CC CT), rs55915836(CT TT), rs7769451(CT TT), rs58313219(CT TT), rsl3204347(CT TT), rs4498331(CC CT), rs4295458(AA AG), rsl3194331(AG GG), rsl3208589(AA AG), and rsl3208720(AA AG). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs67860814(AG GG), rs67041778(AA AG), rsl2525263(CT TT), rs34949735(AG GG), rs34355880(AG GG), rs35120521(AG GG), rs72881924(AA AG), rsl903059(CT TT), rsl 15475482(CT TT), rs35916131(CC CT), rsl2527279(CG GG), rs58368955(CT TT), and rs34630212(CT TT). In an aspect, a Group B SNP may be found within -18439 and 23482 base pairs of SNP rsl2529871 located at 67995171 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within -14071 and 23618 base pairs of SNP
rs 12529871. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs 12529871.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl2573176 in the NCBI db SNP Build 134 and having a genotype AC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 2573176 and having a genotype AC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl2571697(AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs77700257(AG) and
rsl2570093(AT). In an aspect, a Group B SNP may be found within -4867 and 2472 base pairs of SNP rsl2573176 located at 18996761 of the human genome assembly GRCh37.2 sequence on chromosome 10. In an aspect, a Group B SNP may be found within -1398 base pairs of SNP rsl 2573176. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl2573176.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl258236 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl258236 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl258327(AG), rsl268724(AC), rsl270561(CT), and rsl258248(CT). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl258325(CT) and rsl258328(AG). In an aspect, a Group B SNP may be found within -7194 and 19999 base pairs of SNP rsl258236 located at 50916484 of the human genome assembly GRCh37.2 sequence on chromosome 10. In an aspect, a Group B SNP may be found within -8039 and -7126 base pairs of SNP rsl258236. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl258236.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 12618741 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 12618741 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs 17048319(TT), rs56403060(CC) and rs35881743(TT). In an aspect, a Group B SNP may be found within range -5744 and 535 base pairs of SNP rsl2618741 located at 115118072 of the human genome assembly GRCh37.2 sequence on chromosome 2. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl2618741.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 1265140 in the NCBI db SNP Build 134 located at 103201058 of the human genome assembly GRCh37.2 sequence on chromosome 8 and having a genotype CG.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 1266382 in the NCBI db SNP Build 134 located at 236682164 of the human genome assembly GRCh37.2 sequence on chromosome 1 and having a genotype CT.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 12680523 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl2680523 and having a genotype CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs28481615(CG), rsl0505197(CT), rs72682194(AG), rsl0093481(CT), rsl2678623(AT), rs28662129(AC), rsl2675765(CG), rsl6884282(CT), rs60838519(AG), rs59097425(AG), rsl6884294(AT), rsl6884296(CT), rs59936026(CT), rsl6884324(AG), rsl6884331(CT), rs3967800(CT), rs28470386(AG), rs72685838(GT), rs4551388(AT), rs28721970(AG), rs2204094(CT), rsl6884347(CT), rsl0088226(CG), rs72685859(CT), rs28694438(CT), rs28591225(AC), rs28696836(CT), rs28838615(CT), rsl0955648(CT), rs6985122(AT), rs 17679991 (AT), rsl6884363(AC), rsl2681814(AG), rsl568552(CT), rsl522062(GT), rsl879739(AC), rsl 879740(d), rsl7606762(CT), rs6995851(CT), rsl 1996690(AC), rs60648602(AG), rsl480445(AG), rsl 480461(CT), rs72670745(AG), rs72670752(CG), rs72670765(CT), and rs72670772(GT). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs7012235(CT), rsl 1997737(CT), and rs6993801(AC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs7833953(CT), rsl2675523(AG), rs7817251(CT),
rs61239354(CT), rs55810383(AG), rs56077880(CT), rs59592387(AG), rsl0505202(AG), rsl l995255(AG), rs72687658(AG), rs72687660(CT), rs72687663(AG), rsl6884440(AG), rs16884442(CG), rs 10094251(CT), rs60488095(GT), rs60083181(AG), rs72687677(AG), rs72687683(AG), rs56191500(AG), rsl2678760(AT), rs72670712(CT), rs72670715(CT), rs72670719(CT), rsl0104117(CT), rs72670733(CT), rs7823590(CT), rs72670739(AG), rs72670741(CT), rsl6884503(CT), rs72670750(AG), rsl6884505(CT), rs7460075(AG), rs72670754(AC), rs72670756(AG), rs59549863(CT), rsl2674571(CT), rs72670769(CT), and rsl0505203(AG). In an aspect, a Group B SNP may be found within -179063 and 250093 base pairs of SNP rsl2680523 located at 114139597 of the human genome assembly
GRCh37.2 sequence on chromosome 8. In an aspect, a Group B SNP may be found within 111164 and 156916 base pairs of SNP rsl2680523. In an aspect, a Group B SNP may be found within -167586 and 220793 base pairs of SNP rsl 2680523. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 2680523.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl2918570 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl2918570 and having a genotype CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs8050263(GT) and rsl2599738(AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs35699483(AG), rs2468496(CT), and rs55798918(AG). In an aspect, a Group B SNP may be found within -22379 and -8924 base pairs of SNP rsl2918570 located at 58268436 of the human genome assembly GRCh37.2 sequence on chromosome 16. In an aspect, a Group B SNP may be found within -18782 and -9414 base pairs of SNP rsl2918570. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl2918570.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 1294227 in the NCBI db SNP Build 134 and having a genotype CC TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl294227 and having a genotype CC TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl294230(CC TT), rsl294229(AA GG),
rsl294228(GG TT), rsl294226(CC TT), rsl294206(CC TT), rsl294205(GG TT), rsl294204(CC TT), rsl294200(GG TT), rsl294198(AA GG), and rsl294196(CC GG). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl294247(AA GG), rsl294241(AA GG), rsl294240(AA GG), rsl294238(AA GG), rsl294237(CC TT), rsl294236(CC TT), rsl294235(AA GG), rsl294233(CC TT), rsl294232(CC TT), rs78344883(GG TT), rsl294225(AA GG), rsl294224(AA GG), rsl294223(AA GG), rsl294219(GG TT), rsl294218(AA TT), rsl294217(AA GG), rsl294216(CC TT), rsl294215(AA GG), rsl294214(AA GG), rsl294213(CC TT), rsl294212(CC TT), rs67260725(AA CC), rsl294211(GG TT), rsl294210(AA GG), rsl294209(CC TT), rsl294203(CC TT), rsl294202(AA GG), rsl294197(AA GG), rsl294195(AA GG), rsl294193(AA GG), rsl772747(CC TT), rsl743264(AA GG), rsl294192(CC TT), and rsl294188(AA GG). In an aspect, a Group B SNP may be found within -1020 and 4593 base pairs of SNP rsl294227 located at 233520845 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within -8272 and 5866 base pairs of SNP rsl294227. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl294227.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl2951391 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl2951391 and having a genotype CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs67352698(AG), rs67710396(CT), rs34218923(AG), rs35073524(AG), rsl6976995(AT), rs2341313(CT), rsl 6977012(AG), rsl2941303(CT), and rs66487109(CG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2058010(AG), rsl6976977(AG), rs9901105(CT),
rsl990186(AG), rs62064241(CG), rs35138359(CT), rsl2944813(AT), rsl2948260(CG), rs35346619(CG), rs7223297(CT), rs7223670(CG), rs7224246(AT), rs7209111(CT), and rs7210343(AT). In an aspect, a Group B SNP may be found within -50206 and 48154 base pairs of SNP rsl2951391 located at 69911582 of the human genome assembly GRCh37.2 sequence on chromosome 17. In an aspect, a Group B SNP may be found within -1957 and 6876 base pairs of SNP rsl2951391. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl2951391.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl3153368 in the NCBI db SNP Build 134 and having a genotype CC TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 3153368 and having a genotype CC TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs780428(AA GG), rs2545858(AA GG), rsl947323(CC TT), rs6897417(AA TT), rsl0071133(AA GG), rsl3155352(AA GG), rs6897142(CC GG), rs2404820(AA CC), rsl3187783(AA GG), rsl972629(AA TT), rsl2153752(AA GG), rsl3152919(CC GG), rsl3153472(AA GG), rs9327113(AA GG), rs2404819(CC TT), and rsl0064579(CC GG). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs328650(AA TT), rs328649(CC TT), rsl62197(CC TT), rsl79274(CC TT), rs780425(AA TT), rs7443141(CC TT), rs2194055(CC TT), rsl0039600(CC GG), and rsl0079548(AA GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs329144(AA CC), rsl 1948290(AA GG), and rsl813407(AA GG). In an aspect, a Group B SNP may be found within -27737 and 20717 base pairs of SNP rsl3153368 located at 119017509 of the human genome assembly GRCh37.2 sequence on chromosome 5. In an aspect, a Group B SNP may be found within -36272 and 11784 base pairs of SNP rsl3153368. In an aspect, a Group B SNP may be found within -21353 and 11530 base pairs of SNP rsl3153368. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl3153368.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl3190448 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl3190448 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl0515016(TT), rsl7209998(CC), rs 12517623 (AA), rs34370411(CC), rsl3170214(CC), and rs4501302(AA). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs34382006(CC) and rs62362294(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl2517640(AA) and rs6896102(GG). In an aspect, a Group B SNP may be found within 5573 and 24406 base pairs of SNP rsl3190448 located at 65936799 of the human genome assembly GRCh37.2 sequence on chromosome 5. In an aspect, a Group B SNP may be found within -6046 and -2253 base pairs of SNP rsl3190448. In an aspect, a Group B SNP may be found within 3805 and 22252 base pairs of SNP rsl3190448. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl3190448.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 13247490 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 13247490 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl2701465(CG), rs4723467(AG), rs4720189(AG),
rs4723468(CT), rsl986699(AG), rs4720192(CT), rsl2701466(CT), rsl0259364(CT), rsl0243962(CT), rsl0273557(AG), rs7790354(AG), rs7791337(AG), rsl 0277914(AG), rsl3246529(CT), rsl3246736(AG), rsl3246545(CG), rsl2701467(AG), and
rsl 0271411(GT). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2718011(CT), rs78749960(CT), and rs7791437(AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2700943(AT), rs2710809(AG), and rs6462645(AC). In an aspect, a Group B SNP may be found within -23542 and 574 base pairs of SNP rsl3247490 located at 36115303 of the human genome assembly GRCh37.2 sequence on chromosome 7. In an aspect, a Group B SNP may be found within -17433 and -1144 base pairs of SNP rsl3247490. In an aspect, a Group B SNP may be found within -14117 and 309 base pairs of SNP rs 13247490. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl3247490.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl3250662 in the NCBI db SNP Build 134 and having a genotype CT TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 13250662 and having a genotype CT TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1, including a Group B SNP selected from the group consisting of rs35290218(AG GG). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs9657078(CC CT) and rs62510126(CC CT). In an aspect, a Group B SNP may be found within -4306 base pairs of SNP rs 13250662 located at 64072039 of the human genome assembly GRCh37.2 sequence on chromosome 8. In an aspect, a Group B SNP may be found within -13336 and 698 base pairs of SNP rs 13250662. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs 13250662.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl3273073 in the NCBI db SNP Build 134 and having a genotype GG TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 13273073 and having a genotype GG TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl3265208(AA CC), rsl3274775(AA CC), rsl3274892(CC GG), rs7002330(AA GG), rsl0101061(AA TT), rsl3257987(CC GG), rsl3261166(AA GG), rsl2716531(CC TT), rs7004766(CC TT), rs7004910(CC TT), rs7835797(AA GG), rsl550279(CC GG), rsl550280(CC TT), rs57220043(AA TT), and rs7830933(AA GG). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs6991688(GG TT), rs62500432(CC GG), rsl3251678(CC TT), rs6981261(CC TT), and rs7001541(AA TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl 3249197(GG TT), rs6983481(GG TT),
rsl 1986562(CC TT), rs9644033(AA TT), and rsl561105(GG TT). In an aspect, a Group B SNP may be found within -5822 and 26573 base pairs of SNP rsl3273073 located at
23584226 of the human genome assembly GRCh37.2 sequence on chromosome 8. In an aspect, a Group B SNP may be found within -1317 and 12168 base pairs of SNP rsl3273073. In an aspect, a Group B SNP may be found within -988 and 19098 base pairs of SNP rsl3273073. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl3273073.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl342836 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 342836 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2139982(AA), rs505489(CC), rs3766875(TT), rs627201(GG), rsl475678(GG), rsl2725455(CC), rs490057(AA), rs489969(AA), rs625006(GG), and rs2184014(AA). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs490987(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl0925487(CC). In an aspect, a Group B SNP may be found within 19122 base pairs of SNP rsl342836 located at 237805965 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within 6602 base pairs of SNP rsl342836. In an aspect, a Group B SNP may be found within -6491 and 8933 base pairs of SNP rsl342836. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl342836.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 344747 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 344747 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs816069(CC), rs2778936(AA), rs7141608(TT),
rs4904452(CC), rs7144432(GG), rsl2437422(GG), rs8017811(GG), rs4904454(TT), rs2033418(CC), rsl0873392(TT), rs7146241(TT), and rs930181(TT). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs376698(GG), rs4531 12(AA), rsl627444(GG), rs845757(GG), rs2297129(GG), rs61542857(AA), rs7141363(AA), rs2274736(GG), rs28482235(TT), rsl0132554(CC), rs3783889(TT), rs2401751(AA), rs28711639(CC), rs8017689(TT), rs816072(TT), rsl864744(GG), rs28371093(AA), rsl0150594(AA), rs79681439(AA), rs816075(AA), rsl 152376(GG), rsl 152377(AA), and rs7142053(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl2586714(CC), rsl028455(AA), rs865285(AA),
rsl099698(CC), rs845758(CC), rs845769(AA), rs7161660(GG), rsl288122(TT),
rs879932(TT), rs7160717(TT), rsl 1845147(AA), rs7160471(CC), rs9323830(AA), rs7160647(TT), rs7143642(GG), rsl0143744(CC), rsl999177(AA), rsl999176(AA), rsl864746(GG), rsl864747(GG), rs7151164(TT), rsl2433026(TT), rsl0138139(CC), rsl0138002(TT), rsl0150311(CC), rsl0138309(CC), rsl 1847417(TT), rs3783885(GG), rsl l l59857(TT), rs4390529(CC), rs4301952(AA), rs4516145(CC), rs4594187(CC), rs4514599(GG), rs61975276(AA), rs61975277(TT), rs61975278(CC), rs61984675(GG), rs73317739(CC), rs28666030(AA), rs28493481(GG), rsl0150986(GG), rsl2050316(GG), rs4899955(AA), rs3742681(CC), and rsl 1629164(GG). In an aspect, a Group B SNP may be found within -187594 and 16649 base pairs of SNP rsl344747 located at 89014435 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -156205 and -36497 base pairs of SNP rsl344747. In an aspect, a Group B SNP may be found within -47099 and 4273 base pairs of SNP rsl 344747. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl344747.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 348181 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 1348181 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs9395579(CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl2204300(CC). In an aspect, a Group B SNP may be found within 51945 base pairs of SNP rsl348181 located at 50239686 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within 6397 base pairs of SNP rs 1348181. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs 1348181.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl355597 in the NCBI db SNP Build 134 and having a genotype CC CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 1355597 and having a genotype CC CT. In another aspect, a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rs2426474(CT TT), rs2426476(AT TT), rs2426477(CG GG), rs726479(AA AC), rs2426481(CC CG), rs2250513(CG GG), and rs2250540(AC CC). In an aspect, a Group B SNP may be found within -12811 and 8923 base pairs of SNP rs 1355597 located at 51874769 of the human genome assembly GRCh37.2 sequence on chromosome 20. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl355597.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl363560 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl363560 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs7708354(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl874460(CC), rs3797719(GG), and rs4976539(GG). In an aspect, a Group B SNP may be found within -20117 and -8614 base pairs of SNP rsl363560 located at 167645888 of the human genome assembly GRCh37.2 sequence on chromosome 5. In an aspect, a Group B SNP may be found within -1595 base pairs of SNP rs 1363560. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl363560.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl373649 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 1373649 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs3796410(AG), rs 1373651 (AG), rs3775030(GT),
rs7655484(AG), rsl2505736(AT), rsl 15009478(AG), rs75136387(CG), rsl444928(CT), rs1444927(AG), rsl0516956(AG), rs7673752(AC), rs3796417(CT), rs3796418(GT), rs3796419(CT), rsl2513378(AG), rsl 1946254(CT), rs7699472(AG), rs7661049(AG), rs6823752(AG), rs7673943(GT), rsl3121253(GT), rsl444925(CG), rsl444924(CT), rs7658478(AG), rs3796422(CT), rs3796423 (AG), rs3796425(CT), rsl3118309(CT), rsl3149539(AG), rsl 1934132(d), rsl 1722010(CT), rsl3106009(AG), rsl373648(AC), rs7698033(AG), rsl2508693(AG), rsl2505093(GT), rsl2505819(AT), rsl2505823(CT), and rsl2509564(AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2120835(AG) and rs6815064(AG). In an aspect, a Group B SNP may be found within -28141 and 2387 base pairs of SNP rsl373649 located at
95892711 of the human genome assembly GRCh37.2 sequence on chromosome 4. In an aspect, a Group B SNP may be found within -29686 and 1864 base pairs of SNP rsl 373649. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 373649.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl37794 in the NCBI db SNP Build 134 and having a genotype AA AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 37794 and having a genotype AA AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs6006512(CT TT), rsl37732(AA AG), rsl37734(AA AG), rsl37736(CT TT), rsl37742(CT TT), rsl37743(CT TT), rsl37744(CG GG), rsl37746(CC CT), rsl37749(AG GG), rsl37751(CC CT), rs2157230(CT TT), rsl37757(CT TT), rsl37767(CT TT), rsl37790(AA AG), rsl37798(CT TT), rsl37801(AA AT), rsl37806(AA AC), rs4823131(GT TT), rs4823091(AA AG), rs2374775 (AA AT), rsl883362(AA AG), rsl013039(CC CT), rsl474622(AA AG), rs5764257(CG GG), rs5764258(AG GG), rs738412(AA AG), rs4823138(GT TT), rs4823094(AA AG), rs4823095(CC CT), rs2401410(CC CT), rs5764272(AG GG), rsl894629(CT TT), rs5764295(CC CT), rs6006544(CT TT), rs4823140(CC CT), rs5764301(CC CT), rs5764302(GG GT), rs5764305(GG GT), rs5764310(AC CC), rs5763996(AA AT), rs4823144(GT TT), and rs4823145(CC CT). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs78743998(CT TT), rs8139430(CT TT), rs6006511(AC CC), rsl37719(AG GG), rsl37765(GG GT), rsl37822(CT TT), rs5764253(CC CT),
rs6006443(AA AC), rs739234(AA AG), rs5764287(CC CG), rs5764290(CT TT), and rsl894631(AA AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs62227020(CC CT). In an aspect, a Group B SNP may be found within -62373 base pairs of SNP rsl37794 located at 44079680 of the human genome assembly GRCh37.2 sequence on chromosome 22. In an aspect, a Group B SNP may be found within -81852 and 98292 base pairs of SNP rsl37794. In an aspect, a Group B SNP may be found within -59504 and 120955 base pairs of SNP rsl37794. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs 137794.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 1386440 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 1386440 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl386441(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs6983250(AA). In an aspect, a Group B SNP may be found within -567 base pairs of SNP rsl386440 located at 32177531 of the human genome assembly GRCh37.2 sequence on chromosome 8. In an aspect, a Group B SNP may be found within -147 base pairs of SNP rsl386440. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl386440.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 1411820 in the NCBI db SNP Build 134 and having a genotype CC CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 1411820 and having a genotype CC CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs7851174(AG GG). In an aspect, a Group B SNP may be found within range 3411 base pairs of SNP rs 1411820 located at 119026907 of the human genome assembly GRCh37.2 sequence on chromosome 9. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl411820.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl421940 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 1421940 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 1954863(AA), rs62357176(CC), rs72758633(CC), rs72758635(TT), rsl0940288(AA), and rs716436(TT). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs62360261(CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs3756541(TT) and rsl 1741738(GG). In an aspect, a Group B SNP may be found within -2668 and 14016 base pairs of SNP rsl421940 located at 52306013 of the human genome assembly GRCh37.2 sequence on chromosome 5. In an aspect, a Group B SNP may be found within -65794 base pairs of SNP rsl421940. In an aspect, a Group B SNP may be found within -68516 and - 15579 base pairs of SNP rsl421940. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl421940.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl445943 in the NCBI db SNP Build 134 and having a genotype AA CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl445943 and having a genotype AA CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs3212424(AA CC), rs3756537(CC TT), rsl6880669(CC GG), rs3822558(AA GG), rs3776787(CC TT), rsl2657429(AA GG), rsl2657501(AA CC), rs3797498(CC TT), rs3797496(AA CC), rs3797495(GG TT), rs3212438(AA GG), rs3212439(CC TT), rs3212441(CC TT), rsl363192(AA CC), rsl316250(AA GG), rs3926397(GG TT), rs3212457(CC TT), rs3212458(GG TT), rsl 1959632(AA GG), rsl421937(CC TT), rs3212461(GG TT), rs56296421(AA TT), rsl2657972(AA GG), rs3212478(AA GG), rs3212480(AA GG), rs3212481(CC TT), rs3212486(AA GG), and rs6880055(AA GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8 selected from the group consisting ofln another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8 selected from the group consisting of rsl862191(AA GG), rs67719154(CC TT),
rs989073(AA CC), rsl2652168(CC TT), rs3212464(AA GG) and rs3212472(AA TT). In an aspect, a Group B SNP may be found within -14009 and 351 base pairs of SNP rsl 445943 located at 52342409 of the human genome assembly GRCh37.2 sequence on chromosome 5. In an aspect, a Group B SNP may be found within -18956 and 47019 base pairs of SNP rsl445943. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl445943.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl457238 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 457238 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 1902965(CC), rs897832(AA), rsl457235(AA),
rsl902622(TT), rs7584446(AA), rs7579481(TT), rs6432602(AA), rsl0497208(GG), rs7569555(GG), rsl6844824(AA), rs35720878(TT), rs3796103(CC), and rs2357861(TT). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs7563574(AA), rsl l895959(GG), rsl l885142(AA), rs4265965(TT), rsl0929970(AA), rsl 1897691(CC), rs4664313(AA), rs6432600(CC), rs6432601(AA), rsl0929971(CC), rsl3027372(GG), rs2061290(TT), rsl457236(TT), rs34064895(TT), and rs7568816(CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium
correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs7608267(GG), rs7583743(AA), rsl457237(AA), rs4580348(GG), rs2357773(TT), rsl457233(TT), rs996112(GG), rs6432603(TT), rsl840894(TT), rsl471120(CC), and rs748427(GG). In an aspect, a Group B SNP may be found within -7209 and 90839 base pairs of SNP rsl457238 located at 160985462 of the human genome assembly GRCh37.2 sequence on chromosome 2. In an aspect, a Group B SNP may be found within -17454 and 1694 base pairs of SNP rsl457238. In an aspect, a Group B SNP may be found within -6344 and 18736 base pairs of SNP rsl457238. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl457238.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl478842 in the NCBI db SNP Build 134 and having a genotype AA AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl478842 and having a genotype AA AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl478840(CC CT), rs7623616(AG GG),
rsl3320363(AG GG), rs4626038(AA AG), and rs4626039(AA AG). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2035258(CC CG) and rs4425207(AA AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs4455282(CC CT). In an aspect, a Group B SNP may be found within 6980 base pairs of SNP rsl478842 located at 35152160 of the human genome assembly GRCh37.2 sequence on chromosome 3. In an aspect, a Group B SNP may be found within 3001 and 15875 base pairs of SNP rsl478842. In an aspect, a Group B SNP may be found within 312 and 10133 base pairs of SNP rsl478842. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl478842.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl53141 in the NCBI db SNP Build 134 located at 52304996 of the human genome assembly GRCh37.2 sequence on chromosome 5 and having a genotype GG.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl560582 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 1560582 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs62188519(TT), rs4146101(AA), rsl7350136(TT),
rs56010921(CC), rs7568828(CC), rs62188521(CC), rsl946596(AA), rsl432263(CC), rsl3012052(CC), rs62178745(GG), rs6739940(AA), rs62178759(CC), rs62181060(CC), rs62181061(TT), rs2893647(CC), and rsl2151654(AA). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs 12467416(GG), rs62188516(CC), rsl 6862321(GG), rs62188517(CC), rsl7415118(CC), rsl469623(CC), rsl0498103(AA), rsl3016782(AA), rs72966437(TT), rs62178744(AA), rs2116539(GG), rs28589527(TT), rsl6862406(GG), and rsl6862412(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2008081(TT), rs56202506(CC), and rs62188514(GG). In an aspect, a Group B SNP may be found within -34375 and -30306 base pairs of SNP rsl560582 located at 222107115 of the human genome assembly GRCh37.2 sequence on chromosome 2. In an aspect, a Group B SNP may be found within -20243 and 25462 base pairs of SNP rsl560582. In an aspect, a Group B SNP may be found within -7533 and 18114 base pairs of SNP rsl 560582. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl560582.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl560941 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 560941 and having a genotype AA GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs9999331(CC TT) and rs7687559(CC GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl3128029(AA TT), rs4593111(CC TT), rsl3104542(CC GG), rsl3105829(CC TT), rsl 1099882(CC TT), rs9760689(AA GG), rs9760673(CC TT), rsl 1732163(AA GG), rs7693862(CC TT), and rs71620317(CC GG). In an aspect, a Group B SNP may be found within -13176 and 8853 base pairs of SNP rsl560941 located at 154378744 of the human genome assembly GRCh37.2 sequence on chromosome 4. In an aspect, a Group B SNP may be found within 1215 and 7181 base pairs of SNP rs 1560941. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs 1560941.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl563632 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 1563632 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2605141(TT), rs2605143(TT), rs2605145(AA),
rsl2946752(CC), rs3764404(AA), rs7225932(CC), rsl563634(TT), rs4924846(TT), and rs6502647(AA). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2605144(CC), rs921985(AA), rs4925179(TT), and rs2688036(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs669340(GG). In an aspect, a Group B SNP may be found within 43187 base pairs of SNP rs 1563632 located at 18220770 of the human genome assembly GRCh37.2 sequence on chromosome 17. In an aspect, a Group B SNP may be found within -49822 and 41776 base pairs of SNP rs 1563632. In an aspect, a Group B SNP may be found within -
56531 and 4207 base pairs of SNP rs 1563632. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl563632.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 1605461 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 1605461 and having a genotype AG. In another aspect, a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rsl507559(CT). In an aspect, a Group B SNP may be found within -61700 base pairs of SNP rs 1605461 located at 189556081 of the human genome assembly GRCh37.2 sequence on chromosome 2. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs 1605461.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 1667223 in the NCBI db SNP Build 134 and having a genotype AA CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 1667223 and having a genotype AA CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs 1667221(AA GG) and rs57305209(AA GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl667222(CC TT). In an aspect, a Group B SNP may be found within -149 base pairs of SNP rs 1667223 located at 29136399 of the human genome assembly GRCh37.2 sequence on chromosome 18. In an aspect, a Group B SNP may be found within -386 and - 386 base pairs of SNP rs 1667223. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs 1667223.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl6953047 in the NCBI db SNP Build 134 and having a genotype GT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 16953047 and having a genotype GT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl6953048(CT), rsl2927155(CT), rs8058661(AC),
rs2665270(AT), rs2540775(AG), rsl 1076020(AG), rs2540776(AG), and rs2689264(CT). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl 071501 (AG), rs2540774(AG), rs718388(CT), rsl 2445828(CT), and rsl2931414(AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium
correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl015279(AT) and rsl2932373(CT). In an aspect, a Group B SNP may be found within - 14929 and -2487 base pairs of SNP rsl6953047 located at 54130170 of the human genome assembly GRCh37.2 sequence on chromosome 16. In an aspect, a Group B SNP may be found within 1511 and 4823 base pairs of SNP rsl 6953047. In an aspect, a Group B SNP may be found within 1913 and 7810 base pairs of SNP rsl 6953047. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 6953047.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl 7014760 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 7014760 and having a genotype AA GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl865175(AA CC). In an aspect, a Group B SNP may be found within range -6002 base pairs of SNP rsl7014760 located at 130340880 of the human genome assembly GRCh37.2 sequence on chromosome 4. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 7014760.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl7114618 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl7114618 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl7114612(GG) and rs36082687(CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl7114670(AA). In an aspect, a Group B SNP may be found within 68803 base pairs of SNP rsl 7114618 located at 44443127 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -1386 and -403 base pairs of SNP rsl7114618. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl7114618.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl7151969 in the NCBI db SNP Build 134 and having a genotype AA CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl7151969 and having a genotype AA CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs7006052(GG TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl 18105212(AA GG). In an aspect, a Group B SNP may be found within 4055 base pairs of SNP rsl7151969 located at 10301469 of the human genome assembly GRCh37.2 sequence on chromosome 8. In an aspect, a Group B SNP may be found within -10061 base pairs of SNP rsl7151969. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl7151969.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl7172693 in the NCBI db SNP Build 134 located at 46430673 of the human genome assembly GRCh37.2 sequence on chromosome 7 and having a genotype CC.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl7188228 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl7188228 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl0143767(CC), rs61984683(CC), rs61984684(CC), rs61984708(CC), rs4635267(TT), rsl7188046(TT), rs61984736(CC), rs8006652(TT), rsl2587200(GG), rsl2431548(TT), rs61984737(AA), rsl2586348(GG), rsl2434935(TT), rsl 7260380(TT), rs58984912(AA), rsl7188207(GG), rs61986664(AA), rs8018755(TT), rs8020072(CC), rsl7260408(GG), rsl2589982(GG), rs8021690(CC), rs61986669(AA), rs61986670(AA), rs61986671(GG), rsl 7260415(GG), rsl956406(CC), rs61983300(GG), rsl 1159868(CC), rs7157149(CC), rs2224333(TT), rsl2590826(GG), rs57889459(TT), rsl950806(TT), rs58550317(CC), rs61982733(TT), rs2145120(AA), and rsl2588535(GG). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of
rs79579293(GG), rs60310240(CC), rsl7772064(TT), rsl7698817(CC), rsl2589467(CC), rsl2433464(GG), rs56987357(AA), rsl955599(TT), rsl955600(AA), rsl7772222(GG), rs7145588(AA), rs61977049(CC), rsl7772288(AA), rsl2587386(TT), rs55722539(AA), rsl2589480(TT), rs61977058(CC), rs74071851(AA), rsl 1159856(GG), rsl7124652(GG), rs2295135(GG), rsl7124700(TT), rs3814855(AA), rs2274737(CC), rs2297128(CC), rs74074098(GG), rsl864748(CC), rs77306894(GG), rs59136503(AA), rsl998670(TT), rsl816372(GG), rs60878614(GG), rs76559451(CC), rsl 123421(GG), rs2004329(CC), rsl2436326(TT), rsl7203789(TT), rsl7798341(CC), rsl0134008(TT), rs891750(AA), rs891749(TT), rs56144430(AA), rs57118463(CC), rs61984746(TT), rs61986665(CC), rsl2587598(CC), rs78077739(TT), rs58655091(AA), rs78068036(CC), and rs61983303(CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs77382318(GG), rs61977053(AA), rs61579615 (TT), rs60213984(AA), rs61975260(CC), rsl2587528(GG), rs2274735(GG), and rs7143853(GG). In an aspect, a Group B SNP may be found within -383136 and -160444 base pairs of SNP rsl7188228 located at 89205265 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -383197 and 25538 base pairs of SNP rsl7188228. In an aspect, a Group B SNP may be found within -224054 and 42979 base pairs of SNP rsl7188228. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl7188228.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 17209998 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 17209998 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1, including a Group B SNP selected from the group consisting of rsl0515016(TT) and rsl2517623(AA). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs34382006(CC), rs62362294(AA), rs34370411(CC), rsl3170214(CC), and rs4501302(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl2517640(AA) and rs6896102(GG). In an aspect, a Group B SNP may be found within 1694 and 20527 base pairs of SNP rsl7209998 located at 65940678 of the human genome assembly GRCh37.2 sequence on chromosome 5. In an aspect, a Group B SNP may be found within -9925 and 18373 base pairs of SNP rs 17209998. In an aspect, a Group B SNP may be found within -74 and 1623 base pairs of SNP rs 17209998. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl7209998.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl7278159 in the NCBI db SNP Build 134 located at 66012846 of the human genome assembly GRCh37.2 sequence on chromosome 5 and having a genotype CT TT.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 17318470 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 17318470 and having a genotype CT. In another aspect, a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rs3784336(CT). In an aspect, a Group B SNP may be found within 66 base pairs of SNP rsl7318470 located at 68616610 of the human genome assembly GRCh37.2 sequence on chromosome 15. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs 17318470.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl7395296 in the NCBI db SNP Build 134 and having a genotype AA AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 17395296 and having a genotype AA AG. In another aspect, a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rsl7304075(CT TT). In an aspect, a Group B SNP may be found within -267 base pairs of SNP rsl7395296 located at 26689105 of the human genome assembly GRCh37.2 sequence on chromosome 22. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl7395296.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 174948 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 174948 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl74937(AG). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs 174936(AG), rsl74938(AG), rsl74940(CT), rsl74952(AG), and rsl74953(CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs6955101(CT). In an aspect, a Group B SNP may be found within - 27456 base pairs of SNP rs 174948 located at 29889233 of the human genome assembly GRCh37.2 sequence on chromosome 7. In an aspect, a Group B SNP may be found within - 4323 and 16496 base pairs of SNP rs 174948. In an aspect, a Group B SNP may be found within -4151 base pairs of SNP rs 174948. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs 174948.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl74957 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl74957 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl74960(AG). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl74954(CG) and rsl74958(AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl74959(CT) and rs 174961 (AG). In an aspect, a Group B SNP may be found within 4927 and 10424 base pairs of SNP rsl74957 located at 29910227 of the human genome assembly GRCh37.2 sequence on chromosome 7. In an aspect, a Group B SNP may be found within -3502 and 1335 base pairs of SNP rs 174957. In an aspect, a Group B SNP may be found within 7875 base pairs of SNP rs 174957. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs 174957.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl7507051 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl7507051 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl0782795(GG), rs4662169(TT), and rsl2116630(TT). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs7536953(GG), rs7537016(GG), rsl2144579(GG), rsl 1163579(TT), rsl 409793 (AA), rs7547723(CC), and rsl2025463(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs391580(GG). In an aspect, a Group B SNP may be found within -16349 base pairs of SNP rsl 7507051 located at 83271130 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within -13843 and -2179 base pairs of SNP rsl7507051. In an aspect, a Group B SNP may be found within -7059 and 12393 base pairs of SNP rsl7507051. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl7507051.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 17724627 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 17724627 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1, including a Group B SNP selected from the group consisting of rs62208408(CC). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs6126098(AA) and rs6122978(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of
rsl0154012(TT), rs2094743(AA), rsl 1698998(AA), rs8126174(GG), rs6123028(CC), rsl546869(AA), rs2294439(AA), rs4811185(TT), rs2235469(AA), rs2235467(TT), rs2294438(TT), rs2206135(TT), rs2235460(AA), rs2235459(CC), rs6126298(GG), rsl 1700341(GG), rs4811231(CC), rs4811234(TT), rs73292682(CC), rs56132947(AA), rs4811243(TT), rs4811247(AA), rs717599(AA), rsl 106966(GG), rs6126390(TT), rs6126401(TT), rs6096675(TT), rs6126413(CC), and rs6126414(GG). In an aspect, a Group B SNP may be found within -86444 and 133982 base pairs of SNP rsl7724627 located at 36376580 of the human genome assembly GRCh37.2 sequence on chromosome 20. In an aspect, a Group B SNP may be found within 14252 and 14323 base pairs of SNP rsl7724627. In an aspect, a Group B SNP may be found within 42729 base pairs of SNP rsl 7724627. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 7724627.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl7781459 in the NCBI db SNP Build 134 and having a genotype AG GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl7781459 and having a genotype AG GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl041978(GT TT). In an aspect, a Group B SNP may be found within range 6068 base pairs of SNP rsl7781459 located at 57564265 of the human genome assembly GRCh37.2 sequence on chromosome 18. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl7781459.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl7839997 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 17839997 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs7759025(TT) and rs7738673(AA). In an aspect, a Group B SNP may be found within range 7625 and 7723 base pairs of SNP rsl7839997 located at 30339293 of the human genome assembly GRCh37.2 sequence on chromosome 6. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl7839997.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs 1805100 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 1805100 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2941473(TT), rs2977944(AA), rs2977945(AA),
rs2272669(AA), rs2941477(AA), rs2941481(AA), rsl515020(TT), rs2943539(TT), rs2977948(TT), and rs2943593(TT). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs59192202(AA), rs2941487(CC), and rsl913641(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2941465(TT), rs2941484(TT), rsl913640(GG), and rs2941423(CC). In an aspect, a Group B SNP may be found within -10487 and 43573 base pairs of SNP rsl805100 located at 76476396 of the human genome assembly GRCh37.2 sequence on chromosome 8. In an aspect, a Group B SNP may be found within - 1677 and 6843 base pairs of SNP rs 1805100. In an aspect, a Group B SNP may be found within -3836 and 5399 base pairs of SNP rsl805100. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl805100. In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl813758 in the NCBI db SNP Build 134 and having a genotype GT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl813758 and having a genotype GT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2183308(CT), rsl974108(AG), and rs2247975(CT). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl819391(AG). In an aspect, a Group B SNP may be found within 4631 and 6626 base pairs of SNP rsl813758 located at 51518287 of the human genome assembly GRCh37.2 sequence on chromosome 20. In an aspect, a Group B SNP may be found within 1665 base pairs of SNP rsl813758. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl813758.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl823790 in the NCBI db SNP Build 134 and having a genotype AA AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 1823790 and having a genotype AA AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 1681499(GG GT), rsl0196547(CT TT),
rs2068502(CT TT), and rsl 3398119(CC CG). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl2690513(CG GG), rsl3022966(AG GG), rsl2476926(CC CT), rsl3391691(GT TT), rs3845718(CC CT), rsl2693236(CC CT), rsl2693237(AA AG), rsl2465099(AT TT), rsl401262(CC CT), rsl 1677472(AA AG), rsl2620845(GT TT), rs3914747(AC CC), rsl0185223(AA AG), rsl7191654(CT TT), rs4289144(AA AG), and rsl0803939(GG GT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl2475106(CC CG), rsl349720(AA AG), and rs7588050(GT TT). In an aspect, a Group B SNP may be found within 5955 and 18071 base pairs of SNP rsl823790 located at 181277132 of the human genome assembly GRCh37.2 sequence on chromosome 2. In an aspect, a Group B SNP may be found within -144140 and -40746 base pairs of SNP rs 1823790. In an aspect, a Group B SNP may be found within -9810 and -5443 base pairs of SNP rs 1823790. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 823790.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl897833 in the NCBI db SNP Build 134 and having a genotype GT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl 897833 and having a genotype GT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 1959160(AC), rsl2517890(AG), rsl897834(AG), rsl0514324(AT), and rs3952709(AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2366613(AG) and rs3096032(CT). In an aspect, a Group B SNP may be found within -2943 and 7549 base pairs of SNP rsl 897833 located at 89649118 of the human genome assembly GRCh37.2 sequence on chromosome 5. In an aspect, a Group B SNP may be found within -3281 and 3238 base pairs of SNP rsl897833. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl897833.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl915279 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl915279 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2353417(CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl 523416(CT). In an aspect, a Group B SNP may be found within -52866 base pairs of SNP rsl915279 located at 239075714 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within -3402 base pairs of SNP rsl915279. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs 1915279.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl950806 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs 1950806 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl0143767(CC), rs61984683(CC), rs61984684(CC), rs61984708(CC), rs4635267(TT), rsl7188046(TT), rs61984736(CC), rs8006652(TT), rsl2587200(GG), rsl2431548(TT), rs61984737(AA), rsl2586348(GG), rsl2434935(TT), rsl 7260380(TT), rs58984912(AA), rsl7188207(GG), rs61986664(AA), rs8018755(TT), rs8020072(CC), rsl7260408(GG), rsl2589982(GG), rs8021690(CC), rs61986669(AA), rs61986670(AA), rs61986671(GG), rsl 7260415(GG), rsl956406(CC), rs61983300(GG), rsl 1159868(CC), rs7157149(CC), rs2224333(TT), rsl2590826(GG), rs57889459(TT), rs58550317(CC), rs61982733(TT), rs2145120(AA), and rsl2588535(GG). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs79579293(GG), rs60310240(CC), rsl7772064(TT), rsl 7698817(CC), rsl2589467(CC), rsl2433464(GG), rs56987357(AA), rsl955599(TT), rsl955600(AA), rsl7772222(GG), rs7145588(AA), rs61977049(CC), rsl7772288(AA), rsl2587386(TT), rs55722539(AA), rsl2589480(TT), rs61977058(CC), rs74071851(AA), rsl 1159856(GG), rsl7124652(GG), rs2295135(GG), rsl7124700(TT), rs3814855(AA), rs2274737(CC), rs2297128(CC), rs74074098(GG), rsl864748(CC), rs77306894(GG), rs59136503(AA), rsl998670(TT), rsl816372(GG), rs60878614(GG), rs76559451(CC), rsl 123421(GG), rs2004329(CC), rsl2436326(TT), rsl7203789(TT), rsl7798341(CC), rsl0134008(TT), rs891750(AA), rs891749(TT), rs56144430(AA), rs57118463(CC), rs61984746(TT), rs61986665(CC), rsl2587598(CC), rs78077739(TT), rs58655091(AA), rs78068036(CC), and rs61983303(CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs77382318(GG), rs61977053(AA), rs61579615(TT), rs60213984(AA), rs61975260(CC), rsl2587528(GG), rs2274735(GG), and rs7143853(GG). In an aspect, a Group B SNP may be found within - 418627 and -195935 base pairs of SNP rsl950806 located at 89240756 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -418688 and -9953 base pairs of SNP rsl950806. In an aspect, a Group B SNP may be found within -259545 and 7488 base pairs of SNP rsl 950806. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl 950806. In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rsl991013 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rsl991013 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2974978(CC), rs2075616(CC), rs2075617(CC),
rs2974976(GG), rs2910971(AA), rsl421932(CC), rsl421931(CC), rsl421930(CC), rs2910965(AA), rs2974987(AA), rs3212522(GG), rs2897457(GG), rs3212527(AA), rsl421929(TT), rs3212533(AA), rsl2517446(AA), rs2287871(AA), rs3212591(GG), and rsl2518279(CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8 selected from the group consisting of rs2303123(CC), rs3212640(GG) and rs990602(TT). In an aspect, a Group B SNP may be found within 19085 and 23898 base pairs of SNP rsl991013 located at 52359934 of the human genome assembly GRCh37.2 sequence on chromosome 5. In an aspect, a Group B SNP may be found within -15097 and 11436 base pairs of SNP rs 1991013. In yet another aspect, a Group B SNP may be within 1 cM of SNP rsl991013.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2016224 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2016224 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2880801(AA), rs2880802(TT), rs2099229(AA),
rsl604699(CC), rs4858925(TT), rs4858969(TT), rs6778211(GG), rs6770013(AA), rs6781226(GG), rsl2714696(AA), rs7630716(GG), rs9863076(TT), rsl 1717021(TT), rsl503433(CC), rs9855839(TT), rs9878862(AA), rs7629565(CC), rs7652406(TT), rsl3074576(CC), rs9825216(GG), rsl469569(CC), rsl 1717413(CC), rsl0511136(GG), rs6785333(CC), rs9852704(AA), and rs2344185(CC). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs9861809(TT), rsl835543(GG), rs4858972(GG), rs4858974(CC), rs6781901(GG), rs4858975(CC), rsl431153(CC), rs9310061(GG), rs9842748(CC), rs4858928(AA), rs35040143(CC), rs2163423(AA), rs6551262(AA), rs7637503(TT), rsl 7549213(AA), rs55840331(AA), rs60099577(GG), rs68042814(CC), rsl7549345(GG), rsl 1128018(TT), rsl 1915058(AA), rs9880480(GG), and rs9859034(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs 1946569(TT) and rs67047416(AA). In an aspect, a Group B SNP may be found within -21780 and 36977 base pairs of SNP rs2016224 located at 88041650 of the human genome assembly GRCh37.2 sequence on chromosome 3. In an aspect, a Group B SNP may be found within -2497 and 48322 base pairs of SNP rs2016224. In an aspect, a Group B SNP may be found within -12911 and 47026 base pairs of SNP rs2016224. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2016224.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2020860 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2020860 and having a genotype CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl6864136(AC), rs78893152(AG), rsl2086257(CT), rsl2078869(AG), rsl2087971(CT), rs28369834(AT), rsl2091865(CT), rs28969551(CT), rsl6864165(AT), rs28369868(AG), rs28369872(CT), rs28369886(AG), rs2020865(GT), rsl6864191(AG), rs73032526(AG), rs6668231(CT), rs58324390(AG), rsl 13133510(CT), rsl 11659296(CT), rs74122287(AT), rsl2066662(AG), rs74874902(AT), rsl 16433670(AC), rsl 2067810(AG), rs58956470(AT), rs56233063(AG), rs56159716(GT), rs59910498(AG), rs2205726(AG), rsl 14666880(CT), and rs6689616(AG). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl 2072321(CT). In an aspect, a Group B SNP may be found within -28694 and 57220 base pairs of SNP rs2020860 located at 171162583 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within 39581 base pairs of SNP rs2020860. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2020860.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2024408 in the NCBI db SNP Build 134 and having a genotype CT TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2024408 and having a genotype CT TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs715414(CG GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2110653 (AA AG). In an aspect, a Group B SNP may be found within 12867 base pairs of SNP rs2024408 located at
38432937 of the human genome assembly GRCh37.2 sequence on chromosome 7. In an aspect, a Group B SNP may be found within 1427 base pairs of SNP rs2024408. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2024408.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2027363 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2027363 and having a genotype AA GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1, including a Group B SNP selected from the group consisting of rsl0780954(CC TT), rsl 1142517(CC TT),
rsl0868862(CC GG), and rsl538670(AA CC). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs7045775(CC TT), rs4322073(CC TT), and rs7868028(AA CC). In an aspect, a Group B SNP may be found within -12956 and 2684 base pairs of SNP rs2027363 located at 73252653 of the human genome assembly GRCh37.2 sequence on chromosome 9. In an aspect, a Group B SNP may be found within -4983 and 838 base pairs of SNP rs2027363. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2027363.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2048070 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2048070 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl506798(GG). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2174678(CC). In an aspect, a Group B SNP may be found within -2524 base pairs of SNP rs2048070 located at 11188974 of the human genome assembly GRCh37.2 sequence on chromosome 4. In an aspect, a Group B SNP may be found within 2928 base pairs of SNP rs2048070. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2048070.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2069643 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2069643 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs 17652611 (AG) and rs2455229(AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2455234(AG). In an aspect, a Group B SNP may be found within 18959 base pairs of SNP rs2069643 located at 75919662 of the human genome assembly GRCh37.2 sequence on chromosome 5. In an aspect, a Group B SNP may be found within 11010 and 13055 base pairs of SNP rs2069643. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2069643.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2069912 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2069912 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2069914(AA). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2069913(CC) and rs973760(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of
rs34703177(AA), rs6747862(GG), rs34441363(TT), rs4359587(AA), rs4300780(GG), rsl2613252(CC), rsl2613254(AA), rsl2619391(AA), rsl3414676(AA), rsl3409933(GG), rsl l899601(CC), rsl0167294(AA), rs28807127(CC), rsl0209678(AA), rsl2692064(GG), rsl3017103(GG), rs6430935(TT), rsl2614320(AA), rs3738948(GG), rs4150514(GG), rs4150506(TT), rs58063879(TT), rsl 143407(GG), rsl3403918(TT), rs2134794(CC), rs4150434(AA), rs9923(TT), rsl3429925(GG), rs34601617(AA), rs59027829(CC), rs6430937(CC), rsl2613413(CC), rs7584659(GG), rs4662721(TT), rsl0928764(CC), rs6716392(TT), rs6735779(AA), rsl 1684068(CC), rsl 2477214(TT), rs67771362(AA), rs2139142(AA), rs4662724(CC), rs34006114(AA), rs2276682(AA), rs35708549(CC), rs2069918(AA), and rs2069921(GG). In an aspect, a Group B SNP may be found within - 213470 and 1647 base pairs of SNP rs2069912 located at 128178191 of the human genome assembly GRCh37.2 sequence on chromosome 2. In an aspect, a Group B SNP may be found within 68 and 2030 base pairs of SNP rs2069912. In an aspect, a Group B SNP may be found within 81 base pairs of SNP rs2069912. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2069912.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2069915 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2069915 and having a genotype AA GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2069920(CC TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2069910(CC TT). In an aspect, a Group B SNP may be found within -404 base pairs of SNP rs2069915 located at 128178378 of the human genome assembly GRCh37.2 sequence on chromosome 2. In an aspect, a Group B SNP may be found within 1268 base pairs of SNP rs2069915. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2069915.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2069948 in the NCBI db SNP Build 134 and having a genotype CT TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2069948 and having a genotype CT TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs3746427(AG GG), rs6088734(AA AT),
rs6088747(GT TT), rs2069945(CG GG), rs2069952(CT TT), rs9574(CG GG),
rsl415773(AA AG), rsl415774(AG GG), rs2065978(CT TT), rs2065979(CC CT), rs6088753(CT TT), rs6060285(GT TT), rs2378337(AA AG), rs6087683(CT TT), rs4911472(AT TT), rs6058202(AG GG), rs633198(CT TT), rs663550(AA AT),
rs4911476(AA AC), rs4911478(AA AC), rsl577924(CC CG), rs34515766(CG GG), rs6142320(AA AG), rs6142321 (AG GG), rs6142322(AC CC), rs6142324(CC CT), rs2093058(AG GG), rsl2481169(CT TT), and rs2180568(CG GG). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2145559(AG GG), rsl407202(CC CT), rs6060197(CC CT), rs6060199(AA AG), rs66535333(AG GG), rsl544047(CT TT), rs2038503(AG GG), rs6058198(AT TT), rs945960(AG GG), rs6060282(CT TT), rs6119581(AT TT), rs6142313(AA AG), rs35193912(CC CT), rs2103971(CT TT), rs8114671 (AC CC), and rs6142327(AA AT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs6088666(AG GG), rs6120778(CC CT), rs6060139(CC CT), rs6060140(AA AG), rs2425006(GT TT), rs734308(CT TT),
rs745849(CC CT), rsl885114(AA AG), rs2425012(AG GG), rs3746438(CC CT), rs6058154(AG GG), rs4616(AG GG), rs3746432(AG GG), rs62213676(AA AT), rs6141526(GG GT), rs6060165(AA AC), rs6060168(CT TT), rs6142280(AA AC), rs4911461(AA AC), rs3803936(AA AG), rsl3042358(AG GG), rs6142284(AG GG), rs6142285(GT TT), rs2038504(CT TT), rs2104083(AG GG), rs2104084(CC CG), rs6142290(AA AC), rs6142294(AA AG), and rsl7404569(AA AC). In an aspect, a Group B SNP may be found within -197919 and -88412 base pairs of SNP rs2069948 located at 33762489 of the human genome assembly GRCh37.2 sequence on chromosome 20. In an aspect, a Group B SNP may be found within -110764 and 30658 base pairs of SNP rs2069948. In an aspect, a Group B SNP may be found within -32025 and 32305 base pairs of SNP rs2069948. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2069948.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2073619 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2073619 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 1149812(CT), rs3784936(CG), rs4536500(CG), rs8050662(CT), rs8053632(CT), rsl l646418(CG), rs3851735(AG), rs7202284(AT), rs8048677(CG), rs8055609(CT), rs8054586(CG), rs4993971(CG), rs4888393(CT), rs468079(AG), rs247438(CG), rs247427(CT), rsl 85052(CT), rs42472(AT), rsl540(CG), rs247447(AG), and rs37602(CT). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl010631(CG), rai l 149814(CT), rsl0871307(GT), rs7187690(CT), rs4888381(AC), rs3844219(GT), rs2059257(AG), and rs4888394(CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs4888371(AG), rs6564245(CT), rs4887813(AG), rs4888375(CT), rs2865532(CT), rs9933956(CT), rsl2932952(CT), rsl 074961(CT), rs8046184(CT), rs4888395(GT), rs247437(GT), rs467780(AG), rs247434(AG), rs247436(GT), rs247423(AC), rs247425(CT), rs247443(CG), rs40217(AC), rs247450(AC), rs37599(CT), and rs37605(CG). In an aspect, a Group B SNP may be found within -19135 and 178656 base pairs of SNP rs2073619 located at 75327916 of the human genome assembly GRCh37.2 sequence on chromosome 16. In an aspect, a Group B SNP may be found within 674 and 85793 base pairs of SNP rs2073619. In an aspect, a Group B SNP may be found within -4271 and 177130 base pairs of SNP rs2073619. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2073619.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2073721 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2073721 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl30078(CG), rs2240059(CT), rs2073723(CT),
rsl065461(CT), rs3132528(CT), rs9263804(CT), rs9263805(AC), rs3130502(AG), rs3132524(CT), and rs3132523(CT). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs3094226(CT), rs2073719(CT), rs3130575(AG), and rs3130501 (AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs3094663(CT), rs3130464(AG), rs2285803(CT), rs2233942(CG), rsl30073(CT), rs3094225 (AG), rs3132538(AG), rs9263758(AG), rs2073722(AC), rs3130503(AG), and rs3132517(CT). In an aspect, a Group B SNP may be found within - 22529 and 12220 base pairs of SNP rs2073721 located at 31129616 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within -16717 and 6837 base pairs of SNP rs2073721. In an aspect, a Group B SNP may be found within -11051 and 7216 base pairs of SNP rs2073721. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2073721.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2076977 in the NCBI db SNP Build 134 and having a genotype CT TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2076977 and having a genotype CT TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl746269(AA AG), rs4949545(AA AG),
rs733823(AG GG), rs910629(AC CC), and rs2376909(GT TT). In an aspect, the Group B
SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl746268(AC CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl746267(AG GG). In an aspect, a Group B SNP may be found within -729 base pairs of SNP rs2076977 located at 30574158 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within -946 base pairs of SNP rs2076977. In an aspect, a Group B SNP may be found within -1024 and 509 base pairs of SNP rs2076977. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2076977.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2110167 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2110167 and having a genotype AA GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl558777(CC TT), rsl0849302(AA GG),
rsl0849303(CC TT), rs3782599(AA TT), and rsl0774349(AA GG). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs4140862(AA CC), rs7133972(AA GG), rs728342(GG TT), and rs7969805(CC TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs3782588(AA CC),
rs6489644(AA GG), rs7486468(CC TT), rs7954629(CC TT), rsl074027(CC TT), rs3782604(AA GG), rs2192190(GG TT), rs4930771(CC TT), rs7969693(AA CC), rsl0774350(CC TT), rs7972926(CC TT), rs4930772(AA GG), rs4930773(GG TT), and rs2361577(CC TT). In an aspect, a Group B SNP may be found within -36762 and 12743 base pairs of SNP rs2110167 located at 5734319 of the human genome assembly GRCh37.2 sequence on chromosome 12. In an aspect, a Group B SNP may be found within -29435 and -21778 base pairs of SNP rs2110167. In an aspect, a Group B SNP may be found within - 20870 and 2333 base pairs of SNP rs2110167. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2110167.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2159688 in the NCBI db SNP Build 134 located at 31756362 of the human genome assembly GRCh37.2 sequence on chromosome 7 and having a genotype AA.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2170169 in the NCBI db SNP Build 134 and having a genotype AG GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2170169 and having a genotype AG GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl7531077(AA AG). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs34655914(AG GG), rs35267671(CC CT), rsl7465420(CT TT), rs28493395(CC CT), rs28683126(AG GG), rs28435150(CC CT), rs28570969(AA AG), rs28611172(AG GG), rs7555461(CT TT), rsl0890238(AA AT), rsl2138115(AG GG), rs4072980(AA AG), and rs7366048(CT TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs28428561(AA AG), rs4360494(CC CG), rs61776719(AC CC), and rs67631072(CC CT). In an aspect, a Group B SNP may be found within 26142 and 53657 base pairs of SNP rs2170169 located at 38408164 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within -10823 and 55340 base pairs of SNP rs2170169. In an aspect, a Group B SNP may be found within 7343 base pairs of SNP rs2170169. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2170169.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2178032 in the NCBI db SNP Build 134 and having a genotype CC TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2178032 and having a genotype CC TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 1914583(AA GG), rs6765349(AA CC),
rs6778364(AA GG), rs9881238(CC TT), rs7640764(AA GG), rs7621878(AA CC), rs9816363(CC GG), rs9840055(CC TT), rs7625005(CC TT), rsl918396(CC GG), rsl3078338(AA GG), rs9827925(CC TT), rsl013607(CC GG), rsl527322(CC TT), rs4591533(CC TT), rs4677427(AA GG), rs7651319(CC TT), rsl527527(GG TT), rsl527528(CC GG), rs9844746(AA CC), rsl921434(AA CC), rsl609108(GG TT), rs6788938(AA CC), rs6804039(CC TT), rs9873597(CC GG), rs9842422(AA CC), rs9814134(GG TT), rsl3326322(AA GG), rs6762509(CC GG), rs6781158(AA TT), rs9821295(AA GG), rs9883367(CC TT), rsl405663(AA TT), rsl527323(GG TT), rs2178034(AA TT), and rs6549658(AA GG). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs7643124(GG TT), rs6549655(AA GG), rs6549656(CC TT), rs34728067(AA CC), rs7612314(CC GG), rs9838240(CC TT), rs4521282(AA GG), rs9855537(AA TT), rsl918390(AA TT), rsl3064972(CC GG), rsl0222550(CC TT), rs34454189(AA GG), rs2049623(AA GG), rs9877628(AA CC), rsl 1128403(CC TT), rsl0865686(AA GG), rsl 1128404(CC TT), rsl 1128405(CC TT), rsl3084178(CC TT), rsl3079644(AA CC), rs55808643(CC TT), rs56346616(CC TT), rsl997460(AA CC), rsl2714813(CC TT), rsl921433(CC TT), rs9880621(CC TT), and rs68081 11(CC TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs6803546(GG TT), rs7642555(AA GG), rs9861122(CC TT), rs9837543(CC TT), rsl584333(AA GG), rsl 1924855(CC TT), rs4131575(CC TT), rsl3061773(AA GG), rs6549652(AA CC), rsl569066(AA GG), rsl3091900(CC TT), rsl3071109(AA GG), rs4450864(AA GG), rs34584259(CC GG), rs9846280(GG TT), rs4405955(AA GG), rs9867922(AA GG), rs9861352(AA TT), rsl918399(AA TT), rsl918398(CC TT), rs4441699(AA GG), rsl918397(AA TT), rsl2714812(AA GG), rsl3092130(GG TT), rs6794991(GG TT), rsl852546(GG TT), rs6789695(CC TT), rs9859437(AA GG), rsl7502968(CC GG), rsl2638219(CC TT), rs4677426(CC TT), rs2875127(CC GG), rs56233320(CC GG), rs9825374(CC TT), rsl527529(CC TT), rs34893252(AA GG), and rs73108822(AA GG). In an aspect, a Group B SNP may be found within -98014 and 2583 base pairs of SNP rs2178032 located at 74860393 of the human genome assembly GRCh37.2 sequence on chromosome 3. In an aspect, a Group B SNP may be found within -66500 and - 8618 base pairs of SNP rs2178032. In an aspect, a Group B SNP may be found within - 33263 and 672 base pairs of SNP rs2178032. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2178032.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2222202 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2222202 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs3024500(CC), rs3024496(GG), rsl878672(CC), and rs3024491(AA). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs3024502(AA), rsl800896(CC), and rsl800893(TT). In an aspect, a Group B SNP may be found within -4550 and -335 base pairs of SNP rs2222202 located at 206945381 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within -5071 and 1786 base pairs of SNP rs2222202. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2222202.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2240660 in the NCBI db SNP Build 134 and having a genotype CC TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2240660 and having a genotype CC TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl008571(AA CC), rsl6966646(CC TT), rs2240663(AA GG), rs2270086(CC TT), rsl 1084620(CC TT), rs7247295(CC TT), rsl001377(CC GG), rsl005161(AA GG), rs2270049(CC TT), rsl468476(CC TT), rs8102421(AA CC), rs4297806(AA TT), and rs8112773(AA GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2270085(CC TT), rs55818570(CC TT), rs2270087(AA TT), rs59974647(AA GG), rsl2610427(GG TT), rs62636860(AA GG), rsl468477(AA GG), rsl7717774(CC TT), rs7252455(CC TT), rsl7774514(AA TT), rs2867741 (AA GG), and rs 11879703(CC TT). In an aspect, a Group B SNP may be found within 831 and 35117 base pairs of SNP rs2240660 located at 32535207 of the human genome assembly GRCh37.2 sequence on chromosome 19. In an aspect, a Group B SNP may be found within -6731 and 20420 base pairs of SNP rs2240660. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2240660.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2246277 in the NCBI db SNP Build 134 and having a genotype CC TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2246277 and having a genotype CC TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2665986(CC TT), rs2665985(AA GG), and rs2598450(CC TT). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs7409(CC TT), rs2598444(AA GG), rs2598445(AA GG), rs2598446(AA GG), rs2665977(AA GG), rs2665978(CC TT), rsl530834(CC TT), rs2598432(AA CC), rs2665979(CC TT), rs2598433(AA GG), rs8071679(AA GG), rs2598434(AA CC), rs2598435(CC TT), rs2665972(AA GG), rs2665973(CC TT), rs2665974(AA GG), rs2665975(GG TT), rs8071975(CC TT), rs9899725(GG TT), rs2665998(CC TT), rs2665999(AA GG), rs4238985(AA GG), rs2598448(CC TT), rs7217737(AA GG), rs55784778(CC TT), rs4789241(AA GG), rs2443168(AA TT), rs2598414(CC TT), rs2257020(AA GG), rs2257028(AA GG), rs8836(CC GG), and rs2246274(AA GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs55666832(CC TT), rs4789242(GG TT), rs2256879(AA GG), and rs2665987(CC TT). In an aspect, a Group B SNP may be found within -18883 and -2268 base pairs of SNP rs2246277 located at 74081345 of the human genome assembly GRCh37.2 sequence on chromosome 17. In an aspect, a Group B SNP may be found within -45802 and -129 base pairs of SNP rs2246277. In an aspect, a Group B SNP may be found within -1507 and 273 base pairs of SNP rs2246277. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2246277.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2257096 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2257096 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2490929(GG), rs2483038(TT), rs2257106(GG), and rs2257095(CC). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2618674(CC), rs2779371(CC), rs2805450(CC), and rsl975960(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2257101(GG), rs2618657(GG), rs988168(TT), rs2618652(CC),
rs2779388(CC), rs2805462(AA), rs2805465(TT), rs2805466(GG), rs2805469(GG), and rs2805470(GG). In an aspect, a Group B SNP may be found within -87 and 19140 base pairs of SNP rs2257096 located at 237703401 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within -983 and 595 base pairs of SNP rs2257096. In an aspect, a Group B SNP may be found within -246 and 112 base pairs of SNP rs2257096. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2257096.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs227397 in the NCBI db SNP Build 134 located at 70407769 of the human genome assembly GRCh37.2 sequence on chromosome 14 and having a genotype CC TT.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2274737 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2274737 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2297128(CC), rs74074098(GG), rs59136503(AA), rsl816372(GG), rs60878614(GG), rs76559451(CC), rsl 123421(GG), rsl2436326(TT), rsl7203789(TT), rsl 7798341(CC), rsl0134008(TT), rs891750(TT), and rs891749(AA). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of
rs79579293(GG), rs60310240(CC), rsl7772064(TT), rsl7698817(GG), rsl2589467(CC), rsl2433464(GG), rs56987357(AA), rsl955599(TT), rsl955600(AA), rsl7772222(GG), rs7145588(AA), rs61977049(CC), rsl7772288(AA), rsl2587386(AA), rs61579615 (TT), rs60213984(AA), rs55722539(AA), rsl2589480(TT), rs61977058(CC), rs74071851(AA), rsl l l59856(GG), rs2295135(GG), rsl7124700(TT), rs3814855(TT), rsl2587528(GG), rs77306894(GG), rsl998670(TT), rsl0143767(CC), rs2004329(GG), rs61984683(CC), rs61984684(CC), rs61984708(CC), rs4635267(TT), rs56144430(AA), rsl7188046(AA), rs61984736(CC), rs8006652(TT), rsl2587200(CC), rsl2431548(TT), rs61984737(AA), rsl2586348(GG), rsl2434935(TT), rs61984746(TT), rsl 7260380(TT), rs58984912(AA), rsl7188207(GG), rs61986664(AA), rs61986665(CC), rs8018755(TT), rs8020072(CC), rsl7260408(GG), rsl2589982(GG), rs8021690(CC), rs61986669(AA), rsl2587598(CC), rs61986670(AA), rs61986671(GG), rs78077739(TT), rsl 7260415(CC), rs58655091(AA), rsl956406(CC), rs61983300(GG), rs78068036(CC), rsl l l59868(CC), rs61983303(CC), rs7157149(CC), rs2224333(TT), rsl2590826(GG), rs57889459(TT), rs58550317(CC), rs61982733(TT), rs2145120(AA), and rsl2588535(CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs77382318(GG), rs61977053(AA), rsl7124652(GG), rs61975260(CC), rs4375590(GG), rsl864748(GG), rs2274735(CC), rs4516145(TT), rs7143853(GG), and rs57118463(CC). In an aspect, a Group B SNP may be found within -113522 and 196515 base pairs of SNP rs2274737 located at 88935651 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -113583 and 312593 base pairs of SNP rs2274737. In an aspect, a Group B SNP may be found within 603 and 81586 base pairs of SNP rs2274737. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2274737.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2276932 in the NCBI db SNP Build 134 located at 148984321 of the human genome assembly GRCh37.2 sequence on chromosome 4 and having a genotype AG.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2280665 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2280665 and having a genotype AA GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs34543522(AA TT), rsl3105469(AA GG),
rs7698726(AA GG), rs7699267(AA GG), rsl 1132296(AA GG), rsl3136095(CC TT), rsl3136735(AA GG), rsl3111957(CC TT), rs62347787(GG TT), rs7672235(AA GG), rsl2643943(GG TT), rs60129514(CC TT), rsl 1132299(AA CC), rs2280666(AA GG), and rs2280664(CC TT). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs7655203(AA GG), rs66614520(CC TT), rs35201112(GG TT),
rsl2651618(AA GG), rsl2651620(AA GG), rsl3136424(CC TT), rs34432579(CC TT), rsl 3111968(CC TT), rs3112861(AA GG), rs3112862(AA GG), rs3112863 (GG TT), rs3112864(AA GG), rs3112865(CC TT), rsl2503547(CC TT), rs2310160(CC TT), rsl l l2943(CC TT), rs31 12869(AA TT), rs3108224(AA GG), rsl534145(CC TT), rs3108271(CC TT), rs31 12872(AA GG), rsl2501185(AA GG), rsl2640745(CC TT), rsl2641710(CC TT), rsl2641719(CC TT), rsl2642709(AA TT), and rsl288534(CC TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs35745736(AA GG), rs3108229(AA GG), rsl3106074(AA CC),
rs7698980(AA GG), rs3108228(CC TT), rs3108227(GG TT), rs3112866(CC TT), rs3108270(CC TT), rs3806822(AA GG), and rs3806823(CC TT). In an aspect, a Group B SNP may be found within -20925 and 46849 base pairs of SNP rs2280665 located at
186185293 of the human genome assembly GRCh37.2 sequence on chromosome 4. In an aspect, a Group B SNP may be found within -21950 and 23422 base pairs of SNP rs2280665. In an aspect, a Group B SNP may be found within -16236 and 258 base pairs of SNP rs2280665. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2280665.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2310160 in the NCBI db SNP Build 134 and having a genotype CC TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2310160 and having a genotype CC TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs3112862(AA GG), rs3112863(GG TT),
rs3112864(AA GG), rs3112865(CC TT), rsl2503547(CC TT), rsl l l2943(CC TT), rs3112869(AA TT), rs3108224(AA GG), rsl534145(CC TT), rs3108271(CC TT), rs3112872(AA GG), rsl2641710(CC TT), rsl2641719(CC TT), and rsl2642709(AA TT). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs35201112(GG TT), rsl2651620(AA GG), rsl3136424(CC TT), rs34432579(CC TT), rs34543522(AA TT), rsl3105469(AA GG), rs7698726(AA GG), rs7699267(AA GG), rsl 1132296(AA GG), rsl3136095(CC TT), rsl3136735(AA GG), rsl3111957(CC TT), rsl3111968(CC TT), rs62347787(GG TT), rs7672235(AA GG), rsl2643943(GG TT), rs60129514(CC TT), rsl 1132299(AA CC), rs2280666(AA GG), rs2280664(CC TT), rs3112861 (AA GG), rs3108270(CC TT), rsl2501185(AA GG), rsl2640745(CC TT), and rsl288534(CC TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs7655203(AA GG), rs66614520(CC TT), rsl2651618(AA GG),
rsl3106074(AA CC), rs7698980(AA GG), rs3112866(CC TT), rs3112867(AA GG), rsl288537(CC TT), rsl288539(CC TT), rsl288547(AA GG), rs2587162(GG TT), rsl404996(AA GG), rsl288557(CC TT), rs6837989(AA GG), rs3806822(AA GG), rs3806823(CC TT), rsl3142118(CC TT), and rs7697454(CC TT). In an aspect, a Group B SNP may be found within -26951 and 68748 base pairs of SNP rs2310160 located at
186190294 of the human genome assembly GRCh37.2 sequence on chromosome 4. In an aspect, a Group B SNP may be found within -24071 and 18421 base pairs of SNP rs2310160. In an aspect, a Group B SNP may be found within -3752 and 17073 base pairs of SNP rs2310160. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2310160. In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2322784 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2322784 and having a genotype CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs61635271 (AG), rs76041652(AG), rs79907399(CT), rs2322782(CT), rs2322783(GT), rs79220483(AG), rs77747619(AT), rs76443947(AG), rs74779487(AC), rs76951420(CT), rs80265552(AG), rs75295067(GT), and rs79753841(CT). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of
rs78906703(CT). In an aspect, a Group B SNP may be found within -533 and 1585 base pairs of SNP rs2322784 located at 12969292 of the human genome assembly GRCh37.2 sequence on chromosome 17. In an aspect, a Group B SNP may be found within 785 base pairs of SNP rs2322784. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2322784.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2341551 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2341551 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs909792(CT), rs2880075(CT), rs62442787(CT),
rs62442788(AG), rsl7732745(AG), rs4897131(AG), rs4897132(CG), rs7753560(AT), rs7774597(AG), rs9404039(CT), rs9377223(CT), rsl2663698(CT), rs9322184(CT), rs761617(CT), rs9404042(AG), rs9390689(AG), and rs9373596(AG). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs6911016(AC), rs60404985(AG), rsl474640(CG), rs4897133(AG), rs6570968(AG), rsl2524946(AG), rs62442790(AC), rsl2665533(CT), rs9399689(CT), rs9498368(AG), rs78296717(AG), rs4897137(AG), rs4897138(AG), rsl 125107(CT), rsl0485097(AG), rs62442795(CT), rs9800648(CT), rs4897139(AT), rs9689569(AG), rs9377224(CG), rs9406344(AG), rs62442798(CT), rs3813675(GT), rs9404043(AC), rs9404044(AG), rs9373595(AG), rs9399690(AG), rs4869701(CT), rs62439776(AC), and rs28580659(AT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs4897128(AC), rs62442789(AC), rs9390688(GT), and rs4869797(AG). In an aspect, a Group B SNP may be found within -1400 and 54002 base pairs of SNP rs2341551 located at 149814762 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within -4112 and 66652 base pairs of SNP rs2341551. In an aspect, a Group B SNP may be found within -630 and 67061 base pairs of SNP rs2341551. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2341551.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2394824 in the NCBI db SNP Build 134 and having a genotype AA AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2394824 and having a genotype AA AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 1769855(CG GG), rs56134009(GT TT), rs740208(CC CT), rsl 1762810(CT TT), rs62479768(CC CT), rs56006208(AT TT), rs55765204(CC CT), rs55761857(AA AG), rsl 1768678(AA AG), rs4729404(CC CG), rsl l761896(CT TT), rs4729408(CT TT), rsl 1772060(GT TT), rsl 1773169(AA AG), rsl 1762771(AA AG), rsl039057(GT TT), and rsl532380(CC CT). In an aspect, the Group B SNP may further include a Group B SNPIn an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs56174823(CC CT), rs62479773(CC CT), rs56389625(CC CG), rsl7169325(CT TT), rs62479797(CC CG), rs56088922(AA AG), and rs58911561(CC CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs73143018(CT TT), rs884897(AA AG), and rs56034325(CT TT). In an aspect, a Group B SNP may be found within -44923 and 102001 base pairs of SNP rs2394824 located at 97739317 of the human genome assembly GRCh37.2 sequence on chromosome 7. In an aspect, a Group B SNP may be found within -14120 and 55484 base pairs of SNP rs2394824. In an aspect, a Group B SNP may be found within - 41872 and 96568 base pairs of SNP rs2394824. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2394824. In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2501976 in the NCBI db SNP Build 134 and having a genotype CT TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2501976 and having a genotype CT TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs62411911(CG GG), rsl 13952954(CG GG), rs9473541(AA AC), rs73425947(GT TT), rsl924999(GT TT), rs2477402(AC CC), rs2182012(AA AG), rs2182013(AT TT), rs2493439(AA AG), rs2147570(AG GG), rs2493440(AA AT), rs2501977(CT TT), rs2477405(AC CC), rs2477406(AG GG), rs2501979(CC CT), rs9473547(AA AG), rs2501980(CC CT), and rs4573082(GG GT). In an aspect, the Group B SNP may further include a Group B SNP In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs77608740(AT TT), rs9473549(AA AG), rs9463473(AG GG), rs9463474(GG GT), rs9463475(CC CT), rsl2196937(GG GT), rs9463476(AG GG), rs60982898(AT TT), rs9463477(AG GG), rs9473551(AT TT), rs9473552(CC CG), rs9463479(AG GG), rs9473553(CT TT), rsl0456622(CG GG), rs9463480(GT TT), rs9473555(CC CG), rs6458690(AG GG), rsl l41321(AA AG), rs9296616(GG GT), rs4715129(CT TT), rs4715130(CC CT), rs6923124(AG GG), rs7769646(AA AG), rsl2202075(AG GG), rs9473560(AG GG), rs9296617(CC CG), rs9473561(AA AG), rs7750918(CG GG), rs3806988(AG GG), rs3823114(AA AC), rs4267943(AA AG), rs4469291(AA AT), rs6458694(CC CT), rs2448707(AA AG), rs2501962(AA AT), rs9473563(AA AG), and rs2501963(CC CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs9473557(CC CT), rs9463483(AT TT), rs7744595(CG GG), rs6458693(GG GT), rs3729619(AT TT), rs4348317(AA AC), rs9473566(CC CG), and rs6901278(AG GG). In an aspect, a Group B SNP may be found within 38753 and 87113 base pairs of SNP rs2501976 located at 49370984 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within -22690 and 83297 base pairs of SNP rs2501976. In an aspect, a Group B SNP may be found within -22972 and 7208 base pairs of SNP rs2501976. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2501976.
I l l In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2515481 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2515481 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl807209(CC), rs2515480(AA), rsl984860(TT),
rsl984859(CC), rsl984857(CC), rs2959811(AA), rs2515483(CC), rs2959809(TT), and rs2442600(AA). In an aspect, a Group B SNP may be found within range -2471 and 3938 base pairs of SNP rs2515481 located at 6390027 of the human genome assembly GRCh37.2 sequence on chromosome 8. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2515481.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2531894 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2531894 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2531861(TT), rs2531862(AA), rs2779253(GG),
rs2779254(CC), rs2531863(AA), rs2531864(AA), rsl889022(GG), rsl0853181(GG), rs2531866(GG), rs2779257(AA), rs2531871(AA), rs2531872(TT), rs2779258(TT), rs2531873(GG), rs2531874(GG), rs2779259(CC), rs2779260(CC), rs2531880(AA), rs2779261(GG), rs2779262(CC), rs2531883(AA), rs2779263(CC), rs2531886(TT), rs2531887(CC), rs2779273(CC), rs2779272(CC), rs2779269(AA), rs2779268(CC), rs2779267(GG), rs2779277(AA), rs2779278(GG), and rs4063746(GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2531870(TT), rs2531875(GG), rs2531879(AA), rs2531881(AA), rs2779271(GG), rs2779270(CC), and rs2531892(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2779255(CC) and rsl2939068(AA). In an aspect, a Group B SNP may be found within -36405 and -17729 base pairs of SNP rs2531894 located at 26173945 of the human genome assembly GRCh37.2 sequence on chromosome 17. In an aspect, a Group B SNP may be found within -28566 and -346 base pairs of SNP rs2531894. In an aspect, a Group B SNP may be found within -37362 and -2564 base pairs of SNP rs2531894. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2531894.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2598414 in the NCBI db SNP Build 134 and having a genotype CC TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2598414 and having a genotype CC TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs7409(CC TT), rs2598444(AA GG), rs2598446(AA GG), rsl530834(CC TT), rs2665979(CC TT), rs2598434(AA CC), rs2598435(CC TT), rs2665972(AA GG), rs8071975(CC TT), rs2665995(CC TT), rs2665998(CC TT), rs4789241(AA GG), rs2443168(AA TT), rs2257020(AA GG), rs8836(CC GG),
rs2246274(AA GG), and rs2598450(CC TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2598445(AA GG), rs2665977(AA GG), rs2665978(CC TT), rs2598432(AA CC), rs2598433(AA GG), rs8071679(AA GG), rs2665973(CC TT), rs2665974(AA GG), rs2665975(GG TT), rs9899725(GG TT), rs2665999(AA GG), rs4238985(AA GG), rs2598448(CC TT), rs7217737(AA GG), rs55784778(CC TT), rs4789242(GG TT), rs2256879(AA GG), rs2257028(AA GG), rs2665986(CC TT), and rs2665985(AA GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8 selected from the group consisting of rs55666832(CC TT) and rs2665987(CC TT). In an aspect, a Group B SNP may be found within -4637 and 11978 base pairs of SNP rs2598414 located at 74067099 of the human genome assembly GRCh37.2 sequence on chromosome 17. In an aspect, a Group B SNP may be found within -29891 and 13772 base pairs of SNP rs2598414. In an aspect, a Group B SNP may be found within -31556 and 14519 base pairs of SNP rs2598414. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2598414.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2653814 in the NCBI db SNP Build 134 and having a genotype GT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2653814 and having a genotype GT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs7388959(AG), rs6559294(CT), rs4355854(AG),
rs7020071(AG), rs2818245(AC), rs2799698(AG), rs2653813(AG), rs2799696(CT), and rsl875621(CG). In an aspect, a Group B SNP may be found within range -11723 and 535 base pairs of SNP rs2653814 located at 91423611 of the human genome assembly GRCh37.2 sequence on chromosome 9. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2653814.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2665981 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2665981 and having a genotype AA GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2243481(CC TT), rs2243486(CC TT), rs2246623(CC TT), rs2246632(CC TT), rs2084666(AA GG), rs2246859(GG TT), rs2598451(CC GG), rs2665983(CC GG), rs2598411(CC GG), rs2246999(CC TT), rs2247007(AA GG), rs2598412(CC GG), rs2598413(AA GG), rs2250054(CC TT), rs2243536(CC TT), rs2243538(AA GG), rs2250081(AA GG), rs2665980(CC GG), rs2443166(AA GG), rs2457693(AA GG), rs2457692(AA GG), rs7501512(AA GG), rs8064909(CC TT), rs7208391(CC GG), rsl 1656686(CC TT), rs2666009(CC TT), rs2666010(GG TT), and rs2666011(AA GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2290246(AA CC), rs2246621(CC TT), rsl868820(AA GG), and rs7212071(AA CC). In an aspect, a Group B SNP may be found within -5406 and 6582 base pairs of SNP rs2665981 located at 74089311 of the human genome assembly GRCh37.2 sequence on chromosome 17. In an aspect, a Group B SNP may be found within -5363 and 1879 base pairs of SNP rs2665981. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2665981.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2694418 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2694418 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 0.9, including a Group B SNP selected from the group consisting of rsl 164856(AA), rsl 164858(TT), rs2694419(GG), and rs2559643(CC). In an aspect, a Group B SNP may be found within -3247 and -714 base pairs of SNP rs2694418 located at 105038670 of the human genome assembly GRCh37.2 sequence on chromosome 12. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2694418.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2695027 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2695027 and having a genotype AA GG. In another aspect, a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rs2520456(GG TT) and
rs2695028(AA GG). In an aspect, a Group B SNP may be found within -17161 and -4194 base pairs of SNP rs2695027 located at 18631680 of the human genome assembly GRCh37.2 sequence on chromosome 7. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2695027.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2716555 in the NCBI db SNP Build 134 located at 74070632 of the human genome assembly GRCh37.2 sequence on chromosome 16 and having a genotype GG.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2716601 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2716601 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 1642967(AA). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl2920224(CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium
correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs 12919941(CC), rs2526050(AA), rs7190649(AA), and rsl2597028(AA). In an aspect, a Group B SNP may be found within 1483 and 10048 base pairs of SNP rs2716601 located at 74076252 of the human genome assembly GRCh37.2 sequence on chromosome 16. In an aspect, a Group B SNP may be found within 1683 base pairs of SNP rs2716601. In an aspect, a Group B SNP may be found within -1280 base pairs of SNP rs2716601. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2716601.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2721952 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2721952 and having a genotype CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2737220(CT), rs2721942(CT), rs2737225(GT),
rs2737226(CT), rs2721946(GT), rs2721948(CT), and rs2737227(AG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2721938(CT), rs2737219(AG), rs2721939(CT), rs2721940(AC), rs2142329(CT), rs2142331(CT), and rs2721943(CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs28447075(AT). In an aspect, a Group B SNP may be found within -6738 base pairs of SNP rs2721952 located at 116645056 of the human genome assembly GRCh37.2 sequence on chromosome 8. In an aspect, a Group B SNP may be found within -9445 and -7057 base pairs of SNP rs2721952. In an aspect, a Group B SNP may be found within -7371 and -935 base pairs of SNP rs2721952. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2721952.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2728981 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2728981 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs9681875(AA), rs9682433(GG), rs9310686(TT), and rs2695629(AA). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs6782722(AA), rs6550668(AA), rs6550670(GG),
rs6808997(CC), rsl7638166(CC), rs9310687(GG), rsl2107233(GG), rsl7689605(CC), rs2728972(CC), rsl527634(GG), rs 1609173 (AA), rs2728980(GG), rs2035852(AA), rs2035854(CC), rs2638136(GG), rs2638138(GG), rs2638144(AA), rsl491877(GG), and rsl388548(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs6785603(AA), rs6550671(GG), rs7641644(AA),
rs77394845(TT), rsl609175(CC), rs2728978(TT), rs2638127(CC), rs2728979(TT), rs2728986(CC), rs2638143(TT), rs2728995(GG), and rs2728996(GG). In an aspect, a Group B SNP may be found within -36319 and 20339 base pairs of SNP rs2728981 located at 22253194 of the human genome assembly GRCh37.2 sequence on chromosome 3. In an aspect, a Group B SNP may be found within -40251 and 22293 base pairs of SNP rs2728981. In an aspect, a Group B SNP may be found within -26709 and -9553 base pairs of SNP rs2728981. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2728981.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2729140 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2729140 and having a genotype AG. In another aspect, a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rs2729138(AG). In an aspect, a Group B SNP may be found within -1163 base pairs of SNP rs2729140 located at 1128796 of the human genome assembly GRCh37.2 sequence on chromosome 3. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2729140.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2729547 in the NCBI db SNP Build 134 located at 111817732 of the human genome assembly GRCh37.2 sequence on chromosome 7 and having a genotype CC TT.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2756901 in the NCBI db SNP Build 134 located at 27218053 of the human genome assembly GRCh37.2 sequence on chromosome 9 and having a genotype CC.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2827845 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2827845 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl87888(CT), rs4816892(AG), rsl98127(CT), rsl98118(GT), rsl98121(AG), and rsl98100(AG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs 1605173(AG), rsl98119(AT), rsl98120(AG), rsl98101(AG), and rs9977914(CT). In an aspect, a Group B SNP may be found within - 17525 and 6193 base pairs of SNP rs2827845 located at 24464910 of the human genome assembly GRCh37.2 sequence on chromosome 21. In an aspect, a Group B SNP may be found within -5288 and 9535 base pairs of SNP rs2827845. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2827845.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2829523 in the NCBI db SNP Build 134 and having a genotype AC CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2829523 and having a genotype AC CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs9981873(CG GG), rs9981938(AT TT),
rs2829503(CC CT), rs7280570(AT TT), rs967719(AT TT), rs2247897(GT TT),
rs4550741(CT TT), rs2829506(AC CC), rs2829509(AG GG), rs2829510(CT TT), rs2829513(GT TT), rs2829514(AA AT), rs2829515(AA AG), rs7279510(CC CT), rs2829516(CT TT), rs8127682(CC CG), rs9975803(AA AG), rs2105695(AC CC), rs4283495(CC CT), rs2829517(CG GG), rs2829518(CC CT), rs2829519(CC CG), rs5029370(CC CG), rs2829520(CC CG), rs2829522(AA AT), rsl 158137(CC CT), rs2829524(AG GG), rs981374(AC CC), rs981373(AA AG), rs2154527(AG GG), rs4816996(CC CT), rs4816997(CC CT), rs9977817(AC CC), rs2829528(CC CT), rs2829529(AA AG), rs2829530(CC CT), rs9980592(GT TT), rs8133464(CC CT), rs8130629(CC CG), rs8130760(CC CT), rs2829531(AG GG), and rs2829532(AG GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl2626874(CG GG), rs2187060(AA AG), rs2829511(CT TT), rs2829512(AG GG), rs2156391(CC CT), rs9979690(AC CC), rs2829525(AG GG), rs75065594(CC CT), and rsl 1910556(CC CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2829504(AA AG), rs2829507(AC CC), and rs2245286(CG GG). In an aspect, a Group B SNP may be found within -31147 and 29685 base pairs of SNP rs2829523 located at 26414531 of the human genome assembly GRCh37.2 sequence on chromosome 21. In an aspect, a Group B SNP may be found within -34685 and 26710 base pairs of SNP rs2829523. In an aspect, a Group B SNP may be found within -34253 and 28374 base pairs of SNP rs2829523. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2829523.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2916755 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2916755 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2916702(AA), rs3020212(TT), rs2922906(AA),
rs3020213(TT), rs3020214(GG), rs2922903(CC), rs3020216(AA), rs3020218(CC), rs2916736(GG), rs2979671(CC), and rs2916731(CC). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl975616(CC), rsl870(TT), rs2922804(AA), rs2408342(AA), rs2167071(CC), rs2959793(AA),
rs2916729(CC), rs2922901(AA), rs2916726(CC), rs3020219(TT), rs2959791(GG), rs2916725(TT), rs2959790(CC), rsl3281117(AA), rs2922897(TT), rs3020221(TT), and rsl0087345(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs34744896(TT), rs2916715(CC), rs2922805(TT),
rs2959794(CC), rsl 1776519(GG), rs3020210(AA), rs75429999(TT), rs2916756(AA), rs3020215(TT), rs2916735(AA), rs2979673(GG), rsl961222(TT), and rsl7077317(CC). In an aspect, a Group B SNP may be found within -12257 and 12642 base pairs of SNP rs2916755 located at 6369350 of the human genome assembly GRCh37.2 sequence on chromosome 8. In an aspect, a Group B SNP may be found within -13111 and 11805 base pairs of SNP rs2916755. In an aspect, a Group B SNP may be found within -8170 and 3133 base pairs of SNP rs2916755. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2916755.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2941483 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2941483 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2941469(TT), rs2941471(GG), rs2941475(TT),
rs2943612(AA), rs2941479(CC), rs2943538(GG), rs2941485(AA), and rs2977946(AA). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2977931(AA), rs2977932(AA), rs2943554(AA), rsl800922(GG),
rs2977937(AA), rs2056090(GG), rs2272667(TT), rs2941468(CC), rsl805098(GG), rs2941470(GG), rs2941480(TT), and rs2943540(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2941453(TT), rs2941454(GG), rs2943586(CC), rsl515016(GG), rs938343(AA), rs2006717(CC), rs2941460(AA), rs2941462(GG), rs2941463(GG), rs2943541(AA), rs2977926(GG), rs2943543(AA), rs2943545(TT), rs2943546(GG), rs2977928(AA), rs2943549(GG), rs2943551(GG), rs2943552(TT), rs2943553(TT), rs2977938(AA), rs2943591(AA), rs2941489(CC), rsl464092(CC), rsl399564(CC), rsl399565(GG), rsl399567(TT), rsl399568(AA), rs2941491(TT), rs2943597(TT), rs2977952(TT), rs2941492(AA), rs2941494(GG), rs2977955(AA), rs2943589(CC), rs2977956(TT), rs2977958(CC), rsl0957767(AA), rs2941496(CC), rsl828910(TT), rs2977962(GG), rsl818539(TT), rs2977967(AA), rs2943561(GG), rs2977968(TT), rs2977969(GG), rs2922777(AA), rs2943563(TT), rs2943564(TT), rs2941499(CC), rs2943565(AA), rs2977971(GG), rs2941501(AA), rs2383936(GG), rs2122263(CC), rs2922780(CC), rs2977892(AA), rs2977893(TT), rs2922783(AA), rs2943570(AA), rs2943572(CC), rs2943573(AA), rsl996226(GG), rsl996227(TT), rsl375644(CC), rs2922784(AA), rs2977894(GG), rs2012410(GG), rs2941414(AA), rs2941415(GG), rs2977897(TT), rsl 17727764(AA), rs2383935(CC), rs2383933(GG), rs2977899(TT), rsl375646(AA), rsl449552(CC), rsl449553(TT), rsl449554(AA), rsl449555(AA), rs962711(AA), rs962712(GG), rs2941422(CC), rs2941424(CC), rs2941425(CC), rs2941426(AA), rs2922793(TT), rsl839333(CC), and rsl449558(CC). In an aspect, a Group B SNP may be found within -36321 and 44626 base pairs of SNP rs2941483 located at 76478616 of the human genome assembly GRCh37.2 sequence on chromosome 8. In an aspect, a Group B SNP may be found within -23209 and 1334 base pairs of SNP rs2941483. In an aspect, a Group B SNP may be found within -9585 and 1706 base pairs of SNP rs2941483. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2941483.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2942917 in the NCBI db SNP Build 134 and having a genotype AA AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs2942917 and having a genotype AA AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs3010158(AG GG), rs2989960(AG GG),
rs2989962(AG GG), rs2942920(AA AG), rs2942921(AA AG), rs2989971(AG GG), rs2942923(CC CT), rs2989974(AC CC), rs2989976(CT TT), rs3010156(AA AG), rs2942924(CT TT), rs2989981(AA AG), rs2989982(AA AG), rs3010164(CC CT), rs2989983(GG GT), rs2942926(CC CT), rs2989984(AG GG), rs2942927(CC CT), rs2989985(AG GG), rs2942912(AA AC), rs2942913(AG GG), rs2942914(AG GG), rs9427617(AA AT), rs3010167(AG GG), rs3010168(AA AT), rs3010169(AG GG), rs3010170(CT TT), rs990927(AG GG), rs990924(AG GG), rs3010171(CT TT),
rsl548295(CC CT), rsl548294(CC CG), rs3010173(AA AG), rs2942916(CT TT), rs3010174(GT TT), rs3010176(AG GG), rs3010177(AA AT), rsl0801450(AG GG), rs2989986(CC CT), rs3010178(AG GG), rs2989987(CC CT), rs7554138(AA AG), rs 10921921(GT TT), rsl0921922(CC CG), rs 10801451 (AG GG), rsl0801452(AC CC), rsl0921923(AA AT), rsl0801453(AA AT), rs4657813(CG GG), rsl0801454(CC CG), rsl0754149(CC CT), rs6658511(CT TT), rs4353070(AA AG), rs7520731(AA AG), rs7523221(AA AT), rs4504873(AG GG), rs6683699(CG GG), rs4393138(CT TT), rs4504871(AT TT), rs6676210(CC CG), rs6428301(AG GG), rs6428302(CC CT), rs4313376(AC CC), rs4521977(AG GG), rs4408131(AA AG), rsl2563650(AG GG), rsl2562966(CT TT), rs4604678(AC CC), rs4130440(AA AG), rs6428303(CC CT), rs6428304(CT TT), rs4350188(AA AG), rs6686736(AG GG), rsl0737655(CC CT), rsl0801455(AA AG), rsl0754151(AA AT), rsl0754152(CT TT), rsl0801456(CT TT), rsl0754153(CT TT), rsl0754154(AG GG), rsl0921929(AG GG), rsl0921930(AA AG), rs4489536(CT TT), rs4601567(CC CT), rs9701139(AT TT), rsl2031957(CT TT), rsl2034411(AG GG), rsl2034444(GG GT), rsl2031297(AT TT), rsl0801457(AA AG), rsl 1581892(AA AG), rs4351619(CC CT), rsl0754155(AA AG), rsl0754156(CT TT), rsl0801458(AC CC), rsl2033878(GT TT), rsl2033909(GT TT), rsl0921933(CC CT), rsl0921934(GG GT), rsl0921935(AA AG), rsl0921936(AA AC), rsl0921937(AA AG), rsl0921938(AC CC), rsl2565826(AG GG), rsl0921939(CT TT), rsl0921940(AG GG), rsl0921941(CT TT), rsl0921942(AG GG), rs6681536(AA AG), rs4539117(CC CT), rs4424491(AG GG), rs4394633(CT TT), rs4256793(CC CT), rs4266862(AA AG), rs4367774(AA AG), rs4525025(AG GG), rs4488010(CT TT), rs6699302(GG GT), rs6691116(AA AT), rs6702353(AG GG), rs4631670(CC CT), rs4564122(AG GG), rsl0754157(AA AG), rsl0737658(CC CT), rs4600030(GG GT), rs4596864(GG GT), rs4531277(CC CG), rs4351620(AA AG), rs 10921943 (AA AC), rsl0801459(CC CT), rsl0737660(AC CC), rsl0921947(AG GG), rs7519009(AG GG), rsl0801460(CC CG), rs4644473(AC CC), rs7418871(AA AG), rs4639736(AC CC), rs4443868(CT TT), rsl0921948(AG GG), rsl0921949(AG GG), rsl0436908(AA AG), rsl0921950(GT TT), rsl2738902(CT TT), rsl0921953(AG GG), rsl2034298(CC CT), rsl0801469(CC CT), rsl0801470(AT TT), rs 10801471(AA AC), rs4607868(CT TT), rsl0801472(AA AT), rs7541902(CC CT), rs4390158(AA AG), rs7542096(CC CT), rs7542104(AC CC), rsl0801473(CT TT), rsl0801474(AG GG), rsl0801475(CG GG), rsl0801476(AT TT), rsl0754164(CT TT), rsl0754165(AG GG), rsl0754166(CC CT), rs4518882(AA AG), rs4436371(CC CT), rs4436372(CC CT), rsl2081890(CT TT), rs4469700(AA AC), rs6428305(GT TT), rs6428308(CC CT), rs7534294(CC CG), rsl0921956(CT TT), rsl0921957(AG GG), rsl 1807812(CT TT), rsl 1808958(GT TT), rs 10921958(AA AC), rsl2039564(AA AG), rsl2040353(GT TT), rsl2042722(CG GG), rsl2040356(AT TT), rsl2089361(GG GT), rs4501823(AT TT), rs4634886(CT TT), rsl0737664(AA AG), rsl0737665(CT TT), rsl0754167(AT TT), rs4390160(AG GG), rs6682388(CT TT), rs4272603(AG GG), rs4462122(AC CC), rs4537534(AA AG), rs7522510(CC CT), rs4466638(CC CT), rs7553148(CC CT), rs7530086(AG GG), rs7522363(CT TT), rs7553244(CC CT), rs61820610(AA AG), rs34167524(AG GG), rs35278954(GG GT), rsl0921960(CT TT), rsl2083144(AA AG), rs6679783(AG GG), rs6679891(AG GG), rs7411386(AC CC), rs4475728(CC CT), rs4256794(AG GG), rs4548419(AA AG), rs4415544(AG GG), and rsl0801477(AG GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs4512627(AA AT),
rsl0754150(CT TT), rs62635828(CG GG), rs4520401(AG GG), rs4991124(AA AG), rs4991123(AA AG), rs4294395(AA AG), rsl0737656(CT TT), rsl0737657(CT TT), rs4359019(CC CT), rs4495676(GT TT), rs4269753(AG GG), rsl0737661(CT TT), rsl0737662(CT TT), rs4399134(CC CT), rsl0801462(GG GT), rsl0801464(AA AC), rsl0921951(CT TT), rsl0801465(CG GG), rsl0801466(CC CT), rsl0801467(AG GG), rsl0801468(AG GG), rsl0754158(AG GG), rsl0754159(AG GG), rsl0754160(CT TT), rsl0754161(AG GG), rs4269755(CC CT), rsl0754163(CC CT), rsl 1585686(AT TT), rs4440838(CC CT), rs4484908(AA AT), rs6428306(AA AG), rs6428307(CC CT), rs6428309(CC CT), rs34435407(AG GG), rsl2040330(AA AT), rsl2021959(CG GG), rsl2058917(CC CT), rsl2089400(AG GG), rsl2058921(CC CT), rsl2089437(GG GT), rsl2084932(AA AT), rs4495679(AA AG), rs4532815(AT TT), rsl0737663(AA AG), rs4390159(AG GG), rs4465184(CT TT), rs4523504(AA AG), rs4460616(CC CT), rs4431826(CC CT), rs4276894(AG GG), rs61820611(GT TT), rs35172199(CT TT), rsl0921959(AT TT), rs6655952(CC CG), rsl0921961(AG GG), rs4345788(CC CT), rs4330904(AA AG), and rs4402108(AT TT). In an aspect, a Group B SNP may be found within 17799 and 49291 base pairs of SNP rs2942917 located at 195778671 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within -36576 and 49818 base pairs of SNP rs2942917. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs2942917.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs2989946 in the NCBI db SNP Build 134 located at 227178948 of the human genome assembly GRCh37.2 sequence on chromosome 1 and having a genotype AG.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3024496 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3024496 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs3024500(CC), rs3024491(AA), rsl800896(CC), and rsl800893(TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs3024502(AA) and rsl878672(CC). In an aspect, a Group B SNP may be found within -1033 and 5303 base pairs of SNP rs3024496 located at
206941864 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within -1554 and 1849 base pairs of SNP rs3024496. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3024496.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs310244 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs310244 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9,selected from the group consisting of rs310235(AG), rs310233(AG), and rs831578(AC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium
correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2780816(AC), rs2780891(CT), rsl67454(AG), rs310241 (AG), rs2780818(GT),
rs2780819(CT), rs2780820(AG), rs2780895(CT), rs2230588(AG), rs2780896(CT), and rs2780822(CT). In an aspect, a Group B SNP may be found within -3464 and 6706 base pairs of SNP rs310244 located at 65305877 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within 29446 and 38407 base pairs of SNP rs310244. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs310244.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3118050 in the NCBI db SNP Build 134 and having a genotype CT TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3118050 and having a genotype CT TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl323816(CT TT) and rs3131735(AA AG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs3131743(CT TT), rs3118059(AG GG), rs3131746(AC CC), and rs723572(CC CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl 155492(AG GG). In an aspect, a Group B SNP may be found within 16980 base pairs of SNP rs3118050 located at 58219167 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within 14966 and 22270 base pairs of SNP rs3118050. In an aspect, a Group B SNP may be found within - 1383 and 91 base pairs of SNP rs3118050. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3118050.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3130454 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3130454 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs3094663(CT), rs3130464(AG), rs2285803(CT), and rsl30073(CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs3094226(CT), rs2073719(CT), rs3130575(AG), rsl30078(CG), rs2073721(AG), rs2073722(AC), rs2073723(CT), rsl 065461(CT), rs3132528(CT), rs9263804(CT), rs3130502(AG), rs3132524(CT), and rs3132523(CT). In an aspect, a Group B SNP may be found within 4414 and 28347 base pairs of SNP rs3130454 located at 31108485 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within -1398 and 2695 base pairs of SNP rs3130454. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3130454.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3176876 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3176876 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl2129732(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs3917018(AA), rs3176877(AA), and rs3181092(AA). In an aspect, a Group B SNP may be found within 1614 and 4036 base pairs of SNP rs3176876 located at 101200608 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within 9045 base pairs of SNP rs3176876. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3176876.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3176877 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3176877 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs3917018(AA) and rs3181092(AA). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of
rsl2129732(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs3917019(AA). In an aspect, a Group B SNP may be found within -1041 base pairs of SNP rs3176877 located at 101203395 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within 6258 base pairs of SNP rs3176877. In an aspect, a Group B SNP may be found within -1173 and 1249 base pairs of SNP rs3176877. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3176877.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3179969 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3179969 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs453112(AA), rs845757(GG), and rs845769(AA). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl028455(AA), rs376698(AA), rsl627444(CC), rsl099698(CC), rs845758(CC),
rs2297129(GG), rs61542857(GG), rs7161660(CC), rs7141363(TT), rs2274736(GG), rs28482235(AA), rsl0132554(TT), rs3783889(AA), rs879932(CC), rs2401751(AA), rs28711639(GG), rs8017689(CC), rs816072(TT), rsl864744(GG), rs28371093(CC), rsl0150594(GG), rs816075(AA), rsl 152376(GG), rs7160717(CC), rs816069(CC), rs7142053(GG), and rs4904452(CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl955598(AA), rsl2586714(CC),
rsl2435019(CC), rsl950280(TT), rs865285(AA), rs449338(TT), rsl288122(CC),
rs79681439(TT), rsl 152377(GG), rsl 1845147(AA), rs2778936(AA), rsl346996(TT), rs7160471(TT), rs9323830(AA), rs7160647(TT), rs7143642(GG), rsl0143744(CC), rsl999177(GG), rsl999176(CC), rsl864746(GG), rsl864747(GG), rs7151164(TT), rsl2433026(TT), rsl0138139(GG), rsl0138002(TT), rsl0150311(CC), rsl0138309(TT), rsl 1847417(TT), rs3783885(TT), rsl 1159857(TT), rs4390529(CC), rs4301952(AA), rs4516145(TT), rs4594187(GG), rs4514599(GG), rs61975276(GG), rs61975277(CC), rs61975278(TT), rs61984675(AA), rs73317739(TT), rs28666030(GG), rs28493481(TT), rs7141608(TT), rsl0150986(AA), rsl2050316(GG), rs7144432(GG), rsl2437422(AA), rs8017811(GG), rs4904454(TT), rs2033418(CC), rsl0873392(CC), rsl344747(AA), rs7146241(TT), rs930181(TT), rsl2436642(AA), and rsl 1159859(GG). In an aspect, a
Group B SNP may be found within -38874 and 165362 base pairs of SNP rs3179969 located at 88862529 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -32554 and 121144 base pairs of SNP rs3179969. In an aspect, a Group B SNP may be found within -3528 and 65270 base pairs of SNP rs3179969. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3179969.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs321224 in the NCBI db SNP Build 134 and having a genotype CC TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs321224 and having a genotype CC TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs4556171(AA GG) and rs62552362(AA GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs7850754(CC TT), rs321228(CC TT), rs72698082(CC TT), rs62547293(AA GG), rs61172105(CC GG), rsl3298189(CC GG), rsl3284524(AA GG), rsl3288861(AA GG), and rs62552370(CC TT). In an aspect, a Group B SNP may be found within -26246 and 17188 base pairs of SNP rs321224 located at 20221607 of the human genome assembly GRCh37.2 sequence on chromosome 9. In an aspect, a Group B SNP may be found within -30769 and - 1587 base pairs of SNP rs321224. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs321224.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3212435 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3212435 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs3776789(TT), rs3797500(AA), rs62357234(TT), rs2287950(AA), rs3212446(CC), rs3212465(TT), and rs3212483(TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl445942(CC), rsl445941(CC), rs2303124(AA), rsl900182(AA), and rsl7298242(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl 1741738(GG), rs77816287(AA), rs3212537(TT), rs3212556(TT), and rs3212603(TT). In an aspect, a Group B SNP may be found within -17297 and 36484 base pairs of SNP rs3212435 located at 52337326 of the human genome assembly GRCh37.2 sequence on chromosome 5. In an aspect, a Group B SNP may be found within 36762 and 54948 base pairs of SNP rs3212435. In an aspect, a Group B SNP may be found within - 8366 and 6575 base pairs of SNP rs3212435. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3212435.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3212439 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3212439 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs3212424(CC), rs3756537(GG), rsl6880669(CC),
rs3822558(GG), rs3776787(AA), rsl2657429(AA), rsl2657501(AA), rs3797498(AA), rs3797496(CC), rs3797495(CC), rs3212438(AA), rs3212441(CC), rsl363192(TT), rsl316250(TT), rs3926397(TT), rs3212457(CC), rs3212458(TT), rsl 1959632(GG), rsl421937(AA), rs56296421(AA), rsl2657972(AA), rs3212467(CC), rs3212478(AA), rs3212481(CC), and rs3212486(GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl862191(CC), rs989073(CC), rs3212461(TT), rs3212464(AA), rs3212480(GG), and rs6880055(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs67719154(CC), rsl2652168(CC), rs3212472(TT), rs3212619(GG), rs2303122(CC), rsl2521915(CC), rsl2515364(TT), and rs6898333(GG). In an aspect, a Group B SNP may be found within - 5597 and 51586 base pairs of SNP rs3212439 located at 52337783 of the human genome assembly GRCh37.2 sequence on chromosome 5. In an aspect, a Group B SNP may be found within -9383 and 51645 base pairs of SNP rs3212439. In an aspect, a Group B SNP may be found within -14330 and 6263 base pairs of SNP rs3212439. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3212439.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3212461 in the NCBI db SNP Build 134 and having a genotype GG TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3212461 and having a genotype GG TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs3212424(AA CC), rs3756537(CC TT), rsl6880669(CC GG), rs3822558(AA GG), rs3776787(CC TT), rsl2657429(AA GG), rsl2657501(AA CC), rs3797498(CC TT), rs3797496(AA CC), rs3797495(GG TT), rs3212438(AA GG), rs3212441(CC TT), rsl363192(AA CC), rsl316250(AA GG), rs3926397(GG TT), rs3212457(CC TT), rs3212458(GG TT), rsl 1959632(AA GG), rsl421937(CC TT), rs56296421(AA TT), rsl2657972(AA GG), rs3212478(AA GG), rs3212480(AA GG), rs3212481(CC TT), rs3212486(AA GG), and rs6880055(AA GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl862191(AA GG), rs67719154(CC TT), rs989073(AA CC), rsl2652168(CC TT), rs3212464(AA GG), and rs3212472(AA TT). In an aspect, a Group B SNP may be found within -12710 and 1650 base pairs of SNP rs3212461 located at 52341110 of the human genome assembly GRCh37.2 sequence on chromosome 5. In an aspect, a Group B SNP may be found within -17657 and 48318 base pairs of SNP rs3212461. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3212461.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3212464 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3212464 and having a genotype AA GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs3212424(AA CC), rs3756537(CC TT),
rsl6880669(CC GG), rs3822558(AA GG), rs3776787(CC TT), rsl2657429(AA GG), rsl2657501(AA CC), rs3797498(CC TT), rs3797496(AA CC), rs3797495(GG TT), rs3212438(AA GG), rs3212441(CC TT), rsl363192(AA CC), rsl316250(AA GG), rs3926397(GG TT), rs3212457(CC TT), rs3212458(GG TT), rsl 1959632(AA GG), rsl421937(CC TT), rs56296421(AA TT), rsl2657972(AA GG), rs3212478(AA GG), rs3212481(CC TT), and rs3212486(AA GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs67719154(CC TT), rs3212480(AA GG), and rs6880055(AA GG). In an aspect, a Group B SNP may be found within -9326 and 47916 base pairs of SNP rs3212464 located at 52341512 of the human genome assembly GRCh37.2 sequence on chromosome 5. In an aspect, a Group B SNP may be found within -18059 and 2534 base pairs of SNP rs3212464. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3212464.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3212481 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3212481 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs3212424(CC), rs3756537(CC), rsl6880669(GG),
rs3822558(GG), rs3776787(TT), rsl2657429(AA), rsl2657501(AA), rs3797498(TT), rs3797496(CC), rs3797495(GG), rs3212438(AA), rs3212441(CC), rsl363192(AA), rsl316250(AA), rs3926397(TT), rs3212457(CC), rs3212458(TT), rsl 1959632(GG), rsl421937(TT), rs56296421(AA), rsl2657972(AA), rs3212478(AA), and rs3212486(GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs3212480(GG) and rs6880055(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl862191(GG), rs67719154(CC), rs989073(CC), rsl2652168(CC), rs3212472(TT), rs3212619(GG), rs2303122(GG), rsl2521915(GG), rsl2515364(TT), and rs6898333(GG). In an aspect, a Group B SNP may be found within -15402 and 45567 base pairs of SNP rs3212481 located at 52343802 of the human genome assembly GRCh37.2 sequence on chromosome 5. In an aspect, a Group B SNP may be found within -9 and 45626 base pairs of SNP rs3212481. In an aspect, a Group B SNP may be found within -20349 and 244 base pairs of SNP rs3212481. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3212481. In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3212640 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3212640 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs990602(TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2910971(TT), rsl421931(GG), rsl421930(TT), rs2910965(TT), rs2974987(AA), rs3212522(AA), rs2897457(TT), rs3212527(AA), rsl421929(AA), rsl2517446(AA), rs2287871(TT), rs3212591(GG), and rs2303123(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2974978(TT), rs2075616(TT), rs2075617(GG),
rs2974976(AA), rsl421932(GG), rs3212533(GG), and rs 12518279(CC). In an aspect, a
Group B SNP may be found within -38881 and -12348 base pairs of SNP rs3212640 located at 52383718 of the human genome assembly GRCh37.2 sequence on chromosome 5. In an aspect, a Group B SNP may be found within -35232 and -4699 base pairs of SNP rs3212640. In an aspect, a Group B SNP may be found within 114 base pairs of SNP rs3212640. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3212640.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs359447 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs359447 and having a genotype CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs359450(AT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2914325(AG). In an aspect, a Group B SNP may be found within -1613 base pairs of SNP rs359447 located at 173271163 of the human genome assembly GRCh37.2 sequence on chromosome 5. In an aspect, a Group B SNP may be found within 1080 base pairs of SNP rs359447. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs359447. In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3733138 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3733138 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2507941(CT), rsl7814364(AG), rs78544469(CT), rs77422813(CT), rsl7228684(AG), rs75425697(AG), rsl 2054441(CT), rs74985154(AT), rs3733140(AC), rs75619156(CT), rsl7229924(AG), rs2162356(AG), rs74786716(AG), rs77820597(AG), rsl 12585731(AG), rs79149273(CT), rsl 7230261 (AG), rs2162355(GT), rs76952775(GT), rs75469174(GT), rs78210776(AG), and rs77162103(AG). In an aspect, a Group B SNP may be found within range -24652 and 19436 base pairs of SNP rs3733138 located at 37560708 of the human genome assembly GRCh37.2 sequence on chromosome 3. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3733138.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3742484 in the NCBI db SNP Build 134 and having a genotype AT TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3742484 and having a genotype AT TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs3759607(AG GG). In an aspect, a Group B SNP may be found within range -331 base pairs of SNP rs3742484 located at 23566474 of the human genome assembly GRCh37.2 sequence on chromosome 14. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3742484.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3742486 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3742486 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1, including a Group B SNP selected from the group consisting of rs3794456(AC), rs74842241(CG), rs2236137(GT),
rs79721426(AG), rsl 17069221(CT), rsl7126531(CG), rs74521162(CG), rs74701584(CT), and rs2236136(CG). In an aspect, a Group B SNP may be found within range -22577 and 3395 base pairs of SNP rs3742486 located at 23568376 of the human genome assembly GRCh37.2 sequence on chromosome 14. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3742486.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3746766 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3746766 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs6011445(TT), rsl056984(CC), rs6011447(TT),
rs3746765(TT), rs2273083(TT), rs6010778(CC), rs7265084(AA), rs2294998(TT), and rs6512324(AA). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs6011442(GG), rs3746772(GG), rs6512322(GG), and rs6090154(GG). In an aspect, a Group B SNP may be found within -4639 and 4822 base pairs of SNP rs3746766 located at 61519988 of the human genome assembly GRCh37.2 sequence on chromosome 20. In an aspect, a Group B SNP may be found within -6118 and 4551 base pairs of SNP rs3746766. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3746766.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3751501 in the NCBI db SNP Build 134 and having a genotype AA AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3751501 and having a genotype AA AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs3794456(AA AC), rs2236137(GG GT),
rs3742486(AA AG), and rs2236136(CG GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs74842241(CG GG), rs79721426(AG GG), rs 117069221(CC CT), rsl7126531(CC CG), rs74521162(CC CG), and rs74701584(CC CT). In an aspect, a Group B SNP may be found within 5496 and 20480 base pairs of SNP rs3751501 located at 23549285 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -3486 and 22486 base pairs of SNP rs3751501. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3751501. In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3768777 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3768777 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs3911239(TT) and rsl0174098(AA). In an aspect, a Group B SNP may be found within range 14190 and 36621 base pairs of SNP rs3768777 located at 187456121 of the human genome assembly GRCh37.2 sequence on chromosome 2. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3768777.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3783889 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3783889 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2297129(TT), rs61542857(AA), rs7141363(AA), rs2274736(TT), rs28482235(TT), rsl0132554(CC), rs2401751(CC), rs28711639(CC), rs8017689(TT), rsl864744(GG), rs28371093(AA), rs7142053(AA), and rs4904452(AA). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs376698(GG), rs453112(GG), rsl627444(GG), rs845757(AA),
rs7161660(GG), rs879932(TT), rs816072(GG), rsl0150594(AA), rs79681439(AA), rsl l52376(TT), rsl 152377(AA), rs7160717(TT), rs816069(TT), rsl 1845147(GG), rs2778936(AA), rs7160471(CC), rs9323830(GG), rs7160647(CC), rs7143642(AA), rsl0143744(TT), rsl999177(AA), rsl999176(AA), rsl864746(AA), rsl864747(AA), rs7151164(CC), rsl2433026(GG), rsl0138139(CC), rsl0138002(CC), rsl0150311(TT), rsl0138309(CC), rsl l847417(CC), rs3783885(GG), rsl l l59857(CC), rs4390529(AA), rs4301952(GG), rs4594187(CC), rs4514599(TT), rs61975276(AA), rs61975277(TT), rs61975278(CC), rs61984675(GG), rs73317739(CC), rs28493481(GG), rs7141608(TT), rsl0150986(GG), rsl2437422(GG), rs8017811(AA), rs4904454(GG), rs2033418(CC), rsl0873392(TT), rs7146241(CC), and rs930181(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl955598(AA), rsl2586714(CC), rsl028455(AA), rsl950280(CC), rs865285(TT), rs449338(CC), rsl099698(TT), rs845758(CC), rs845769(CC), rsl288122(TT), rs2274735(AA),
rsl346996(CC), rs4516145(CC), rs28666030(AA), rsl2050316(GG), rs4899955(AA), and rsl 1629164(AA). In an aspect, a Group B SNP may be found within -118326 and 89103 base pairs of SNP rs3783889 located at 88941981 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -83751 and 76727 base pairs of SNP rs3783889. In an aspect, a Group B SNP may be found within - 6056 and 41692 base pairs of SNP rs3783889. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3783889.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3813026 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3813026 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1, including a Group B SNP selected from the group consisting of rs34712518(CC) and rs3813027(GG). In an aspect, a Group B SNP may be found within range -2497 and -65 base pairs of SNP rs3813026 located at 76123528 of the human genome assembly GRCh37.2 sequence on chromosome 17. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3813026.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3814855 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3814855 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs79579293(GG), rs60310240(CC), rsl7772064(TT), rsl7698817(CC), rsl2589467(CC), rsl2433464(GG), rs56987357(AA), rsl955599(TT), rsl955600(AA), rsl7772222(GG), rs7145588(AA), rs61977049(CC), rsl7772288(AA), rsl2587386(TT), rs55722539(AA), rsl2589480(TT), rs61977058(CC), rs74071851(AA), rsl l l59856(GG), rsl7124652(GG), rs2295135(GG), and rsl7124700(TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs77382318(GG), rs61977053(AA), rs61579615(TT), rs60213984(AA), rs61975260(CC), rs2297128(CC), rs74074098(GG), rsl864748(CC), rs77306894(GG), rs59136503(AA), rsl998670(TT), rsl816372(GG), rs60878614(GG), rsl0143767(CC), rs76559451(CC), rsl l23421(GG), rs2004329(CC), rsl2436326(TT), rsl7203789(TT), rsl7798341(CC), rsl0134008(TT), rs891750(AA), rs891749(TT), rs61984683(CC), rs61984684(CC), rs61984708(CC), rs4635267(TT), rsl7188046(TT), rs61984736(CC), rs8006652(TT), rsl2587200(GG), rsl2431548(TT), rs61984737(AA), rsl2586348(GG), rsl2434935(TT), rsl 7260380(TT), rs58984912(AA), rsl7188207(GG), rs61986664(AA), rs8018755(TT), rs8020072(CC), rsl7260408(GG), rsl2589982(GG), rs8021690(CC), rs61986669(AA), rs61986670(AA), rs61986671(GG), rsl 7260415(GG), rsl956406(CC), rs61983300(GG), rsl 1159868(CC), rs7157149(CC), rs2224333(TT), rsl2590826(GG), rs57889459(TT), rs58550317(CC), rs61982733(TT), rs2145120(AA), and rsl2588535(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs4375590(GG), rsl0139921(AA), rsl2587528(GG), rs2274735(GG), rs56144430(AA), rs57118463(CC), rs61984746(TT), rs61986665(CC), rsl2587598(CC), rs78077739(TT), rs58655091(AA), rs78068036(CC), and rs61983303(CC). In an aspect, a Group B SNP may be found within -15682 and 297443 base pairs of SNP rs3814855 located at 88933360 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -111231 and 314884 base pairs of SNP rs3814855. In an aspect, a Group B SNP may be found within -111292 and -27731 base pairs of SNP rs3814855. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3814855.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3816253 in the NCBI db SNP Build 134 and having a genotype CC CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3816253 and having a genotype CC CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 982241(CC CT) and rs2304825(CT TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9 selected from the group consisting ofrsl l629561(GG GT), rsl 1631100(AA AG), rs2044098(GT TT), rsl2904700(AG GG), rs2868607(AA AG), rsl2911405(AC CC), rsl2910386(AA AC), and rsl2915634(AA AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl2903696(CC CT), rsl 1855354(AA AG), rsl 1630776(CG GG), rsl2438666(CC CT), rs8032618(CT TT), rs 12912695 (AA AG), rsl 1638547(GT TT), rsl2915990(CG GG), and rs8035724(AA AG). In an aspect, a Group B SNP may be found within -19467 and 12057 base pairs of SNP rs3816253 located at 78458485 of the human genome assembly GRCh37.2 sequence on chromosome 15. In an aspect, a Group B SNP may be found within -20363 and 14824 base pairs of SNP rs3816253. In an aspect, a Group B SNP may be found within -5763 and 312 base pairs of SNP rs3816253. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3816253.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3847794 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3847794 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs4761583(CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs55890603(AT). In an aspect, a Group B SNP may be found within -5132 base pairs of SNP rs3847794 located at 94528825 of the human genome assembly GRCh37.2 sequence on chromosome 12. In an aspect, a Group B SNP may be found within -6988 base pairs of SNP rs3847794. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3847794.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3848668 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3848668 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 17232954(CT), rs6010995(GT), rs73920920(CT), rs75526725(AG), rsl2480249(AG), rsl2481716(CT), rs6010612(CT), rs79979881(CT), rs77221632(GT), rs6010999(AG), rsl2480034(AT), rsl2480876(CG), rs75671088(CT), rs73920928(CG), rs73920931(AG), rs73920933(AG), rsl2481186(AG), rs79391682(AG), rs6011002(AG), rs6011011(CT), rs6010614(CG), rs6011014(CT), rs75897888(CG), rs56010802(CG), rs75451331(GT), and rs76364377(AG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs6010985(CG), rsl 17314802(AG), rs41309933(AG), and rs75123278(AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs6010987(AG), rs6010988(AG), rs6010991(CT), rsl l7038333(AG), rs73920935(CT), rs76832249(AG), rsl 16668146(AG), rs2738787(AG), rs 1291211 (AG), rs2261092(AG), rs6010634(d), rs6011068(AT), rsl 151625(CT), and rs2427536(AG). In an aspect, a Group B SNP may be found within -15597 and 79541 base pairs of SNP rs3848668 located at 62293272 of the human genome assembly GRCh37.2 sequence on chromosome 20. In an aspect, a Group B SNP may be found within -17780 and 19259 base pairs of SNP rs3848668. In an aspect, a Group B SNP may be found within -4455 and 26012 base pairs of SNP rs3848668. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3848668.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3917019 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3917019 and having a genotype AA. In another aspect, a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rs3917018(AA), rs3181092(AA), and rsl2129732(TT). In an aspect, a Group B SNP may be found within -132 and 7299 base pairs of SNP rs3917019 located at 101202354 of the human genome assembly GRCh37.2 sequence on chromosome 1. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3917019.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs3963484 in the NCBI db SNP Build 134 and having a genotype AA AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs3963484 and having a genotype AA AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs9937198(AA AG), rs34164999(AG GG),
rs2131226(CT TT), rs2172310(AG GG), and rsl 1862011(GT TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs28733360(CT TT) and rs7186895(AG GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl0153149(AC CC). In an aspect, a Group B SNP may be found within -5774 base pairs of SNP rs3963484 located at 6931014 of the human genome assembly GRCh37.2 sequence on chromosome 16. In an aspect, a Group B SNP may be found within -23807 and -201 base pairs of SNP rs3963484. In an aspect, a Group B SNP may be found within -6727 and -2613 base pairs of SNP rs3963484. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs3963484.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs397250 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs397250 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl2291809(TT), rsl0770057(TT), rsl 1042476(CC), rsl2805683(AA), rsl2789209(GG), rsl2283521(AA), rsl2801958(CC), rsl2803440(GG), rs34043654(CC), rsl l042480(GG), rsl0840290(GG), rsl2272045(AA), rsl 2272107(TT), rsl2280320(CC), rsl 0840291(GG), rsl0840292(CC), rs7935643(CC), rs7938818(CC), rs7949818(TT), rs2572944(AA), rsl 1042481(CC), rsl 1042482(GG), rsl 1042483(GG), rs2252354(GG), rs2336805(CC), rs2645025(TT), rs2572935(GG), rs4910060(GG), rs2572934(TT), rs4910492(CC), rs4910493(TT), rsl390684(TT), rsl390683(TT), rsl390682(CC), rsl390681(AA), rs2132567(AA), rsl390679(GG), rsl435462(GG), rs920082(TT), rsl874476(TT), rs4910496(CC), rs4910497(TT), rs397602(GG), rs408569(CC),
rsl2421878(TT), rs2649048(TT), rsl2786236(CC), rs581004(GG), rs422061(TT), rs2649046(GG), rs447601(AA), rs534901(CC), rs449005(GG), rs446146(CC),
rs418931(TT), rs399898(AA), rs431908(CC), rs442722(GG), rs424455(TT), rs416804(TT), rs435079(CC), rs440523(AA), and rs389534(CC). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs34063054(TT), rs892856(AA), rs2572942(CC), rsl2272277(TT), rs60466677(CC), rs67867011(CC), rs4910491(TT), rs920080(AA), rs4910495(TT), rs414109(GG), rs429546(CC),
rs443576(AA), rs368731(CC), rs419412(GG), rsl695613(AA), rsl 960386(GG),
rsl 960387(GG), rs4478983(CC), rs2645007(CC), rs2645008(TT), rs2645010(AA), rs2645011(TT), rs2645012(TT), rs2453831(CC), rs2453832(TT), rs452169(GG),
rs385846(AA), rs397686(CC), and rsl 1042486(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl0770056(GG), rs4993191(TT), rs892855(AA), rs2010535(GG), rs892853(AA), rs892852(TT), rs892851(TT),
rsl2794270(CC), rsl2789429(GG), rsl 1604967(TT), rs2252446(GG), rs392815(CC), rs428747(AA), rs2454612(AA), and rs369737(GG). In an aspect, a Group B SNP may be found within -19250 and 12921 base pairs of SNP rs397250 located at 9737574 of the human genome assembly GRCh37.2 sequence on chromosome 11. In an aspect, a Group B SNP may be found within -20491 and 12706 base pairs of SNP rs397250. In an aspect, a Group B SNP may be found within -16521 and 8262 base pairs of SNP rs397250. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs397250.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs397686 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs397686 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs443576(AA), rs368731(CC), rs389534(CC), rs419412(GG), rsl695613(AA), rsl 960387(GG), rs4478983(CC), rs2645008(TT), rs2645011(TT), rs2645012(TT), rs2453831(CC), rs452169(GG), rs385846(AA), and rsl 1042486(TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs34063054(TT), rsl2291809(TT), rsl0770057(TT), rsl 1042476(CC), rsl2805683(AA), rsl2789209(GG), rsl2283521(AA), rsl2801958(CC), rsl2803440(GG), rs34043654(CC), rsl 1042480(GG), rsl0840290(GG), rsl2272045(AA), rsl 2272107(TT), rsl2280320(CC), rsl2272277(TT), rsl 0840291(GG), rsl0840292(CC), rs7935643(CC), rs7938818(CC), rs7949818(TT), rs2572944(AA), rs60466677(CC), rs67867011(CC), rsl 1042481(CC), rsl 1042482(GG), rsl 1042483 (GG), rs2252354(GG), rs2336805(CC), rs2645025(TT), rs2572935(GG), rs4910060(GG), rs4910491(TT), rs2572934(TT), rs4910492(CC), rs4910493(TT), rsl390684(TT), rsl390683(TT), rsl390682(CC), rsl390681(AA), rs2132567(AA), rsl390679(GG), rsl435462(GG), rs920082(TT), rs920080(AA), rsl874476(TT), rs4910495(TT), rs4910496(CC), rs4910497(TT), rs397602(GG), rs408569(CC), rsl2421878(TT), rs2649048(TT), rsl2786236(CC), rs581004(GG), rs422061(TT), rs2649046(GG), rs447601(AA), rs534901(CC),
rs449005(GG), rs446146(CC), rs418931(TT), rs399898(AA), rs414109(GG), rs429546(CC), rs431908(CC), rs442722(GG), rs424455(TT), rs416804(TT), rs435079(CC), rs440523(AA), rsl960386(GG), rs2645007(CC), rs2645010(AA), rs2453832(TT), and rs2454612(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl0770056(GG), rs4993191(TT), rs892856(AA), rs892855(AA),
rs2010535(GG), rs892853(AA), rs892852(TT), rs892851(TT), rsl2794270(CC),
rsl2789429(GG), rs2572942(CC), rsl 1604967(TT), rs392815(CC), rs428747(AA), and rs369737(GG). In an aspect, a Group B SNP may be found within -31321 and 850 base pairs of SNP rs397686 located at 9749645 of the human genome assembly GRCh37.2 sequence on chromosome 11. In an aspect, a Group B SNP may be found within -32562 and -1021 base pairs of SNP rs397686. In an aspect, a Group B SNP may be found within -4258 and 635 base pairs of SNP rs397686. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs397686.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4140512 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4140512 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs5995886(GG), rs6001990(AA), rs7284768(TT),
rsl2158399(GG), rs55775429(AA), rs55746155(AA), rs56203629(AA), rsl7002067(GG), rs733999(GG), rsl7002069(CC), rs6002000(GG), rs5995890(CC), rs73171013(GG), and rs8142396(TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl2627881(CC), rs7292804(GG), rs7293100(GG),
rs56169543(GG), rs7284506(CC), and rs73171017(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs73171007(AA), rs8141330(AA), and rs74593046(CC). In an aspect, a Group B SNP may be found within 16238 and 19931 base pairs of SNP rs4140512 located at 41032863 of the human genome assembly GRCh37.2 sequence on chromosome 22. In an aspect, a Group B SNP may be found within 11730 and 27990 base pairs of SNP rs4140512. In an aspect, a Group B SNP may be found within 938 and 19893 base pairs of SNP rs4140512. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4140512. In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4149338 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4149338 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs4149339(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs 10820731(GG). In an aspect, a Group B SNP may be found within -5094 base pairs of SNP rs4149338 located at 107545903 of the human genome assembly GRCh37.2 sequence on chromosome 9. In an aspect, a Group B SNP may be found within -747 base pairs of SNP rs4149338. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4149338.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4237265 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4237265 and having a genotype CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2993776(AG), rs2993777(CG), rs2993778(AG),
rs2991752(CT), rs2991753(CT), rsl 1143923(GT), rs7871229(GT), and rs7858944(CT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs62550363(CT) and rs4745315(CG). In an aspect, a Group B SNP may be found within -7674 and 947 base pairs of SNP rs4237265 located at 76944002 of the human genome assembly GRCh37.2 sequence on chromosome 9. In an aspect, a Group B SNP may be found within -7675 and -1505 base pairs of SNP rs4237265. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4237265.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs426357 in the NCBI db SNP Build 134 located at 17356447 of the human genome assembly GRCh37.2 sequence on chromosome 10 and having a genotype AG.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4267943 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4267943 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs9473549(AA), rs9463473(GG), rs9463474(GG),
rs9463475(CC), rsl2196937(GG), rs9463476(GG), rs60982898(TT), rs9463477(GG), rs9473551(TT), rs9473552(CC), rs9463479(GG), rs9473553(TT), rsl0456622(GG), rs9463480(TT), rs9473555(CC), rs6458690(GG), rsl 141321(AA), rs9296616(GG), rs4715129(TT), rs4715130(CC), rs6923124(GG), rsl2202075(GG), rs9473560(GG), rs9296617(CC), rs9473561(AA), rs7750918(GG), rs3806988(GG), rs3823114(AA), rs4469291(AA), rs6458694(CC), rs2448707(AA), rs2501962(AA), rs9473563(AA), and rs2501963(CC). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs62411911(GG), rsl 13952954(GG), rs9473541(AA), rs73425947(TT), rsl924999(TT), rs2477402(CC), rs2182012(AA), rs2182013(TT), rs2493439(AA), rs2147570(GG), rs2493440(AA), rs2501977(TT), rs2477405(CC), rs2477406(GG), rs2501979(CC), rs9473547(AA), rs2501980(CC), rs4573082(GG), rs9473557(CC), rs9463483(TT), rs7744595(GG), rs6458693(GG), rs7769646(AA), rs3729619(TT), and rs4348317(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs77608740(TT), rs9473566(CC),
rs6901278(GG), rs60944851(AA), and rs3997172(TT). In an aspect, a Group B SNP may be found within -91511 and 33101 base pairs of SNP rs4267943 located at 49439805 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within -91793 and 558 base pairs of SNP rs4267943. In an aspect, a Group B SNP may be found within -59785 and 14476 base pairs of SNP rs4267943. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4267943.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4322073 in the NCBI db SNP Build 134 and having a genotype CC TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4322073 and having a genotype CC TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs7045775(CC TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl0780954(CC TT), rsl l l42517(CC TT), rs7868028(AA CC), rsl0868862(CC GG) ,and rsl538670(AA CC). In an aspect, a Group B SNP may be found within -2367 base pairs of SNP rs4322073 located at 73250037 of the human genome assembly GRCh37.2 sequence on chromosome 9. In an aspect, a Group B SNP may be found within -10340 and 5300 base pairs of SNP rs4322073. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4322073.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4331850 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4331850 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs4532319(GG). In an aspect, a Group B SNP may be found within range -337 base pairs of SNP rs4331850 located at 65923124 of the human genome assembly GRCh37.2 sequence on chromosome 5. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4331850.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4354185 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4354185 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs4317449(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs4374858(CC) and rs9320321(GG). In an aspect, a Group B SNP may be found within -6220 and -5206 base pairs of SNP rs4354185 located at 110301661 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within 284 base pairs of SNP rs4354185. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4354185.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4369611 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4369611 and having a genotype AA GG. In another aspect, a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rs920808(AA CC), rs2291848(GG TT), rs2291849(AA CC), rs4578600(AA TT), rs9920863(GG TT), rsl2915516(AA GG), rs7172899(CC TT), rs7171531(AA GG), rs4924005(CC TT), and rs6495794(AA GG). In an aspect, a Group B SNP may be found within -3981 and 23730 base pairs of SNP rs4369611 located at 35957584 of the human genome assembly GRCh37.2 sequence on chromosome 15. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4369611.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4371530 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4371530 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl0804855(TT) and rs6795495(TT). In an aspect, a Group B SNP may be found within range 1083 and 1637 base pairs of SNP rs4371530 located at 174951756 of the human genome assembly GRCh37.2 sequence on chromosome 3. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4371530.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4525972 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4525972 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl2506726(CT), rsl 1731245(GT), rs6857741(AT),
rs4622996(AT), rs4697122(AG), rs6857685(AC), rs35004028(AG), rsl 2649775 (AG), rs35809778(CG), rsl0938755(AG), rs4575991(AG), rs4235335(CG), rs4541505(CT), rs4364261(CT), rs68073340(GT), rs60556022(AT), rsl 2646133(AT), rs58237602(GT), rs55986638(AG), rs7670740(CT), rs6835841(GT), rs6830756(CG), rs4074177(GT), rs4697642(GT), rs6827013(AG), rs6834121(AG), and rs6819747(AG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2927522(AG), rsl 027214(AC), rsl490867(AG), rs6846810(AG), rsl532169(AT), rs6846990(GT), rsl2512140(AG), rs7690452(CT), rsl6898235(CG), rsl490882(AG), rs58232663(AG), rs60274101(CT), rs7686440(AG), rs968264(CT), rs6858545(AG), rs4697123(GT), rs7676057(AG), rs4447857(AG), rsl0938758(CT), rsl2646839(CT), rs59459737(AG), rsl2509098(AC), rs62298771(AG), and rsl0938765(CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl3107399(AG) and rsl542739(AC). In an aspect, a Group B SNP may be found within - 171300 and -91566 base pairs of SNP rs4525972 located at 19492256 of the human genome assembly GRCh37.2 sequence on chromosome 4. In an aspect, a Group B SNP may be found within -181904 and 52212 base pairs of SNP rs4525972. In an aspect, a Group B SNP may be found within -81061 and 39052 base pairs of SNP rs4525972. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4525972.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4553010 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4553010 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs4837484(CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2417163(CT). In an aspect, a Group B SNP may be found within 2408 base pairs of SNP rs4553010 located at 133011232 of the human genome assembly GRCh37.2 sequence on chromosome 9. In an aspect, a Group B SNP may be found within -1165 base pairs of SNP rs4553010. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4553010.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4595752 in the NCBI db SNP Build 134 located at 27701578 of the human genome assembly GRCh37.2 sequence on chromosome 15 and having a genotype GT.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4608848 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4608848 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl519312(GG). In an aspect, a Group B SNP may be found within range -1260 base pairs of SNP rs4608848 located at 187010104 of the human genome assembly GRCh37.2 sequence on chromosome 4. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4608848.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4715631 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4715631 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1, including a Group B SNP selected from the group consisting of rsl6887974(TT), rsl 1756977(TT), rs2064591(AA), and rs9396220(TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs9296849(CC), rs4236139(CC), rs4454141(TT),
rs4715626(GG), rs9475713(TT), rs4715627(GG), rs9475714(GG), rs6919608(TT), rs4472350(GG), rs4715629(CC), and rs4712133(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs6459161(TT), rs2273973(TT), rsl 1753813(TT), rs9382635(CC), rs721475(AA), rsl535612(AA), rs45486696(GG), rsl535610(GG), rs6904202(TT), rs4544910(GG), rs9475709(TT), rs7743011(TT), rs4130060(GG), rs4236140(TT), rs9349826(CC), rs4329120(CC), rs9367687(GG), rs9367688(CC), rs9357921(GG), rs7774262(AA), rs4499917(AA), rs4346846(CC), rs4143827(CC), rs7741295(TT), rs4715628(TT), rs7762629(AA), rs9357922(TT), rs6939305(CC), rs7758054(AA), rs6907917(TT), rs6906792(TT), rs9296850(TT), rs4236141(TT), rs6914184(GG), rs7761281(CC), rs7759875(CC), rs7760640(GG), rs6922770(CC), and rsl3219448(CC). In an aspect, a Group B SNP may be found within -90780 and 3841 base pairs of SNP rs4715631 located at 56417545 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within -42791 and -3149 base pairs of SNP rs4715631. In an aspect, a Group B SNP may be found within 1832 and 5316 base pairs of SNP rs4715631. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4715631.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs471814 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs471814 and having a genotype AA. In another aspect, a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rs880004(AA). In an aspect, a Group B SNP may be found within 14447 base pairs of SNP rs471814 located at 119794509 of the human genome assembly GRCh37.2 sequence on chromosome 11. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs471814.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4729408 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4729408 and having a genotype CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 1768678(AG), rsl 1761896(CT), rsl 1772060(GT), rsl 1773169(AG), rsl 1762771 (AG), and rsl039057(GT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl 1769855(CG), rs56134009(GT), rs740208(CT), rsl 1762810(CT), rs62479768(CT), rs56006208(AT), rs55765204(CT), rs55761857(AG), rs4729404(CG), rs62479797(CG), rs56088922(AG), rs58911561(CT), and rsl532380(CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs56174823(CT), rs62479773(CT),
rs56389625(CG), rsl7169325(CT), rs884897(AG), and rs56034325(CT). In an aspect, a Group B SNP may be found within -47461 and 68660 base pairs of SNP rs4729408 located at 97772658 of the human genome assembly GRCh37.2 sequence on chromosome 7. In an aspect, a Group B SNP may be found within -75213 and 63227 base pairs of SNP rs4729408. In an aspect, a Group B SNP may be found within -26271 and 20551 base pairs of SNP rs4729408. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4729408.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4757548 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4757548 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs7104990(TT), rs4756901(AA), rs4756902(AA), rsl 6934410(GG), rs7117283(CC), rs7127834(AA), and rs2355466(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl0832802(TT), rs2240490(GG), rs2240491(CC), rs7106548(CC), rs4562808(TT), rsl076312(TT), rs757986(TT), rs757987(CC), rsl0832804(CC), rs6486380(AA), rs2355467(AA), rs7122124(TT), and rs7105953(CC). In an aspect, a Group B SNP may be found within -4352 and 5055 base pairs of SNP rs4757548 located at 17596313 of the human genome assembly GRCh37.2 sequence on chromosome 11. In an aspect, a Group B SNP may be found within 1509 and 3720 base pairs of SNP rs4757548. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4757548.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4777049 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4777049 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs62001430(TT), rs7173365(AA), rs2415001(AA), and rsl 115528(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs7161791(TT), rs2415002(AA), and rsl2591421(GG). In an aspect, a Group B SNP may be found within - 11873 and -3751 base pairs of SNP rs4777049 located at 68695448 of the human genome assembly GRCh37.2 sequence on chromosome 15. In an aspect, a Group B SNP may be found within -12836 and -7051 base pairs of SNP rs4777049. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4777049.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4876024 in the NCBI db SNP Build 134 located at 2511536 of the human genome assembly GRCh37.2 sequence on chromosome 8 and having a genotype CT.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4936280 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4936280 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs4938033(GG), rsl533053(CC), rs7110736(AA),
rs7114195(AA), rsl567391(CC), rs3802856(TT), rs7926267(AA), rs3851571(AA), rsl0891590(TT), rs 10891591(AA), rs4938051(GG), rs6589395(CC), rs7126671(CC), rsl0750028(CC), rs4351850(AA), and rs2465651(TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs4938029(TT), rsl0891577(TT), rsl 108885(GG), rsl0891578(TT), rs34234382(TT), rsl 1214692(GG), rsl2802646(AA), rs7110738(AA), and rs2511052(CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs7940560(CC), rs2457377(CC), rs2459970(CC), rs2459976(AA), rsl467057(CC), and rs2465648(TT). In an aspect, a Group B SNP may be found within -7800 and 81392 base pairs of SNP rs4936280 located at 113570405 of the human genome assembly GRCh37.2 sequence on chromosome 11. In an aspect, a Group B SNP may be found within -52583 and 50389 base pairs of SNP rs4936280. In an aspect, a Group B SNP may be found within -26292 and 46475 base pairs of SNP rs4936280. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4936280. In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4941183 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4941183 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl2457841(AA), rsl 1872403(GG), rs4987831(TT), and rsl542578(AA). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs4456611(CC), rs3943258(TT), rsl2964150(CC), and rsl 1876772(GG). In an aspect, a Group B SNP may be found within 313 and 11984 base pairs of SNP rs4941183 located at 60802931 of the human genome assembly GRCh37.2 sequence on chromosome 18. In an aspect, a Group B SNP may be found within 7521 and 14775 base pairs of SNP rs4941183. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4941183. In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4952903 in the NCBI db SNP Build 134 and having a genotype GT TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4952903 and having a genotype GT TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs6750131(CT TT), rs4953544(GT TT), rs956488(AA AG), rs6545013(AA AG), rs7580982(CT TT), rs6750246(CG GG), rs4953546(AT TT), rsl825320(AG GG), rs968888(CC CT), rsl878081(CT TT), rs6706664(CG GG), rsl878079(CT TT), rs900511(AG GG), rs 10167776(AA AG), rs900510(AA AG), rs963135(AA AG), rs963133(AT TT), rsl7324704(CC CG), rs7563749(AA AC), rsl483210(CT TT), rs6545019(AA AG), rsl483215(CC CG), rsl473611(AT TT), rs6759902(CG GG), rs6705926(CC CT), and rsl905306(GT TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs4953534(AG GG), rsl601064(AG GG), rsl l l7823(AA AT), rsl0180823(AA AG), rs976416(AA AG), rs999036(AG GG), rs900509(AC CC), rs900508(AG GG), rs7570621(CT TT),
rsl 1125157(AA AT), rs4146019(GT TT), rsl 1125159(CC CG), rs4953539(GG GT), rsl2469627(AC CC), rs4953540(AG GG), rs6545011(GG GT), rsl0203759(CC CT), rsl l l9025(AT TT), rs6735073(CC CT), rs2881938(CC CT), rs4392309(CC CT), rsl471680(AA AT), rs2128718(AA AC), rs2128717(AA AG), rs7609066(CT TT), rs4146021(AC CC), rs2128716(CC CG), rs28460586(CT TT), rs6545017(GG GT), rs4952904(AG GG), rs7609124(AA AG), rs2348717(AA AG), rs2348718(AA AG), rs922902(CC CG), rs990549(AA AC), rs990063(CT TT), rs2882003(CC CT), rs4953555(CC CT), rsl 1125165(AA AG), rs4146603(CT TT), and rs4953557(AA AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs4953536(AG GG), rsl l l25158(CG GG), rs6545010(CC CT), rs60379088(CT TT), rs4953543(CT TT), rsl471681(AA AT), rs6712238(AA AC), rs4952905(AA AG), rs2136456(CC CG), rs58178746(CT TT), and rs973894(CC CG). In an aspect, a Group B SNP may be found within -40688 and 149192 base pairs of SNP rs4952903 located at 48254907 of the human genome assembly GRCh37.2 sequence on chromosome 2. In an aspect, a Group B SNP may be found within -43188 and 146800 base pairs of SNP rs4952903. In an aspect, a Group B SNP may be found within -16966 and 73258 base pairs of SNP rs4952903. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4952903.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4975300 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4975300 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl2510308(TT), rsl948506(TT), and rs4975299(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl 1098951(AA), rs6534675(TT), rs6816625(GG), and rsl0002814(TT). In an aspect, a Group B SNP may be found within -12401 and 2217 base pairs of SNP rs4975300 located at 129160316 of the human genome assembly GRCh37.2 sequence on chromosome 4. In an aspect, a Group B SNP may be found within -10436 and -341 base pairs of SNP rs4975300. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4975300.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs4987821 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs4987821 and having a genotype CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl7677569(CG), rs72941346(AG), rs4987830(CT),
rs56313983(CT), rs72941359(GT), rs4987825(GT), and rsl 7678177(CG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs72941348(CT), and rs72941370(AC). In an aspect, a Group B SNP may be found within - 14605 and 4664 base pairs of SNP rs4987821 located at 60813215 of the human genome assembly GRCh37.2 sequence on chromosome 18. In an aspect, a Group B SNP may be found within -8115 and 3805 base pairs of SNP rs4987821. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs4987821.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs530461 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs530461 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs6012752(CT), rs6012753(AT), rs6020072(AG), rs2149278(AG), rs6020073(CT), rs6095681(AT), rs967305(CG), rs599195(AT), rs595027(GT),
rs537672(AT), rs596195(CT), rs595777(CG), rs686996(CG), rs527892(GT), rs671130(AG), rs627898(AC), rs568124(CT), rs633829(AG), rs483508(CT), and rs536092(CT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs6012750(AG), rs6020074(CT), rs6020075(AG), rs6122835(CT),
rs2025958(AG), rs2982414(AG), and rs648095(AG). In an aspect, a Group B SNP may be found within -33552 and 33635 base pairs of SNP rs530461 located at 48467716 of the human genome assembly GRCh37.2 sequence on chromosome 20. In an aspect, a Group B SNP may be found within -37036 and 26462 base pairs of SNP rs530461. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs530461.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs5847 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs5847 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2234412(AA) and rs2848632(CC). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2848623(AA), rs2729361(AA), and rs2729360(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2649660(AA), rs2649661(GG), and rs2729372(GG). In an aspect, a Group B SNP may be found within -17761 and 4554 base pairs of SNP rs5847 located at 57319339 of the human genome assembly GRCh37.2 sequence on chromosome 11. In an aspect, a Group B SNP may be found within 5041 and 25422 base pairs of SNP rs5847. In an aspect, a Group B SNP may be found within 705 and 34158 base pairs of SNP rs5847. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs5847. In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs589258 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs589258 and having a genotype CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs685049(AT), rs588792(CG), rs497836(GT), rs497636(CT),
rs494817(AG), rs591981(CG), rs603741(CG), rs605033(AG), rs543744(GT), and
rs541134(GT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs622908(CT), rs504825(AG), rs502029(CT), rs637086(CG), rs475933(CT), rs638325(AT), rs618895(AG), rsl0129085(CT), rs9589922(CT),
rsl7196050(AG), and rsl6949545(CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl0161943(CT), rs 1328821 (AG), rsl328822(CG), rsl328823(CG), and rs61570339(CT). In an aspect, a Group B SNP may be found within -169 and 8263 base pairs of SNP rs589258 located at 94807356 of the human genome assembly GRCh37.2 sequence on chromosome 13. In an aspect, a Group B SNP may be found within -3711 and 16790 base pairs of SNP rs589258. In an aspect, a Group B SNP may be found within -403 and 1521 base pairs of SNP rs589258. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs589258.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6012750 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6012750 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs6012752(CT), rs6012753(AT), rs6020072(AG),
rs2149278(AG), rs6020073(CT), rs6095681(AT), rs967305(CG), rs2982414(AG), rs599195(AT), rs595027(GT), rs537672(AT), rs596195(CT), rs595777(CG), rs686996(CG), rs527892(GT), rs671130(AG), rs627898(AC), rs568124(CT), rs633829(AG), rs483508(CT), and rs536092(CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs6020074(CT), rs6020075(AG), rs6122835(CT), rs2025958(AG), and rs648095(AG). In an aspect, a Group B SNP may be found within 17979 and 63498 base pairs of SNP rs6012750 located at 48430680 of the human genome assembly GRCh37.2 sequence on chromosome 20. In an aspect, a Group B SNP may be found within 3484 and 70671 base pairs of SNP rs6012750. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs6012750.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs611003 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs611003 and having a genotype AA. In another aspect, a Group B SNP may include a
Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rsl982774(GG) and rs592483(TT). In an aspect, a Group B SNP may be found within -2321 and - 111 base pairs of SNP rs611003 located at 69445284 of the human genome assembly GRCh37.2 sequence on chromosome 11. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs611003.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6119410 in the NCBI db SNP Build 134 located at 32442607 of the human genome assembly GRCh37.2 sequence on chromosome 20 and having a genotype CT.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs61977053 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs61977053 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs79579293(GG), rs77382318(GG), rs60310240(CC), rsl7772064(TT), rsl 7698817(GG), rsl2589467(CC), rsl2433464(GG), rs56987357(AA), rsl955599(TT), rsl955600(AA), rsl7772222(GG), rs7145588(AA), rs61977049(CC), rsl7772288(AA), rsl2587386(AA), rs55722539(AA), rsl2589480(TT), rs61977058(CC), rs74071851(AA), rsl 1159856(GG), rs2295135(GG), and rsl7124700(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs61579615(TT), rs60213984(AA), rsl7124652(GG), rs61975260(CC), rs4375590(GG), rs2297128(CC), rs74074098(GG), rs77306894(GG), rs59136503(AA), rsl998670(TT), rsl816372(GG), rs60878614(GG), rsl0143767(CC), rs76559451(CC), rsl 123421(GG), rs2004329(GG), rsl2436326(TT), rsl7203789(TT), rsl 7798341(CC), rsl0134008(TT), rs891750(TT), rs891749(AA), rs61984683(CC), rs61984684(CC), rs61984708(CC), rs4635267(TT), rsl7188046(AA), rs61984736(CC), rs8006652(TT), rsl2587200(CC), rsl2431548(TT), rs61984737(AA), rsl2434935(TT), rsl 7260380(TT), rs58984912(AA), rsl7188207(GG), rs61986664(AA), rs61986665(CC), rs8018755(TT), rs8020072(CC), rsl7260408(GG), rsl2589982(GG), rs8021690(CC), rs61986669(AA), rs61986670(AA), rs61986671(GG), rsl7260415(CC), rsl956406(CC), rs61983300(GG), rsl 1159868(CC), rs7157149(CC), rs2224333(TT), rsl2590826(GG), rs57889459(TT), rs58550317(CC), rs61982733(TT), rs2145120(AA), and rsl2588535(CC). In an aspect, a Group B SNP may be found within 19178 and 401024 base pairs of SNP rs61977053 located at 88847220 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -25152 and 58409 base pairs of SNP rs61977053. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs61977053.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs61984684 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs61984684 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl0143767(CC), rs61984683(CC), rs61984708(CC), rs4635267(TT), rsl7188046(AA), rs61984736(CC), rs8006652(TT), rsl2587200(CC), rsl2431548(TT), rs61984737(AA), rsl2434935(TT), rsl 7260380(TT), rs58984912(AA), rsl7188207(GG), rs61986664(AA), rs8018755(TT), rs8020072(CC), rsl7260408(GG), rsl2589982(GG), rs8021690(CC), rs61986669(AA), rs61986670(AA), rs61986671(GG), rsl7260415(CC), rsl956406(CC), rs61983300(GG), rsl l l59868(CC), rs7157149(CC), rs2224333(TT), rsl2590826(GG), rs57889459(TT), rs58550317(CC), rs61982733(TT), rs2145120(AA), and rsl2588535(CC). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs79579293(GG), rs60310240(CC),
rsl7772064(TT), rsl 7698817(GG), rsl2589467(CC), rsl2433464(GG), rs56987357(AA), rsl955599(TT), rsl955600(AA), rsl7772222(GG), rs7145588(AA), rs61977049(CC), rsl7772288(AA), rsl2587386(AA), rs55722539(AA), rsl2589480(TT), rs61977058(CC), rs74071851(AA), rsl 1159856(GG), rs2295135(GG), rsl7124700(TT), rs2297128(CC), rs74074098(GG), rs77306894(GG), rs59136503(AA), rsl998670(TT), rsl 816372(GG), rs60878614(GG), rs76559451(CC), rsl 123421(GG), rs2004329(GG), rsl2436326(TT), rsl7203789(TT), rsl 7798341(CC), rsl0134008(TT), rs891750(TT), rs891749(AA), rs56144430(AA), rsl2586348(GG), rs57118463(CC), rs61984746(TT), rs61986665(CC), rsl2587598(CC), rs78077739(TT), rs58655091(AA), rs78068036(CC), and rs61983303(CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs77382318(GG), rs61579615(TT), rs60213984(AA), rsl7124652(GG), rs61975260(CC), rsl2587528(GG), rsl864748(GG), rs2274735(CC), and rs7143853(GG). In an aspect, a Group B SNP may be found within -203319 and 19373 base pairs of SNP rs61984684 located at 89025448 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -203380 and 205355 base pairs of SNP rs61984684. In an aspect, a Group B SNP may be found within -44237 and 222796 base pairs of SNP rs61984684. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs61984684.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs625006 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs625006 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs505489(CC), rs3766875(TT), rs627201(GG), rsl2725455(CC), rs490987(GG), rs490057(AA), rs489969(AA), and rs2184014(AA). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2139982(AA), rsl475678(GG), and rsl0925487(CC). In an aspect, a Group B SNP may be found within - 10950 and 1772 base pairs of SNP rs625006 located at 237813126 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within -13652 and 11961 base pairs of SNP rs625006. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs625006.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs626545 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs626545 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs670243(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs526706(CC). In an aspect, a Group B SNP may be found within 2105 base pairs of SNP rs626545 located at 131780831 of the human genome assembly GRCh37.2 sequence on chromosome 10. In an aspect, a Group B SNP may be found within -2896 base pairs of SNP rs626545. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs626545.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs640098 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs640098 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs494072(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs670163(AA) and rs565888(AA). In an aspect, a Group B SNP may be found within 5278 and 6811 base pairs of SNP rs640098 located at 128648966 of the human genome assembly GRCh37.2 sequence on chromosome 11. In an aspect, a Group B SNP may be found within 786 base pairs of SNP rs640098. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs640098.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs641153 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs641153 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs609061(AG), rs541862(CT), rs522162(CT), rs760070(CT),
rs550513(CT), rs403569(AG), and rs438999(AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl042663(AG), rs550605(CT), rs653414(CT), and rs497239(CT). In an aspect, a Group B SNP may be found within -9050 and -5419 base pairs of SNP rs641153 located at 31914180 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within - 4018 and 14126 base pairs of SNP rs641153. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs641153.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6446731 in the NCBI db SNP Build 134 located at 3284751 of the human genome assembly GRCh37.2 sequence on chromosome 4 and having a genotype AG.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6482910 in the NCBI db SNP Build 134 and having a genotype CC TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6482910 and having a genotype CC TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs7099134(AA GG), rs4751410(CC TT),
rsl 1018061(AA GG), and rsl 1018063(AA GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs3923628(CC GG),
rsl l018068(CC TT), rs5028277(AA GG), rs5028274(CC GG), rs5028273(GG TT), rs5028272(CC TT), rsl 1018071(CC TT), rsl2219778(CC TT), rs61864027(AA GG), rs61864028(CC TT), rs4750875(AA GG), rs4750876(AA GG), rs4750877(CC TT), rs4750878(AA GG), rsl 1018074(CC TT), rsl0830057(AA GG), rsl 1018076(AA GG), rs4750881(AA GG), rs4750882(CC TT), rs4751411(CC TT), and rs4750883(AA GG). In an aspect, a Group B SNP may be found within 7833 and 12468 base pairs of SNP rs6482910 located at 133367723 of the human genome assembly GRCh37.2 sequence on chromosome 10. In an aspect, a Group B SNP may be found within -784 and 4016 base pairs of SNP rs6482910. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs6482910.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6489851 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6489851 and having a genotype CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs232936(CT), rs232937(CT), rs379808(AT), rsl 1066383(AG), and rs73196540(CG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs6489853(CT). In an aspect, a Group B SNP may be found within 830 base pairs of SNP rs6489851 located at 113128754 of the human genome assembly GRCh37.2 sequence on chromosome 12. In an aspect, a Group B SNP may be found within -10142 and 36 base pairs of SNP rs6489851. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs6489851.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs651844 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs651844 and having a genotype CT. In another aspect, a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rs525007(CT). In an aspect, a Group B SNP may be found within -4768 base pairs of SNP rs651844 located at 108079073 of the human genome assembly GRCh37.2 sequence on chromosome 1. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs651844.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6549946 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6549946 and having a genotype AA GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl347772(GG TT) and rs6807557(AA GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs9883437(CC TT) and rs7648157(AA TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl370786(AA CC), rs9811341(CC TT), rs3856685(AA GG), and rsl814465(CC TT). In an aspect, a Group B SNP may be found within -17769 and -2370 base pairs of SNP rs6549946 located at
29517861 of the human genome assembly GRCh37.2 sequence on chromosome 3. In an aspect, a Group B SNP may be found within 1216 and 1957 base pairs of SNP rs6549946. In an aspect, a Group B SNP may be found within 2640 and 4712 base pairs of SNP rs6549946. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs6549946. In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6713126 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6713126 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 0.9, including a Group B SNP selected from the group consisting of rs6731020(CC). In an aspect, a Group B SNP may be found within -50 base pairs of SNP rs6713126 located at 129914893 of the human genome assembly GRCh37.2 sequence on chromosome 2. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs6713126.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6755175 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6755175 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 1901314(CT). In an aspect, a Group B SNP may be found within range -1132 base pairs of SNP rs6755175 located at 173320520 of the human genome assembly GRCh37.2 sequence on chromosome 2. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs6755175.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6780177 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6780177 and having a genotype CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl7009125(CT), rs73137063(CT), and rs6783237(CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs9810611(CT), rs9815936(CT), rs58009608(AG), rsl 7029417(CT), rs56151931(GT), and rs7633504(CG). In an aspect, a Group B SNP may be found within 4798 and 17687 base pairs of SNP rs6780177 located at 21647818 of the human genome assembly GRCh37.2 sequence on chromosome 3. In an aspect, a Group B SNP may be found within -1599 and 565 base pairs of SNP rs6780177. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs6780177.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs684923 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs684923 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs505489(CC), rs3766875(TT), rs627201(GG), rsl342836(GG), rsl2725455(CC), rs490057(AA), rs489969(AA), rs625006(GG), and rs2184014(AA). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2139982(AA), rsl475678(GG), rs490987(GG), and rsl0925487(CC). In an aspect, a Group B SNP may be found within -12607 and 115 base pairs of SNP rs684923 located at 237814783 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within -15309 and 10304 base pairs of SNP rs684923. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs684923.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6864 in the NCBI db SNP Build 134 and having a genotype AC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6864 and having a genotype AC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2429024(AC), rs2487701(AG), rs2255607(CT), rsl7471869(AG), rs2487702(CG), rs2429030(CT), rs2491023(AG), rs2429031(AG), rs2487706(AG), rs2487707(GT), rs2487708(AG), and rs2491020(AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs7918860(AG), rs2245565(GT), rs58476490(CT), and rs2429036(AC). In an aspect, a Group B SNP may be found within -105898 and 14018 base pairs of SNP rs6864 located at 70776594 of the human genome assembly GRCh37.2 sequence on chromosome 10. In an aspect, a Group B SNP may be found within -36021 and 1972 base pairs of SNP rs6864. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs6864. In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6893958 in the NCBI db SNP Build 134 located at 6842842 of the human genome assembly GRCh37.2 sequence on chromosome 5 and having a genotype AA.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6896102 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6896102 and having a genotype GG. In another aspect, a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rs62362294(AA), rsl0515016(TT), rsl2517623(AA), rsl2517640(AA), rsl3170214(CC), and rs4501302(AA). In an aspect, a Group B SNP may be found within -26659 and -2154 base pairs of SNP rs6896102 located at 65961205 of the human genome assembly GRCh37.2 sequence on chromosome 5. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs6896102.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6909151 in the NCBI db SNP Build 134 and having a genotype AG GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6909151 and having a genotype AG GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2505036(CC CT), rs4245544(CT TT), rs4947044(AC CC), and rs7761045(AA AT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs9372243(AG GG), rs9384731(CC CT),
rsl 1153222(AG GG), rs4463297(AA AG), rs4604302(CG GG), rs9320320(CC CG), and rs4392757(AG GG). In an aspect, a Group B SNP may be found within -2532 and 8030 base pairs of SNP rs6909151 located at 110288776 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within 1964 and 9754 base pairs of SNP rs6909151. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs6909151.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6918854 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6918854 and having a genotype AA GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs9467773(AA GG), rs6926629(CC TT),
rs6903973(AA CC), rs2255070(CC GG), rsl321479(CC TT), rs9461259(AA CC), rs9467774(AA CC), rs3736781(AA GG), rs3736782(AA CC), rs2208331(AA GG), rs9393728(CC GG), rsl056667(CC TT), rs9295694(AA TT), rs9393729(CC TT), rs4713006(AA GG), rs6925703(AA GG), rs6910899(AA GG), rs9461267(GG TT), rs9357010(CC GG), rs9295695(CC TT), rs9393731(CC TT), rsl l756120(CC GG), rs9393732(AA GG), rs28558133(CC GG), rsl321480(AA GG), rsl0946834(CC GG), rsl0946835(CC TT), rs9467778(CC TT), rs2393670(AA GG), rs9467779(AA TT), rsl321481(AA TT), rs4713008(CC TT), rs6933176(AA GG), rs9467782(AA GG), rs9467783(CC TT), rsl884946(CC GG), rs4871(AA GG), rs4573(CC TT), rs9986382(CC TT), rsl2526680(AA GG), rsl884947(GG TT), rs6941022(CC TT), rs6922824(CC GG), rs2224380(AA GG), rs9461271(AA GG), rs6930120(AA GG), rsl0484442(AA GG), rs9467787(GG TT), rs767471(CC TT), rs7753565(AA GG), rs6940188(CC GG), rs6940053(CC TT), rs9467791(AA GG), rsl0214634(AA TT), rs6456733(CC TT), rs6456734(GG TT), rsl535277(GG TT), rsl884948(AA GG), rsl884949(AA GG), rs9467796(AA GG), rs9467797(AA TT), rsl078679(CC TT), rs6932156(GG TT), rs6924838(CC TT), rs6925895(GG TT), rsl001687(CC GG), rsl570059(CC TT), rsl570060(AA GG), rsl977201(CC TT), rs6456735(AA GG), rsl321482(CC TT), rs9467798(AA GG), rsl570061(CC TT), rsl2665431(AA TT), rsl2663883(AA CC), rsl2663894(CC TT), rs6913462(AA GG), rs6918506(CC GG), rs6918360(AA TT), rs9467799(AA GG), rs9467800(AA CC), rs9461272(AA GG), and rs9467802(AA GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs 1407045 (AA GG), rs2024970(AA TT), rsl056668(CC TT), rs9467775(AA GG), rsl535276(CC TT), rs6924865(AA GG), rs35355150(AA GG), rsl056347(CC GG), rs9358954(AA GG), rs6932865(AA CC), rs9461270(AA GG), rsl 1752946(AA CC), rsl0223789(CC TT), rsl0223792(AA GG), and rs9467804(CC TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2073526(AA GG), rsl796520(CC TT), rs742090(AA CC), rsl796521(CC TT), rsl624440(AA GG), rs9295689(CC TT), rs3734540(AA CC), rsl977198(AA CC), rs2393669(CC TT), rs9295698(AA TT), and rs55930917(AA GG). In an aspect, a Group B SNP may be found within -203266 and -738 base pairs of SNP rs6918854 located at
26577924 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within -101769 and 5205 base pairs of SNP rs6918854. In an aspect, a Group B SNP may be found within -79498 and 3244 base pairs of SNP rs6918854. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs6918854.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6922979 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6922979 and having a genotype AA GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs56744910(AA GG), rsl2110525(AA CC), rsl2111179(AA GG), rs7751416(AA TT), rs72917820(CC TT), rs72917822(CC TT), rs72917825(GG TT), rs6910466(CC TT), and rs72929209(CC TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs72945236(AA GG), rsl 1751570(AA GG), rs72926207(AA GG), rs58692702(AA GG), and rs6920199(GG TT). In an aspect, a Group B SNP may be found within -5016 and 22867 base pairs of SNP rs6922979 located at 99627975 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within -14397 and 15265 base pairs of SNP rs6922979. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs6922979.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6925087 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6925087 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs9461275(TT), rs4368798(GG), rs9461276(CC),
rs3800303(GG), rs9467810(CC), rsl490488(GG), rs2494692(AA), rs2451738(TT), rs2451737(GG), rs2494694(AA), rs2494696(GG), rs2101582(AA), rs2101581(AA), rs2451732(TT), rs2451731(GG), rs9295701(CC), rs2451741(GG), rs2494700(TT), rs2451744(TT), rs2494701(TT), rsl027203(GG), rsl027204(CC), rs2504592(CC), rs2504599(TT), rs2504540(GG), rs79447522(TT), rs2504571(TT), rs2504600(AA), rs2130657(TT), rs2504565(AA), rs2498351(TT), rs2504566(GG), rs2494716(CC), rs2504567(GG), and rs2451711(CC). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs9467805(TT), rs9461273(GG),
rsl3207371(AA), rsl3213953(TT), rs7767847(AA), rs62394558(AA), rs2494693(CC), rs2451736(TT), rsl021372(CC), rsl021373(AA), rs2172007(CC), rs2498380(GG), rs2451750(AA), rs2451751(CC), and rs62396201(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs34453863(CC), rs3001369(TT), and rs2498399(CC). In an aspect, a Group B SNP may be found within 35152 and 113691 base pairs of SNP rs6925087 located at 26592853 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within -9487 and 75363 base pairs of SNP rs6925087. In an aspect, a Group B SNP may be found within -2052 and 70257 base pairs of SNP rs6925087. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs6925087.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6941022 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6941022 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs6926629(TT), rs6903973(CC), rs2255070(CC),
rs9467774(CC), rs3736781(GG), rs3736782(CC), rsl056667(TT), rs9295694(AA), rs9393729(CC), rs4713006(AA), rs9461267(TT), rs9357010(CC), rs9295695(TT), rsl0946834(GG), rsl0946835(CC), rs2393670(AA), rs9467779(AA), rsl321481(AA), rs4713008(TT), rs6933176(GG), rs9467782(GG), rs9467783(CC), rs9461270(AA), rsl884946(CC), rs4871(GG), rs4573(TT), rs9986382(TT), rsl2526680(AA),
rsl884947(GG), rs6922824(CC), rs2224380(GG), rs9461271(GG), rs6930120(AA), rsl0484442(AA), rs767471(CC), rs7753565(AA), rs6940188(GG), rs9467791(GG), rs6456733(CC), rsl078679(CC), rs6925895(GG), rsl570059(CC), rsl570060(AA), rs9467798(GG), rs6918506(CC), rs6918360(AA), rs9467800(AA), and rs9461272(GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2024970(TT), rs9467773(AA), rsl321479(TT), rs9461259(CC), rs2208331(AA), rs9393728(GG), rsl056668(TT), rs9467775(GG), rsl535276(TT), rs6924865(GG), rs6925703(GG), rs6910899(AA), rs35355150(AA), rsl056347(CC), rs9393731(CC), rsl l756120(CC), rs9393732(GG), rs9358954(AA), rs28558133(CC), rsl321480(AA), rs9467778(TT), rs6932865(CC), rs9467787(GG), rsl 1752946(AA), rs6940053(CC), rsl0214634(AA), rs6456734(GG), rsl535277(GG), rsl884948(GG), rsl884949(GG), rs9467796(GG), rs9467797(TT), rs6932156(TT), rs6924838(CC), rsl001687(GG), rsl977201(CC), rs6456735(GG), rsl321482(TT), rsl570061(TT), rs 12665431(AA), rsl2663883(CC), rsl2663894(CC), rs6913462(AA), rs9467799(GG), rsl0223792(AA), rs9467802(AA), and rs9467804(CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl796520(TT), rs742090(CC), rsl 796521(CC), rsl624440(AA), rs9295689(TT), rs3734540(CC), rsl977198(CC), rsl 407045 (AA), rs2393669(CC), rs9295698(TT), rs55930917(GG), and rsl0223789(TT). In an aspect, a Group B SNP may be found within -142731 and 26078 base pairs of SNP rs6941022 located at 26553531 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within -56011 and 29598 base pairs of SNP rs6941022. In an aspect, a Group B SNP may be found within - 53628 and 26117 base pairs of SNP rs6941022. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs6941022.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6953258 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6953258 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl2704744(TT) and rs6465431(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl2155354(CC), rs6976389(AA), and rs6973986(AA). In an aspect, a Group B SNP may be found within -4517 and 16962 base pairs of SNP rs6953258 located at 94375808 of the human genome assembly GRCh37.2 sequence on chromosome 7. In an aspect, a Group B SNP may be found within -1892 and -902 base pairs of SNP rs6953258. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs6953258. In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6972943 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6972943 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2888706(AG) and rs2215444(AG). In an aspect, a Group B SNP may be found within range 8674 and 8855 base pairs of SNP rs6972943 located at 89544313 of the human genome assembly GRCh37.2 sequence on chromosome 7. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs6972943.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6977578 in the NCBI db SNP Build 134 located at 8532519 of the human genome assembly GRCh37.2 sequence on chromosome 7 and having a genotype CC.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6981251 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6981251 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs62526621(CC), rs55889147(GG), rsl 1991780(TT), rsl6893240(TT), rs62526625(TT), rs7843080(AA), rs7843579(GG), rsl6893243(CC), rs6982092(AA), rs7002440(TT), rs6987018(GG), rs7007123(TT), rs7007265(TT), rs6987100(AA), rs6987389(AA), and rs58900911(GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs62526622(AA), rs73705442(GG), rs7815122(GG), rsl0955939(AA), rs72690128(CC), and rs7813113(CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl0955938(AA), rs28700049(GG), rs28619135(GG), rs62526624(CC), rs7825443(AA), and rs79607190(TT). In an aspect, a Group B SNP may be found within - 3865 and 1750 base pairs of SNP rs6981251 located at 120873916 of the human genome assembly GRCh37.2 sequence on chromosome 8. In an aspect, a Group B SNP may be found within -9076 and -74 base pairs of SNP rs6981251. In an aspect, a Group B SNP may be found within -9080 and 1646 base pairs of SNP rs6981251. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs6981251.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs6987100 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs6987100 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl6893240(TT), rs7843080(AA), rs7843579(GG),
rsl6893243(CC), rs7002440(TT), rs6987018(GG), and rs6987389(AA). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs62526621(CC), rs55889147(GG), rs7815122(GG), rsl 1991780(TT), rs62526625(TT), rs6982092(AA), rs7007123(TT), rs7007265(TT), and rs58900911(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium
correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs62526622(AA), rs73705442(GG), rsl0955939(AA), rs72690128(CC), and rs7813113(CC). In an aspect, a Group B SNP may be found within -10381 and -1379 base pairs of SNP rs6987100 located at 120875221 of the human genome assembly GRCh37.2 sequence on chromosome 8. In an aspect, a Group B SNP may be found within -10385 and 341 base pairs of SNP rs6987100. In an aspect, a Group B SNP may be found within -2742 and 105 base pairs of SNP rs6987100. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs6987100.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7032817 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7032817 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 7694761(GG), rs7024243(AA), rs4081286(CC),
rsl889539(GG), rsl 1789885(TT), and rsl 1793907(GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs7039813(CC) and rsl 1790417(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs71510420(CC). In an aspect, a Group B SNP may be found within 5646 base pairs of SNP rs7032817 located at 27133385 of the human genome assembly GRCh37.2 sequence on chromosome 9. In an aspect, a Group B SNP may be found within 4843 and 6255 base pairs of SNP rs7032817. In an aspect, a Group B SNP may be found within -64 and 5541 base pairs of SNP rs7032817. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7032817.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7110072 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7110072 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl012552(TT), rsl0767563(TT), rs4923371(TT),
rsl0430848(CC), rs6416050(GG), rsl0734379(TT), and rsl0734382(CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs4582926(AA). In an aspect, a Group B SNP may be found within -3142 base pairs of SNP rs7110072 located at 26661690 of the human genome assembly GRCh37.2 sequence on chromosome 11. In an aspect, a Group B SNP may be found within -15796 and 12493 base pairs of SNP rs7110072. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7110072.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs711173 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs711173 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs711174(TT). In an aspect, a Group B SNP may be found within range 85 base pairs of SNP rs711173 located at 3800995 of the human genome assembly
GRCh37.2 sequence on chromosome 17. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs711173.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7120011 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7120011 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs4466796(TT), rs4600174(CC), rs4597036(CC), and rs6589888(AA). In an aspect, a Group B SNP may be found within range 593 and 1298 base pairs of SNP rs7120011 located at 98953367 of the human genome assembly GRCh37.2 sequence on chromosome 11. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7120011.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7134223 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7134223 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1, including a Group B SNP selected from the group consisting of rsl2424527(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs74891599(CC) and
rsl 17888950(AA). In an aspect, a Group B SNP may be found within 56687 and 276822 base pairs of SNP rs7134223 located at 73854918 of the human genome assembly GRCh37.2 sequence on chromosome 12. In an aspect, a Group B SNP may be found within -9929 base pairs of SNP rs7134223. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7134223.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7242 in the NCBI db SNP Build 134 and having a genotype GT TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7242 and having a genotype GT TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2227673(AA AG), rs2227684(AG GG), rs2070682(CT TT), and rsl 1178(CT TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2227679(CC CT), rs2854236(CT TT), rsl3238709(CC CT), rsl2673157(CC CT), rs35788047(CT TT), rsl 1560324(CC CG), rs757716(CG GG), and rs35760677(GG GT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2227706(AG GG). In an aspect, a Group B SNP may be found within 1850 base pairs of SNP rs7242 located at 100781445 of the human genome assembly GRCh37.2 sequence on chromosome 7. In an aspect, a Group B SNP may be found within -5143 and 6937 base pairs of SNP rs7242. In an aspect, a Group B SNP may be found within -5459 and -361 base pairs of SNP rs7242. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7242.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7292804 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7292804 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl2627881(CC), rs7293100(GG), rsl7002069(CC), rs56169543(GG), rs7284506(CC), and rs73171017(TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs5995886(GG), rs6001990(AA), rs7284768(TT), rsl2158399(GG), rs73171007(AA), rs55775429(AA), rs55746155(AA), rs56203629(AA), rsl7002067(GG), rs733999(GG), rs6002000(GG), rs5995890(CC), rs73171013(GG), and rs8142396(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs8141330(AA). In an aspect, a Group B SNP may be found within 5238 base pairs of SNP rs7292804 located at 41047556 of the human genome assembly GRCh37.2 sequence on chromosome 22. In an aspect, a Group B SNP may be found within -13755 and 5200 base pairs of SNP rs7292804. In an aspect, a Group B SNP may be found within -2963 and 13297 base pairs of SNP rs7292804. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7292804.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7305954 in the NCBI db SNP Build 134 and having a genotype CC TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7305954 and having a genotype CC TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs3825404(AA GG), rsl0783227(CC TT), rs6580647(AA CC), rs9805048(AA GG), rs7132668(CC TT), and rs6580649(CC TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl635529(AA CC), rsl793933(GG TT), rsl793931(GG TT), rs3803183(AA TT), rsl859444(CC TT), rs9651993(AA GG), rsl990029(CC TT), rs72644841(AA GG), rsl l612578(CC TT), rsl 859441(CC TT), rs7310579(AA GG), rs4760614(AA GG), rs4760615(CC TT), rs7957764(CC TT), rs6580651(AA TT), rs4760618(AA GG), rsl018973(CC GG), rs7959755(AA TT), rs72644842(AA GG), rs4760677(CC TT), rsl l612970(CC TT), rs57380031(CC TT), rsl2580764(AA GG), rs3742074(CC TT), rsl7122611(CC TT), rsl7122612(CC GG), rsl7122613(CC TT), rsl 1613485(CC TT), rs60681522(CC TT), rs72644843(AA GG), rs72644844(AA CC), rs7971668(CC TT), rs7963934(CC GG), rs4589362(CC TT), rs7312326(AA GG), rs57054831(CC TT), rs58046797(CC TT), rs7296913(AA GG), rsl968071(CC TT), rs726354(AA GG), rsl 1609399(AA TT), rsl0492080(AA GG), rs757556(CC TT), rs72644845(AA GG), rs78649179(AA TT), rs72644847(AA CC), rs4760683(CC TT), and rs4141065(AA GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl 793917(AA TT), rs917055(AA GG), rsl635536(CC TT), rsl635534(CC TT), rsl793915(AA CC), rsl793912(GG TT), rsl793956(CC GG), rsl793955(AA CC), rsl635528(AA GG), rsl635526(CC TT), rs3803184(CC GG), rsl0783226(AA CC), rs7967762(CC TT), rs4760611(CC TT), rs2286022(CC TT), rs7133249(CC TT), rs59766465(AA GG), rsl476608(CC TT), rs879242(CC TT), rs72644846(AA GG), rs4075913(AA GG), rs4760620(CC TT), rs4760621(AA GG), rs6580656(CC TT), and rs7315258(CC TT). In an aspect, a Group B SNP may be found within -18586 and 169140 base pairs of SNP rs7305954 located at 48403530 of the human genome assembly GRCh37.2 sequence on chromosome 12. In an aspect, a Group B SNP may be found within -8428 and 119969 base pairs of SNP rs7305954. In an aspect, a Group B SNP may be found within - 3599 and 6987 base pairs of SNP rs7305954. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7305954.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7409 in the NCBI db SNP Build 134 and having a genotype CC TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7409 and having a genotype CC TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2598444(AA GG), rs2598446(AA GG), rs2665977(AA GG), rsl530834(CC TT), rs2598432(AA CC), rs2665979(CC TT), rs2598434(AA CC), rs2598435(CC TT), rs2665972(AA GG), rs8071975(CC TT), rs2665995(CC TT), rs2665998(CC TT), rs4789241(AA GG), rs2443168(AA TT), rs2257020(AA GG), rs8836(CC GG), rs2246274(AA GG), and rs2598450(CC TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2598445(AA GG), rs2665978(CC TT), rs2598433(AA GG), rs8071679(AA GG), rs2665973(CC TT), rs2665974(AA GG), rs2665975(GG TT), rs9899725(GG TT), rs2665999(AA GG), rs4238985(AA GG), rs2598448(CC TT), rs7217737(AA GG), rs55666832(CC TT), rs55784778(CC TT), rs4789242(GG TT), rs2256879(AA GG), rs2257028(AA GG), rs2665986(CC TT), and rs2665985(AA GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2666000(AA GG) and rs2665987(CC TT). In an aspect, a Group B SNP may be found within 28994 and 43534 base pairs of SNP rs7409 located at 74035543 of the human genome assembly GRCh37.2 sequence on chromosome 17. In an aspect, a Group B SNP may be found within 1665 and 45328 base pairs of SNP rs7409. In an aspect, a Group B SNP may be found within 1369 and 46075 base pairs of SNP rs7409. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7409.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7425164 in the NCBI db SNP Build 134 located at 16784998 of the human genome assembly GRCh37.2 sequence on chromosome 2 and having a genotype CC.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7444603 in the NCBI db SNP Build 134 located at 53939221 of the human genome assembly GRCh37.2 sequence on chromosome 5 and having a genotype A A CC.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7523607 in the NCBI db SNP Build 134 and having a genotype AA CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7523607 and having a genotype AA CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs4658835(AA GG). In an aspect, a Group B SNP may be found within range 78 base pairs of SNP rs7523607 located at 242767678 of the human genome assembly GRCh37.2 sequence on chromosome 1. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7523607.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7535528 in the NCBI db SNP Build 134 located at 2444414 of the human genome assembly GRCh37.2 sequence on chromosome 1 and having a genotype AA.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7544877 in the NCBI db SNP Build 134 and having a genotype CT TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7544877 and having a genotype CT TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 1184825(CT TT), rsl0881377(CG GG),
rsl2410296(CT TT), rsl 1184827(CT TT), rs7416075(AG GG), rs7516511(AG GG), rsl413423(CG GG), rs4314904(AA AG), rs6699032(CC CT), rs6666028(AA AT), rs4304612(CT TT), rsl2027113(CT TT), rsl2026340(AT TT), rsl591257(AA AG), rsl577137(AG GG), rsl577139(GT TT), rsl334120(AA AG), rsl 1184836(CT TT), rsl360707(AA AG), rsl413424(AG GG), rsl537529(CC CG), rs4590701(AC CC), rs4317837(AG GG), rs7527550(AA AG), rs7518667(CG GG), rs7532907(AA AT), rs7530612(AA AG), and rs7535950(CT TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs61788361(AA AC), rs4363446(CC CT), rs4431871(AA AG), rsl 1184832(CT TT), rs944989(AG GG), rs7546154(CC CT), rs7512901(AA AT), rsl0881378(GT TT), rsl537531(AG GG), rsl334128(AG GG), rsl537530(CC CT), rs4274092(AC CC), rs6698941(CC CG), rsl0881379(CT TT), rsl334132(CC CG), and rs7512065(CC CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl2043480(AA AG), rsl2026372(CC CT), rs78194123(CT TT), rs4269795(CC CT), rsl 1184831(AA AG), rs4567306(AG GG), rsl0785778(AA AC), rs61788366(GT TT), rs5015910(CT TT), and rs4486477(GT TT). In an aspect, a Group B SNP may be found within -11807 and 9747 base pairs of SNP rs7544877 located at 106807637 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within -8169 and 18453 base pairs of SNP rs7544877. In an aspect, a Group B SNP may be found within -11136 and 21652 base pairs of SNP rs7544877. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7544877.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7551773 in the NCBI db SNP Build 134 located at 239060960 of the human genome assembly GRCh37.2 sequence on chromosome 1 and having a genotype AG GG.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7572996 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7572996 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl2617155(AG), rs7583839(AG), rs9710652(AT),
rsl2617990(CT), rs3755053(AC), and rs2666103(AG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs6709228(AG), rsl040009(CT), rsl3018645(AG), rs3755054(AG), rs2666104(AG), rs3755056(AT), rsl058261(CT), and rsl058284(AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl039896(AG), rs2070927(CT),
rsl2991025(CT), rsl2920(CG), rsl2621188(CG), rs2854903(CT), rs4674394(CT), rsl 1685408(CT), rsl0932803(AT), rsl2469789(CT), and rsl 1691617(CT). In an aspect, a Group B SNP may be found within 12846 and 25692 base pairs of SNP rs7572996 located at 220269475 of the human genome assembly GRCh37.2 sequence on chromosome 2. In an aspect, a Group B SNP may be found within -27925 and 16667 base pairs of SNP rs7572996. In an aspect, a Group B SNP may be found within -21030 and 11257 base pairs of SNP rs7572996. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7572996.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7582779 in the NCBI db SNP Build 134 and having a genotype AG GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7582779 and having a genotype AG GG. In another aspect, a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rs2010574(AG GG) and rs3770378(CG GG). In an aspect, a Group B SNP may be found within -55996 and -1419 base pairs of SNP rs7582779 located at 80869195 of the human genome assembly GRCh37.2 sequence on chromosome 2. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7582779.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7610425 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7610425 and having a genotype CC. In another aspect, a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rs6779565(TT), rsl946704(CC), rs4681546(CC), rs6807780(CC), rsl3322801(GG), rsl 0935771(AA), rs9824529(CC), rs4681549(CC), rs62271165(TT), rs62271166(AA), rs9847126(GG), rs62271168(AA), rs9882629(TT), rs9843601(CC), rsl581407(CC), rsl3067331(CC), rsl0935775(GG), rs9883415(AA), rs9843784(GG), rs4681551(TT), rsl851375(GG), rs9848558(AA), and rs4681189(AA). In an aspect, a Group B SNP may be found within -90629 and -3319 base pairs of SNP rs7610425 located at 149485293 of the human genome assembly GRCh37.2 sequence on chromosome 3. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7610425.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7617493 in the NCBI db SNP Build 134 located at 3080200 of the human genome assembly GRCh37.2 sequence on chromosome 3 and having a genotype CT.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7641222 in the NCBI db SNP Build 134 and having a genotype AC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7641222 and having a genotype AC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs6775267(CT), rsl917523(CT), rsl524969(CT), and rsl524968(CT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl 1131030(CT). In an aspect, a Group B SNP may be found within -3024 and 1905 base pairs of SNP rs7641222 located at 65479068 of the human genome assembly GRCh37.2 sequence on chromosome 3. In an aspect, a Group B SNP may be found within 1118 base pairs of SNP rs7641222. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7641222.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7673752 in the NCBI db SNP Build 134 and having a genotype AC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7673752 and having a genotype AC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 15009478(AG), rs75136387(CG), rsl444928(CT), rsl444927(AG), rsl0516956(AG), rs3796417(CT), rs3796418(GT), rs3796419(CT), rsl2513378(AG), rs7699472(AG), rs7661049(AG), rs6823752(AG), rs7673943(GT), rs7658478(AG), rs3796422(CT), rs3796423 (AG), rsl3118309(CT), rsl3149539(AG), rsl l934132(CT), rsl 1722010(CT), rsl3106009(AG), rsl373648(AC), rs7698033(AG), and rsl2505819(AT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs3796410(AG), rsl 373651 (AG), rs3775030(GT),
rs7655484(AG), rsl2505736(AT), rsl 1946254(CT), rsl3121253(GT), rsl444925(CG), rsl 444924(d), rs3796425(CT), rsl2508693(AG), rsl2505093(GT), rsl2505823(CT), and rsl2509564(AG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs2120835(AG) and rs6815064(AG). In an aspect, a Group B SNP may be found within -13110 and 17418 base pairs of SNP rs7673752 located at
95877680 of the human genome assembly GRCh37.2 sequence on chromosome 4. In an aspect, a Group B SNP may be found within -14655 and 16895 base pairs of SNP rs7673752. In an aspect, a Group B SNP may be found within -4983 and 16658 base pairs of SNP rs7673752. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7673752.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7702195 in the NCBI db SNP Build 134 and having a genotype CT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7702195 and having a genotype CT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 0.9, including a Group B SNP selected from the group consisting of rsl0062706(CG), rs80093919(GT), and
rs6893206(CT). In an aspect, a Group B SNP may be found within 2281 and 2824 base pairs of SNP rs7702195 located at 2089221 of the human genome assembly GRCh37.2 sequence on chromosome 5. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7702195.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7795499 in the NCBI db SNP Build 134 and having a genotype CC TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7795499 and having a genotype CC TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl019180(AA TT), rs6975531(AA TT),
rsl0240479(CC TT), rsl0233340(AA GG), rs4723733(AA GG), rs35997004(CC TT), rs7788819(CC TT), rsl 1766312(CC GG), rsl l766341(CC TT), rsl7171307(AA GG), rs2159499(AA GG), rsl0951552(AA GG), rs4723734(AA GG), rsl0282407(AA GG), rs2159501(CC TT), rs4723738(AA GG), and rs6462817(CC TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl860522(CC TT), rsl0480164(CC TT), and rsl2531618(AA GG). In an aspect, a Group B SNP may be found within -49383 and -17530 base pairs of SNP rs7795499 located at 38268395 of the human genome assembly GRCh37.2 sequence on chromosome 7. In an aspect, a Group B SNP may be found within -28355 and - 15531 base pairs of SNP rs7795499. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7795499.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7815122 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7815122 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl0955938(AA), rs28700049(GG), rs28619135(GG), rs7825443(AA), and rs79607190(TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs62526622(AA), rs72690128(CC),
rs55741337(TT), rsl6893240(TT), rs7843080(AA), rs7843579(GG), rsl6893243(CC), rs7813113(CC), rs7002440(TT), rs6987018(GG), and rs6987389(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs62526621(CC), rs55889147(GG), rsl 1991780(TT), rs62526624(CC), rs62526625(TT), rs6982092(AA), rs7007123(TT), rs7007265(TT), and rs58900911(GG). In an aspect, a Group B SNP may be found within -4186 and 6540 base pairs of SNP rs7815122 located at 120869022 of the human genome assembly GRCh37.2 sequence on chromosome 8. In an aspect, a Group B SNP may be found within -4182 and 6304 base pairs of SNP rs7815122. In an aspect, a Group B SNP may be found within 1029 and 6644 base pairs of SNP rs7815122. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7815122.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7861460 in the NCBI db SNP Build 134 and having a genotype GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7861460 and having a genotype GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs7044793(AA) and rs7048239(TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of
rsl3289887(CC), rsl3295101(CC), rs55816307(GG), rsl2348695(AA), rsl930425(CC), rs4355908(TT), rs4596749(TT), and rsl2351127(TT). In an aspect, a Group B SNP may be found within -774 and -502 base pairs of SNP rs7861460 located at 101282313 of the human genome assembly GRCh37.2 sequence on chromosome 9. In an aspect, a Group B SNP may be found within -12213 and 13104 base pairs of SNP rs7861460. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7861460.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7867693 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7867693 and having a genotype AG. In another aspect, a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rs 10819621(CT). In an aspect, a Group B SNP may be found within 1728 base pairs of SNP rs7867693 located at 133003804 of the human genome assembly GRCh37.2 sequence on chromosome 9. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7867693.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7940667 in the NCBI db SNP Build 134 and having a genotype AC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7940667 and having a genotype AC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1, including a Group B SNP selected from the group consisting of rs4245199(GT), rs4438048(CT), rs4938699(CG), and rs2089646(AG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl546465(GT), rsl022080(CT), rs4245198(AT),
rs2089648(AG), rs906827(AC), rsl0892424(GT), rsl 1217369(CT), rsl0892425(CT), and rs4938700(CG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl0892426(CT). In an aspect, a Group B SNP may be found within 5829 base pairs of SNP rs7940667 located at 119510644 of the human genome assembly GRCh37.2 sequence on chromosome 11. In an aspect, a Group B SNP may be found within -3609 and 6161 base pairs of SNP rs7940667. In an aspect, a Group B SNP may be found within -341 and 1471 base pairs of SNP rs7940667. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7940667.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7970821 in the NCBI db SNP Build 134 and having a genotype CC TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7970821 and having a genotype CC TT. In another aspect, a Group B SNP may include a Group B SNP having a linkage disequilibrium correlation coefficient of greater than or equal to 0.8, selected from the group consisting of rsl0772257(CC TT). In an aspect, a Group B SNP may be found within 52505 base pairs of SNP rs7970821 located at 10426987 of the human genome assembly GRCh37.2 sequence on chromosome 12. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7970821. In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7974223 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7974223 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl344677(TT), rs 12300231(AA), rs7962537(GG), and rs7980326(TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs7978063(CC) and rsl344675(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of
rsl2230274(CC). In an aspect, a Group B SNP may be found within -1610 base pairs of SNP rs7974223 located at 105048460 of the human genome assembly GRCh37.2 sequence on chromosome 12. In an aspect, a Group B SNP may be found within 599 and 2212 base pairs of SNP rs7974223. In an aspect, a Group B SNP may be found within 2507 and 4445 base pairs of SNP rs7974223. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7974223.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7979573 in the NCBI db SNP Build 134 and having a genotype AG GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7979573 and having a genotype AG GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 0467132(GG GT), rs7957054(AG GG),
rs9804986(AA AG), rsl514530(CC CT) and rs9630303(AG GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl 0783971(CT TT), rs7959840(GT TT), rsl 1610321(AA AT), rsl2422722(CT TT), rsl0783972(AG GG), rs7970398(AA AT), rs2220854(AA AG), rsl813056(CC CT), and rs972582(AC CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl 1173060(CC CT). In an aspect, a Group B SNP may be found within 14566 base pairs of SNP rs7979573 located at 59886104 of the human genome assembly GRCh37.2 sequence on chromosome 12. In an aspect, a Group B SNP may be found within -45915 and -14779 base pairs of SNP rs7979573. In an aspect, a Group B SNP may be found within - 22346 and 13491 base pairs of SNP rs7979573. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7979573.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7986188 in the NCBI db SNP Build 134 located at 23625664 of the human genome assembly GRCh37.2 sequence on chromosome 13 and having a genotype A A GG.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs7992 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs7992 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs707920(CC), rs7029(GG), rs4569(TT), rs805290(TT), rs707918(AA), rs707917(GG), rs805282(GG), rs805281(CC), rs805277(TT), rs805274(CC), and
rs805288(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs805287(GG). In an aspect, a Group B SNP may be found within 48489 base pairs of SNP rs7992 located at 31630241 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within -1145 and 47787 base pairs of SNP rs7992. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs7992.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs8017689 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs8017689 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2297129(CC), rs61542857(GG), rs7141363(TT),
rs2274736(CC), rs28482235(AA), rsl0132554(TT), rs2401751(TT), rs28711639(GG), rsl864744(CC), rs28371093(CC), rs7142053(GG), and rs4904452(CC). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs376698(AA), rs453112(AA), rsl627444(CC), rs845757(GG), rs7161660(CC), rs879932(CC), rs816072(AA), rsl0150594(GG), rs79681439(TT), rsl 152376(CC), rsl l52377(GG), rs7160717(CC), rs816069(GG), rsl 1845147(AA), rs2778936(GG), rs7160471(TT), rs9323830(AA), rs7160647(TT), rs7143642(GG), rsl0143744(CC), rsl999177(GG), rsl999176(CC), rsl864746(GG), rsl864747(GG), rs7151164(TT), rsl2433026(TT), rsl0138139(GG), rsl0138002(TT), rsl0150311(CC), rsl0138309(TT), rsl 1847417(TT), rs3783885(TT), rsl 1159857(TT), rs4390529(CC), rs4301952(AA), rs4594187(GG), rs4514599(GG), rs61975276(GG), rs61975277(CC), rs61975278(TT), rs61984675(AA), rs73317739(TT), rs28493481(TT), rs7141608(CC), rsl0150986(AA), rsl2437422(AA), rs8017811(GG), rs4904454(TT), rs2033418(GG), rsl0873392(CC), rs7146241(TT), and rs930181(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl955598(GG), rsl2586714(AA), rsl028455(TT), rsl950280(TT), rs865285(CC), rs449338(TT), rsl099698(CC), rs845758(TT),
rs845769(TT), rsl288122(CC), rs2274735(CC), rsl346996(TT), rs4516145(TT),
rs28666030(GG), rsl2050316(AA), rs4899955(CC), and rsl 1629164(GG). In an aspect, a Group B SNP may be found within -126131 and 81298 base pairs of SNP rs8017689 located at 88949786 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -91556 and 68922 base pairs of SNP rs8017689. In an aspect, a Group B SNP may be found within -13861 and 33887 base pairs of SNP rs8017689. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs8017689.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs8020072 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs8020072 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl0143767(CC), rs61984683(CC), rs61984708(CC), rs4635267(TT), rsl7188046(TT), rs61984736(CC), rs8006652(TT), rsl2587200(GG), rsl2431548(TT), rs61984737(AA), rsl2586348(GG), rsl2434935(TT), rsl 7260380(TT), rs58984912(AA), rsl7188207(GG), rs61986664(AA), rs8018755(TT), rsl7260408(GG), rsl2589982(GG), rs8021690(CC), rs61986669(AA), rs61986670(AA), rs61986671(GG), rsl7260415(GG), rsl956406(CC), rs61983300(GG), rsl l l59868(CC), rs7157149(CC), rs2224333(TT), rsl2590826(GG), rs57889459(TT), rs58550317(CC), rs61982733(TT), rs2145120(AA), and rsl2588535(GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs79579293(GG), rs60310240(CC),
rsl7772064(TT), rsl 7698817(CC), rsl2589467(CC), rsl2433464(GG), rs56987357(AA), rsl955599(TT), rsl955600(AA), rsl7772222(GG), rs7145588(AA), rs61977049(CC), rsl7772288(AA), rsl2587386(TT), rs55722539(AA), rsl2589480(TT), rs61977058(CC), rs74071851(AA), rsl 1159856(GG), rsl7124652(GG), rs2295135(GG), rsl7124700(TT), rs2297128(CC), rs74074098(GG), rsl864748(CC), rs77306894(GG), rs59136503(AA), rsl998670(TT), rsl816372(GG), rs60878614(GG), rs76559451(CC), rsl 123421(GG), rs2004329(CC), rsl2436326(TT), rsl7203789(TT), rsl7798341(CC), rsl0134008(TT), rs891750(AA), rs891749(TT), rs56144430(AA), rs57118463(CC), rs61984746(TT), rs61986665(CC), rsl2587598(CC), rs78077739(TT), rs58655091(AA), rs78068036(CC), and rs61983303(CC). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs77382318(GG), rs61579615 (TT), rs60213984(AA), rs61975260(CC), rsl2587528(GG), rs2274735(GG), and rs7143853(GG). In an aspect, a Group B SNP may be found within -358547 and -135855 base pairs of SNP rs8020072 located at 89180676 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -358608 and 50127 base pairs of SNP rs8020072. In an aspect, a Group B SNP may be found within -199465 and 67568 base pairs of SNP rs8020072. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs8020072.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs8028880 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs8028880 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl2899976(CC), rslOl 1061(GG), rs3985768(TT),
rsl2908232(GG), rs55874929(CC), rsl2442165(CC), rsl 1071203(CC), rsl 1853533(TT), rsl2906885(AA), rs4774222(CC), rsl 1632579(AA), rsl 1632762(AA), and rsl2915092(AA). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs34303822(GG), rs4598842(GG), rsl2439011(TT), rsl 1857271(CC), rsl2907772(CC), rsl 1071204(GG), rsl 1857254(TT), rsl0152116(AA), rsl2438394(AA), rsl2905693(CC), rsl 2910180(AA), rsl2914863(GG), rsl2440103(GG), rs66519039(GG), and rsl2907557(TT). In an aspect, a Group B SNP may be found within -35214 and 16114 base pairs of SNP rs8028880 located at 56019653 of the human genome assembly GRCh37.2 sequence on chromosome 15. In an aspect, a Group B SNP may be found within -46515 and 18764 base pairs of SNP rs8028880. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs8028880.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs8041979 in the NCBI db SNP Build 134 and having a genotype AG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs8041979 and having a genotype AG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl 2904017(AG), rsl 1633644(AG), rsl2148168(AG), rsl 1070723(AC), rs35899336(AC), rsl7486097(CT), rs34561282(CT), rsl 1633343(AG), rs34449112(CT), rs35827271 (AG), rs8025533(GT), rsl 1632116(GT), rsl 1632077(CT), rsl7486425(AG), rsl7486446(AG), rsl 1633714(AG), rsl 1633759(CG), rsl 1634914(CT), rs72733056(AG), rs67881470(CT), rsl7486544(CT), rsl2903153(CT), rsl2909447(AT), rs68050343(AC), rsl l633470(AC), rs34404202(AG), rs4275793(AG), rsl059852(AG), rs4494482(AT), rs4544192(CT), rs4494483(AT), rsl 1630021(AC), rsl3329598(AG), rs8036570(CT), rs61618346(AG), rs8042458(AG), rs34845057(CT), and rs4347574(AC). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs72733017(AG), rsl2902979(CT), rsl 1631995(CT), rs34751824(CT), rs8023895(AT), rsl 1633465(d), rsl 1633744(GT), rsl 059851 (AT), rs8038434(AT), rsl 6962999(d), rs7170482(d), rs6493383(AG), rs66809683(AG), rs8031452(CG), and rsl2907836(CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs692391(AT), rsl2372951(AG), rsl 7486663(d),
rsl2185124(d), rsl 0519242(d), rsl 1633571(d), rs28550208(CT), rs7497350(CT), rsl2915207(AG), rsl059850(AG), rsl 6962994(d), rs28706888(CT), rs7172553(CG), and rs7172585(AG). In an aspect, a Group B SNP may be found within -126666 and -6503 base pairs of SNP rs8041979 located at 50163854 of the human genome assembly GRCh37.2 sequence on chromosome 15. In an aspect, a Group B SNP may be found within -85673 and 6781 base pairs of SNP rs8041979. In an aspect, a Group B SNP may be found within - 57107 and 1700 base pairs of SNP rs8041979. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs8041979.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs8128 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs8128 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs7533963(CC). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs222497(GG), rs222498(CC),and
rsl475078(AA). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs4839385(GG), rs222499(CC), rs2336365(CC), and
rs7553926(AA). In an aspect, a Group B SNP may be found within 10778 and 91532 base pairs of SNP rs8128 located at 115110683 of the human genome assembly GRCh37.2 sequence on chromosome 1. In an aspect, a Group B SNP may be found within 31760 and 79347 base pairs of SNP rs8128. In an aspect, a Group B SNP may be found within 77114 base pairs of SNP rs8128. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs8128.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs835481 in the NCBI db SNP Build 134 and having a genotype CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs835481 and having a genotype CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2695996(AA). In an aspect, a Group B SNP may be found within range -2023 base pairs of SNP rs835481 located at 105048914 of the human genome assembly GRCh37.2 sequence on chromosome 12. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs835481.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs8878 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs8878 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rsl7288671(TT), rsl554013(TT), rsl 0000130(CC), rs7670789(GG), rsl0014837(GG), rs3921(CC), rs4859584(GG), rs4859586(TT), rs4859587(AA), rs4859588(GG), rs4241578(TT), rs4257674(AA), rs4309862(AA), rs4417995(TT), rs4386624(GG), rs4371639(GG), rs9884374(AA), rs4241579(AA), rs6532093(GG), rs4859590(AA), rs4859591(GG), rs4859414(GG), rs4859595(CC), rs6844097(TT), rs6814012(CC), rs6814817(CC), rs6845396(AA), rs6850760(TT), rsl0021768(TT), rs6820370(GG), rs6852075(TT), rs6846814(AA), rsl 1097212(TT), rs4302486(AA), rs4580676(GG), rsl0014049(CC), rs6532105(AA), rs4512021(AA), rs4583787(GG), rs4356932(TT), rs4619915(AA), rs7436646(TT), rsl0003240(CC), rsl0025102(GG), rsl0017431(TT), rsl0003382(CC), rsl3130018(GG), rsl3130221(GG), rs6532111(TT), rs4241580(TT), rs4859415(AA), rs6819597(CC), rs6825045(CC), rs6532114(TT), rs7674409(CC), rs4456983(AA), rs4129781(CC), rs4859598(CC), rs4859600(GG), rs7665152(TT), rs6828596(AA), rs4637430(GG), rs6532121(AA), rs7699624(GG), rs7683657(TT), rs7684461(TT), rs7684889(AA), rs7689664(AA), rs7377856(TT), rs6816898(CC), rs4406046(AA), rs6811301(TT), rs6829896(CC), rs6532142(CC), rs4359936(GG), rs4359937(GG), rs6826163(AA), rs6848603(GG), rs6850515(CC), rs6532156(GG), rs6532157(CC), rs4535358(AA), rs6857372(CC), rsl3128319(GG), rs4401475(TT), rs4593163(TT), rs4543147(AA), rs7655350(AA), rs4422436(TT), rs6532158(AA), rs4380549(CC), rsl 1097219(GG), rsl2502834(CC), rsl2510335(GG), rs4616778(AA), rs7688306(AA), rs7664354(CC), rsl0010920(CC), rs6532163(TT), rsl2233806(CC), rs4484324(GG), rs4333205(AA), rsl0017484(CC), rsl0017657(CC), rs6840980(TT), rs5005114(GG), rs4859416(AA), rsl0856875(CC), rsl 1097222(AA), rsl 1097223(GG), rsl 1097224(CC), rsl2640367(CC), rs4304003(GG), and rs6532172(GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl0336(AA), rsl0031452(TT), rs6532083(AA), rs4318674(GG),
rs6532086(GG), rs6856958(TT), rs7659236(TT), rs6532103(GG), rs75844160(GG), rs4345214(TT), rs4859597(TT), rs4478212(AA), rs9999755(GG), rs4241581(GG), rs6835736(TT), rs4859603(AA), rs4859605(GG), rsl 15828298(GG), rsl 16135606(CC), rsl 15936805(CC), rsl3111790(CC), rsl3113455(CC), rsl3113632(CC), rs28681694(AA), rs28433437(AA), rs28505472(CC), rs28642977(CC), rs28548768(TT), rsl0856873(TT), rs6532154(TT), rs6532155(GG), rsl0016135(TT), rs6856681(GG), rs7677924(CC), rs4547819(AA), rs6532159(AA), rs6532160(CC), rs6532161(CC), rs4407534(TT), rs4605683(TT), rs6837830(TT), rs4432767(AA), rs7679394(AA), rs5005109(TT), rsl2509593(TT), and rs4859608(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs4859606(CC), rsl0034055(CC),
rs68156651(TT), rs6826398(AA), rs6826406(AA), and rs6826408(AA). In an aspect, a Group B SNP may be found within 23579 and 31264 base pairs of SNP rs8878 located at 76942300 of the human genome assembly GRCh37.2 sequence on chromosome 4. In an aspect, a Group B SNP may be found within -19312 and 49507 base pairs of SNP rs8878. In an aspect, a Group B SNP may be found within -10299 and 54658 base pairs of SNP rs8878. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs8878.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs922902 in the NCBI db SNP Build 134 and having a genotype CG GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs922902 and having a genotype CG GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs7609124(AA AG), rs2348718(AG GG), rs990549(AC CC), rs990063(CC CT), and rs2882003(CC CT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs4953534(AA AG), rsl601064(AA AG), rsl l l7823(AT TT), rs4953536(AG GG), rsl0180823(AG GG), rs976416(AA AG), rs999036(AA AG), rs900509(AA AC), rs900508(AA AG), rs7570621(CT TT),
rsl 1125157(AT TT), rs4146019(GG GT), rsl 1125158(CG GG), rs6545010(CC CT), rsl l l25159(CC CG), rs4953539(GT TT), rsl2469627(AA AC), rs4953540(AA AG), rs6545011(GT TT), rsl0203759(CT TT), rs60379088(CT TT), rsl 119025(AA AT), rs6735073(CT TT), rs6750131(CC CT), rs2881938(CC CT), rs4392309(CC CT), rsl471681(AA AT), rsl471680(AA AT), rs2128718(AA AC), rs2128717(AA AG), rs7609066(CT TT), rs4146021 (AC CC), rs4953544(GG GT), rs956488(AG GG), rs6545013(AG GG), rs7580982(CC CT), rs6750246(CC CG), rs2128716(CC CG), rs4953546(AA AT), rsl825320(AA AG), rs968888(CC CT), rsl878081(CC CT), rs6706664(CG GG), rsl878079(CC CT), rs900511(AA AG), rs 10167776(AA AG), rs900510(AG GG), rs963135(AG GG), rs963133(AA AT), rsl7324704(CG GG), rs7563749(AA AC), rsl483210(CC CT), rs6545019(AG GG), rsl483215(CG GG), rsl473611(AA AT), rs6759902(CC CG), rs6705926(CC CT), rsl905306(GG GT), rs4952904(AA AG), rs6712238(AA AC), rs2348717(AG GG), rs4952905(AG GG), rs2136456(CC CG), rs4953555(CT TT), rsl 1125165(AG GG), rs4146603(CC CT), and rs4953557(AG GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs4953543(CT TT), rs28460586(CT TT), rs6545017(GG GT), rs58178746(CT TT), rs973894(CG GG), rsl2621844(CT TT), and rsl396826(GT TT). In an aspect, a Group B SNP may be found within -134890 and 71500 base pairs of SNP rs922902 located at 48372254 of the human genome assembly GRCh37.2 sequence on chromosome 2. In an aspect, a Group B SNP may be found within -160535 and 29453 base pairs of SNP rs922902. In an aspect, a Group B SNP may be found within -34900 and 11330 base pairs of SNP rs922902. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs922902.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs9291224 in the NCBI db SNP Build 134 and having a genotype CC TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs9291224 and having a genotype CC TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 0.9, including a Group B SNP selected from the group consisting of rsl562838(AA GG), rsl562839(AA GG),
rs4861224(AA TT), and rs59953230(AA GG). In an aspect, a Group B SNP may be found within -13651 and -3411 base pairs of SNP rs9291224 located at 42827373 of the human genome assembly GRCh37.2 sequence on chromosome 4. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs9291224.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs9296272 in the NCBI db SNP Build 134 located at 38940282 of the human genome assembly GRCh37.2 sequence on chromosome 6 and having a genotype CC TT.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs930181 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs930181 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs816069(CC), rs2778936(AA), rs7141608(TT), rs4904452(CC), rs7144432(GG), rsl2437422(AA), rs8017811(GG), rs4904454(TT), rs2033418(CC), rsl0873392(CC), and rs7146241(TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs376698(AA), rs453112(AA), rsl627444(CC), rs845757(GG), rs2297129(GG), rs61542857(GG), rs7141363(TT), rs2274736(GG), rs28482235(AA), rsl0132554(TT), rs2401751(AA), rs28711639(GG), rs816072(TT), rsl864744(GG), rs28371093(CC), rsl0150594(GG), rs79681439(TT), rs816075(AA), rsl 152376(GG), rsl 152377(GG), rs2274735(GG), and rs7142053(GG). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl2586714(CC), rsl028455(AA), rs865285(AA), rsl099698(CC), rs845758(CC), rs845769(AA), rs7161660(CC), rsl288122(CC), rs879932(CC), rs7160717(CC), rsl l845147(AA), rs7160471(TT), rs9323830(AA), rs7160647(TT), rs7143642(GG), rsl0143744(CC), rsl999177(GG), rsl999176(CC), rsl864746(GG), rsl864747(GG), rs7151164(TT), rsl2433026(TT), rsl0138139(GG), rsl0138002(TT), rsl0150311(CC), rsl0138309(TT), rsl l847417(TT), rs3783885(TT), rsl 1159857(TT), rs4390529(CC), rs4301952(AA), rs4516145(TT), rs4594187(GG), rs4514599(GG), rs61975276(GG), rs61975277(CC), rs61975278(TT), rs61984675(AA), rs73317739(TT), rs28666030(GG), rs28493481(TT), rsl0150986(AA), rsl2050316(GG), rs4899955(CC), rs3742681(TT), and rsl 1629164(GG). In an aspect, a Group B SNP may be found within -191867 and 12376 base pairs of SNP rs930181 located at 89018708 of the human genome assembly GRCh37.2 sequence on chromosome 14. In an aspect, a Group B SNP may be found within -160478 and -40770 base pairs of SNP rs930181. In an aspect, a Group B SNP may be found within - 51372 and -742 base pairs of SNP rs930181. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs930181.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs9372243 in the NCBI db SNP Build 134 and having a genotype AG GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs9372243 and having a genotype AG GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs9384731(CC CT), rs4299868(AG GG),
rsl 1153222(AG GG), rs4259278(AG GG), rs4363073(CC CT), rs4463297(AA AG), rs4604302(CG GG), and rs4392757(AG GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs2505036(CC CT), rs4245544(CT TT), rs4947044(AC CC), rs9320320(CC CG), rs7761045(AA AT), and rs7759173(CT TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs4267976(AA AC). In an aspect, a Group B SNP may be found within 8782 base pairs of SNP rs9372243 located at 110290740 of the human genome assembly
GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within - 4496 and 8856 base pairs of SNP rs9372243. In an aspect, a Group B SNP may be found within 30 and 7790 base pairs of SNP rs9372243. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs9372243.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs9373836 in the NCBI db SNP Build 134 and having a genotype TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs9373836 and having a genotype TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs9373837(AA). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl 1755328(CC) and rs2235266(TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs9386513(CC). In an aspect, a Group B SNP may be found within -5582 base pairs of SNP rs9373836 located at 106616379 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within -13273 and - 12276 base pairs of SNP rs9373836. In an aspect, a Group B SNP may be found within 10324 base pairs of SNP rs9373836. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs9373836.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs9460540 in the NCBI db SNP Build 134 and having a genotype AG GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs9460540 and having a genotype AG GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs4235999(CG GG), rs4710939(AG GG),
rsl 1965062(AA AT), rs2050225(CG GG), and rs979614(AG GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs7755830(CC CT) and rs4710938(AA AG). In an aspect, a Group B SNP may be found within -5540 and 13361 base pairs of SNP rs9460540 located at 20648762 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within - 13876 and -7858 base pairs of SNP rs9460540. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs9460540.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs9554684 in the NCBI db SNP Build 134 located at 101040056 of the human genome assembly GRCh37.2 sequence on chromosome 13 and having a genotype CT.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs9587280 in the NCBI db SNP Build 134 located at 107682425 of the human genome assembly GRCh37.2 sequence on chromosome 13 and having a genotype CT TT.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs958738 in the NCBI db SNP Build 134 and having a genotype AA GG. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs958738 and having a genotype AA GG. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs9488845(AA CC), rs7763110(AA GG),
rs9320557(AA CC), rs4946138(AA GG), rs6915372(GG TT), rs9488853(CC TT), rs9488857(CC TT), rs9481609(CC TT), rsl546943(AA GG), rs2351141(AA GG), rsl 114228(AA TT), and rs7758930(CC TT). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rsl 1965969(GG TT), rs4946140(CC TT), rs6910311(CC TT), rsl2525805(AA GG), and rs9488860(GG TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium
correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs471766(CC TT), and rs513218(AA GG). In an aspect, a Group B SNP may be found within -9084 and 9897 base pairs of SNP rs958738 located at 116470561 of the human genome assembly GRCh37.2 sequence on chromosome 6. In an aspect, a Group B SNP may be found within -18358 and 25156 base pairs of SNP rs958738. In an aspect, a Group B SNP may be found within -17903 and 32607 base pairs of SNP rs958738. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs958738.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs966775 in the NCBI db SNP Build 134 and having a genotype AA. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs966775 and having a genotype AA. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs2382021 (CC), rs2890873(CC), and rsl0060502(CC). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs897747(TT). In an aspect, a Group B SNP may be found within -1360 and 1155 base pairs of SNP rs966775 located at 174763322 of the human genome assembly GRCh37.2 sequence on chromosome 5. In an aspect, a Group B SNP may be found within -1774 base pairs of SNP rs966775. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs966775.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs9815663 in the NCBI db SNP Build 134 and having a genotype CT TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs9815663 and having a genotype CT TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs4684396(CC CT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rsl3318567(CC CT), rsl3317823(AC CC), rs9839458(AG GG), rs7609670(AG GG), and rsl584573(AG GG). In an aspect, a Group B SNP may be found within -980 and 2129 base pairs of SNP rs9815663 located at 3614887 of the human genome assembly GRCh37.2 sequence on chromosome 3. In an aspect, a Group B SNP may be found within -469 base pairs of SNP rs9815663. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs9815663.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs993691 in the NCBI db SNP Build 134 and having a genotype CC TT. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs993691 and having a genotype CC TT. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs7617740(CC GG), rs4683832(CC TT), rs993692(AA GG), rs4683494(AA GG), rsl3064082(CC TT), rs7619971(AA CC), and rsl600405(AA GG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs6439918(AA TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs347332(CC TT). In an aspect, a Group B SNP may be found within 29063 base pairs of SNP rs993691 located at 140120742 of the human genome assembly GRCh37.2 sequence on chromosome 3. In an aspect, a Group B SNP may be found within -6786 base pairs of SNP rs993691. In an aspect, a Group B SNP may be found within -6911 and 11347 base pairs of SNP rs993691. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs993691.
In an aspect of the present invention, a SNP genotype useful for selecting a subject in need thereof may be a Group A SNP designated rs9962772 in the NCBI db SNP Build 134 and having a genotype AC CC. In another aspect, a SNP useful for selecting a subject in need thereof may be a Group B SNP that is in linkage disequilibrium with the Group A SNP designated rs9962772 and having a genotype AC CC. In an aspect, the Group B SNP may be in linkage disequilibrium with a correlation coefficient of 1 , including a Group B SNP selected from the group consisting of rs4413049(CC CT), rsl2966062(AG GG),
rsl2970701(AA AG), rs35338265(AG GG), rs34172107(CC CT), rsl3016(CG GG), rs7232030(AA AG), rs7230515(CG GG), rs9948045(AA AG), rs7231641(CG GG), rs7231651(CC CT), rs9950765(AA AC), rs9953179(CT TT), rs9951591(AA AG), rs9956550(CT TT), rs4541157(GT TT), rs7227487(AG GG), and rs35269051(AA AG). In an aspect, the Group B SNP may further include a Group B SNP in linkage disequilibrium having a correlation coefficient greater than or equal to 0.9, selected from the group consisting of rs34342888(AA AG), rs34291975(CT TT), rs7229077(AA AT), rs4527100(AG GG), rsl2455608(AA AG), and rsl2456208(CT TT). In another aspect, a Group B SNP may further include a Group B SNP having a linkage disequilibrium correlation coefficient greater than or equal to 0.8, selected from the group consisting of rs4341828(AG GG),
rs35525658(AG GG), rs35940266(CT TT), and rs35259614(AA AG). In an aspect, a Group B SNP may be found within -14059 and 2325 base pairs of SNP rs9962772 located at 56151138 of the human genome assembly GRCh37.2 sequence on chromosome 18. In an aspect, a Group B SNP may be found within -13404 and -5253 base pairs of SNP rs9962772. In an aspect, a Group B SNP may be found within -11751 and 3302 base pairs of SNP rs9962772. In yet another aspect, a Group B SNP may be within 1 cM of SNP rs9962772.
A person of ordinary skill in the art, given the current disclosure, could develop, identify, or isolate additional SNPs. For example, the flanking sequences set forth in SEQ ID NOs: 1 to 293 provide a starting point for obtaining SNPs physically linked to the disclosed SNPs.
SNPs that have a high degree of LD are, for example, useful in determining the identity of the allele of interest or disease allele. Knowing the identity of the allele at one SNP can be representative of the allele identity at another SNP in LD. Without being limited by theory, determination of the genotype of a single locus can provide the identity of the genotype of any locus in LD therewith and the higher the degree of linkage disequilibrium the more likely that two SNPs may be used interchangeably. For example, in the population from which the tagged SNPs were identified from the SNP identified by rsl7781459 is in "linkage disequilibrium" with the SNP identified by rsl041978, whereby when the genotype of rsl7781459 is G, the genotype of rsl041978 is T. Similarly, when the genotype of rsl7781459 is A, the genotype of rsl041978 is G. Accordingly, the determination of the genotype at rsl7781459 will provide the identity of the genotype at rsl041978 or any other locus in "linkage disequilibrium" therewith, particularly where such a locus has a high degree of linkage disequilibrium therewith.
LD is useful for genotype-phenotype association studies. For example, if a specific allele at one SNP site (e.g., "A") is the cause of a specific clinical outcome (e.g., call this clinical outcome "B") in a genetic association study then, by mathematical inference, any SNP (e.g., "C") which is in significant LD with the first SNP, will show some degree of association with the clinical outcome. That is, if A is associated (~) with B, i.e., A~B and C~A, then it follows that C~B. Of course, the SNP that will be most closely associated with the specific clinical outcome, B, is the causal SNP - the genetic variation that is
mechanistically responsible for the clinical outcome. Thus, the degree of association between any SNP, C, and clinical outcome will depend on LD between A and C.
LD can identify potential candidate causal SNPs and can also identify a range of SNPs that may be clinically useful for prognosis of clinical outcome or of treatment effect. If one SNP within a gene is found to be associated with a specific clinical outcome, then other SNPs in LD can also have a degree of association and therefore a degree of prognostic usefulness.
The present invention also provides isolated nucleic acid molecules that contain or are capable of determining or detecting a SNP disclosed herein. Preferred isolated nucleic acid molecules contain or are capable of detecting a SNP identified in Table 1 to Table 3. All nucleic acids of the present invention can consist, comprise or consist essentially of the molecules discussed.
The isolated nucleic acid molecules of the present invention also include
oligonucleotides, probes, and primers, which may be used for assaying the disclosed or other SNPs.
As used herein, an 'isolated nucleic acid molecule' generally is one that contains or is capable of detecting a SNP of the present invention or one that hybridizes to such molecule such as a nucleic acid with a complementary sequence, and is separated from most other nucleic acids present in the natural source of the nucleic acid molecule. Moreover, an "isolated" nucleic acid molecule, such as a cDNA molecule containing a SNP of the present invention, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized.
Generally, an isolated SNP-containing nucleic acid molecule of the present invention comprises a SNP position disclosed herein with flanking nucleotide sequences on either side of the SNP positions. A flanking sequence can include nucleotide residues that are naturally associated with the SNP site and/or heterologous nucleotide sequences. In an aspect, the flanking sequence is up to about 500, 300, 100, 60, 50, 30, 25, 20, 15, 10, 8, or 4 nucleotides (or any other length in-between) on either side or both sides of a SNP position. In an aspect, the flanking sequence is 25 nucleotides on either side or both sides of a SNP position. A SNP site, disclosed herein with flanking nucleotide sequences on either side of the SNP position can be equivalently represented by the reverse complement sequence. It is generally appreciated that the allele can be equivalently represented by either the polymorphic nucleotide of the direct strand or by its complementary base.
Nucleic acid molecules of the present invention can contain modified, synthetic, or non-naturally occurring nucleotides or structural elements or other alternative/modified nucleic acid chemistries known in the art. Such nucleic acid analogs are useful, for example, as detection reagents (e.g. , primers/probes) for detecting a SNP identified in Table 2 to Table 3. Furthermore, kits/systems (such as beads, arrays, etc.) that include these analogs are also encompassed by the present invention. For example, PNA oligomers that are based on the polymorphic sequences of the present invention are specifically contemplated. PNA oligomers are analogs of DNA in which the phosphate backbone is replaced with a peptide- like backbone (Lagriffoul et al, Bioorganic & Medicinal Chemistry Letters, 4:1081-1082 (1994), Petersen et al., Bioorganic & Medicinal Chemistry Letters, (5:793-796 (1996), Kumar et al, Organic Letters, 5^:1269-1272 (2001), WO 96/04000).
Additional examples of nucleic acid modifications that improve the binding properties and/or stability of a nucleic acid include the use of base analogs such as inosine, intercalators (U.S. Pat. No. 4,835,263) and the minor groove binders (U.S. Pat. No. 5,801,115). Other examples of nucleic acid analogs and alternative/modified nucleic acid chemistries known in the art are described in Current Protocols in Nucleic Acid Chemistry, John Wiley & Sons, N.Y. (2002).
Oligonucleotides of the present invention are variable length nucleic acids, which may be useful as probes, primers and in the manufacture of microarrays (arrays) for the detection and/or amplification of specific nucleic acids of the present invention. Such DNA or RNA strands may be synthesized by the sequential addition (5 '-3 ' or 3 '-5 ') of activated monomers to a growing chain, which may be linked to an insoluble support. Numerous methods are known in the art for synthesizing oligonucleotides for subsequent individual use or as a part of the insoluble support, for example, in arrays (Bernfield et al, Biol. Chem., 242(18):4134- 43 (1967); Sulston et al., PNAS, 60(2) 409-415 (1968); Gillam et al., Nucleic Acid Res.,
2^:613-624 (1975); Bonora et al, Nucleic Acid Res., 18(11):3 \55-9 (1990); Lashkari et al., PNAS, 92(17):19\2-5 (1995); McGall et al, PNAS, 93(24) \3555-m 1996); Albert et al, Nucleic Acid Res., 31(7) e35 (2003); Gao et al, Biopolymers, 75^:579-96 (2004); and Moorcroft et al, Nucleic Acid Res., 33(8):Q15 (2005)). In general, oligonucleotides are synthesized through the stepwise addition of activated and protected monomers under a variety of conditions depending on the method being used. Subsequently, specific protecting groups may be removed to allow for further elongation and subsequently, once synthesis is complete, all the protecting groups may be removed and the oligonucleotides removed from their solid supports for purification of the complete chains if so desired. As used herein, "oligonucleotides" also includes various analogs that are commonly used in the art, including oligonucleotides synthesized with modified nucleic acids, such as locked nucleic acids (LNA) (as described in, for example, U.S. Pat. No. 6,268,490), and also oligonucleotides having modified backbones. Reagents of the present invention, such as nucleic acid molecules, can be a reagent that specifically detects a specific target SNP position disclosed herein, and that is preferably specific for a particular nucleotide (allele) of the target SNP position (i.e., the detection reagent preferably can differentiate between different alternative nucleotides at a target SNP position, thereby allowing the identity of the nucleotide present at the target SNP position to be determined).
A probe or primer is often a substantially purified oligonucleotide or PNA
oligonucleotide. In an aspect, oligonucleotides typically comprise a region of complementary nucleotide sequence that hybridizes under stringent conditions to at least about 8, 10, 12, 16, 18, 20, 22, 25, 30, 40, 50, 55, 60, 65, 70, 80, 90, 100, 120 (or any other number in-between), or more consecutive nucleotides in a target nucleic acid molecule. Depending on the particular assay, the consecutive nucleotides can either include the target SNP position, or be a specific region in close enough proximity 5', and/or 3', to the SNP position to carry out the desired assay.
"Peptide nucleic acids" (PNA) as used herein refers to modified nucleic acids in which the sugar phosphate skeleton of a nucleic acid has been converted to an N-(2- aminoethyl)-glycine skeleton. Although the sugar-phosphate skeletons of DNA/RNA are subjected to a negative charge under neutral conditions, resulting in electrostatic repulsion between complementary chains, the backbone structure of PNA does not inherently have a charge. Therefore, there is no electrostatic repulsion. Consequently, PNA has a higher ability to form double strands as compared with conventional nucleic acids, and has a high ability to recognize base sequences. Furthermore, PNAs are generally more robust than nucleic acids. PNAs may also be used in arrays and in other hybridization or other reactions as described above and herein for oligonucleotides.
A primer or probe of the present invention is typically at least about 8 nucleotides in length. In one aspect of the invention, a primer or a probe is at least about 10 nucleotides in length. In a preferred aspect, a primer or a probe is at least about 12 nucleotides in length. In a more preferred aspect, a primer or probe is at least about 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleotides in length. While the maximal length of a probe can be as long as the target sequence to be detected, depending on the type of assay in which it is employed, it is typically less than about 50, 60, 65, or 70 nucleotides in length. In the case of a primer, it is typically less than about 30 nucleotides in length. In a specific preferred aspect of the invention, a primer or a probe is within the length of about 18 and about 28 nucleotides. However, in other aspects, such as nucleic acid arrays and other aspects in which probes are affixed to a substrate, the probes can be longer, such as on the order of 30-70, 75, 80, 90, 100, or more nucleotides in length (see the section below entitled "SNP Detection Kits and Systems"). Oligonucleotides can, for example, be between 8 and 80, between 10 and 70, between 12 and 65, between 16 and 60, between 18 and 55, between 20 and 50, between 22 and 40, or between 25 and 30.
Nucleic acid molecules of the present invention can be combined into collections including an addressable collection. An "addressable collection" as used herein is a combination of nucleic acid molecules or peptide nucleic acids capable of being detected by, for example, the use of hybridization techniques or by any other means of detection known to those of ordinary skill in the art. A DNA microarray would be considered an example of an "addressable collection."
The present invention further provides detection kits and systems, including but not limited to, packaged probe and primer sets (e.g., TaqMan™ probe/primer sets),
arrays/microarrays of nucleic acid molecules, and beads that contain one or more probes, primers, or other detection reagents for detecting a SNP of the present invention. Such a kit can include instructions. The kits/systems can optionally include various electronic hardware components; for example, arrays ("DNA chips"), and microfluidic systems ("lab-on-a-chip" systems) provided by various manufacturers typically comprise hardware components. Other kits/systems (e.g., probe/primer sets) may not include electronic hardware components, but may be comprised of, for example, one or more SNP detection reagents (along with, optionally, other biochemical reagents) packaged in one or more containers.
The present invention also provides vectors and host cells containing the nucleic acid molecules described herein. The term "vector" refers to a vehicle, preferably a nucleic acid molecule, which can transport a SNP-containing nucleic acid molecule. When the vector is a nucleic acid molecule, the SNP-containing nucleic acid molecule can be covalently linked to the vector nucleic acid. Such vectors include, but are not limited to, a plasmid, single or double stranded phage, a single or double stranded RNA or DNA viral vector, or artificial chromosome, such as a BAC, PAC, YAC, or MAC.
A vector can be maintained in a host cell as an extrachromosomal element where it replicates and produces additional copies of the SNP-containing nucleic acid molecules. Alternatively, the vector may integrate into the host cell genome and produce additional copies of the SNP-containing nucleic acid molecules when the host cell replicates. Host cells include, for example, prokaryotic cells, lower eukaryotic cells such as yeast, other eukaryotic cells such as insect cells, and higher eukaryotic cells such as mammalian cells.
While not limited to any particular therapeutic agents, agents that have one or more of anti-inflammatory, anti-coagulant, pro-fibrinolytic, and anti-apoptotic activities are preferred. A particularly preferred therapeutic agent is activated protein C. In another aspect, the therapeutic agent may be protein C. Additional therapeutic agents include protein S or a protein S-like drug; tissue factor pathway inhibitors TFPI (e.g., TIFACOGIN™ alpha (Chiron) and the like); antibodies to tissue factor (TF); platelet activating factor hydrolase (e.g., PAFase™ (ICOS) and other PAF-AH enzyme analogues); antibodies to tumor necrosis factor- alpha (e.g., SEGARD™ afelimomab (Abbott)), infliximab (Remicade™; mouse- human chimeric anti-humanTNF monoclonal antibody), adalumimab (Humira™; fully human anti-human TNF monoclonal antibody), ovine polyclonal anti-TNF Fab fragment (CytoFab™), certolizumab (CDP870; polyethylene glycol (PEG)ylated anti-TNF antibody fragment), and afelimomab (Segard™; anti-TNF monoclonal antibody fragment); soluble TNF receptors,; such as etanercept (Enbrel™; p75sTNF -receptor II dimer), lenerecept (p55sTNF receptor I fused to IgGl heavy chain fragment), and PEG-p55 sTNF -receptor I monomer; procysteine; elastase inhibitor; human recombinant interleukin 1 receptor antagonist (IL-1 RA); antibodies, inhibitors and antagonists to: an endotoxin (i.e., lipopolysaccharide, LPS, lipotechoic acid and the like, e.g., E-5531 (Eisai)); IL-6; high- mobility group box 1 (HMGB-1 or HMG-1); tissue plasminogen activator; Bradykinin; CD- 14, and/or IL-10; activators of protein C; and serine protease inhibitors such as antithrombin III. Those skilled in the art are familiar with the dosage and administration of these and other treatment options.
In one aspect, for any of the methods or compositions described herein, activated protein C can be substituted for another therapeutic agent that has anti-inflammatory, anticoagulant, pro-fibrinolytic, and anti-apoptotic activities, particularly anti-inflammatory activity. For example, if a therapeutic agent is substituted for activated protein C, an improved response is with respect to that therapeutic agent. In an aspect, protein C can be substituted for activated protein C.
"Activated protein C" is also known as Drotrecogin alfa (activated) or DrotAA and is sold as XIGRIS™ by Eli Lilly and Company. DrotAA is a serine protease glycoprotein of approximately 55 kilodalton molecular weight and having the same amino acid sequence as human plasma-derived Activated Protein C. The protein consists of a heavy chain and a light chain linked by a disulfide bond. XIGRIS™, Drotecogin alfa (activated) is indicated for the reduction of mortality in adult subjects with severe sepsis (sepsis associated with acute organ dysfunction) who have a high risk of death (e.g. , as determined by an APACHE II score of > 25 or having 2 or more organ system failures).
In another aspect, "activated protein C" may also include "GED-aPC." GED-aPC is an engineered analog of recombinant human activated Protein C (aPC) with enhanced cytoprotective, anti-inflammatory, anti-thrombotic and strong binding to endothelial protein C receptor properties (Cardiome Pharma Corp., Vancouver, British Columbia, Canada).
"Activated protein C" or "protein C like compound" as used herein includes any protein C molecule, protein C derivative, protein C variant, protein C analog and any prodrug thereof, metabolite thereof, isomer thereof, combination of isomers thereof, or
pharmaceutical composition of any of the preceding. Activated protein C or protein C like compound or protein C like compounds may be synthesized or purified. For example, Drotrecogin alfa (activated) is sold as XIGRIS™ by Eli Lilly and Company and has the same amino acid sequence as human plasma-derived Activated Protein C. Examples of
derivatives, variants, analogs, or compositions etc. may be found in US patent applications: 20050176083; 20050143283; 20050095668; 20050059132; 20040028670; 20030207435; 20030027299; 20030022354; and 20030018175 and issued US patents: 6,933,367;
6,841,371; 6,815,533; 6,630,138; 6,630,137; 6,436,397; 6,395,270; 6,162,629; 6,159,468; 5,837,843; 5,453,373; 5,330,907; 5,766,921; 5,753,224; 5,516,650; and 5,358,932 and the following publications: Kerschen et al, JEM, 204(10):2439-2448 (2007); Mosnier et al., Blood, 704:1740-1744 (2004); Gale et al, J. Biol. Chem., 227:28836-28840 (2007); and Gale et al, Protein Sci., 6: 1132-1140 (1997).
DrotAA is a recombinant form of human Activated Protein C, which may be produced using a human cell line expressing the complementary DNA for the inactive human Protein C zymogen, whereby the cells secrete protein into the fermentation medium. The protein may be enzymatically activated by cleavage with thrombin and subsequently purified. Methods, DNA compounds and vectors for producing recombinant activated human protein C are described in US Patent Nos. 4,775,624, 4,992,373, 5,196,322, 5,270,040, 5,270,178, 5,550,036, and 5,618,714, all of which are incorporated herein by reference.
Treatment of sepsis using activated protein C in combination with a bactericidal and endotoxin neutralizing agent is described in US Patent No. 6,436,397; methods for processing protein C is described in US Patent No. 6,162,629; protein C derivatives are described in US Patent Nos. 5,453,373 and 6,630,138; glycosylation mutants are described in US Patent No. 5,460,953; and Protein C formulations are described in US Patent Nos. 6,630,137, 6,436,397, 6,395,270, and 6,159,468, all of which are incorporated herein by reference.
XIGRIS™ DrotAA is available in 5 mg and 20 mg single-use vials containing sterile, preservative-free, lyophilized drug. The vials contain 5.3 mg and 20.8 mg of drotrecogin alfa (activated; Drot AA), respectively. The 5 and 20 mg vials of XIGRIS™ also contain 40.3 and 158.1 mg of sodium chloride, 10.9 and 42.9 mg of sodium citrate, and 31.8 and 124.9 mg of sucrose, respectively. XIGRIS™ is currently recommended for intravenous administration at an infusion rate of 24 mcg/kg/hr for a total duration of infusion of 96 hours. Dose adjustment based on clinical or laboratory parameters is currently not recommended. If the infusion is interrupted, it is currently recommended that when restarted the infusion rate should be 24 mcg/kg/hr. Dose escalation or bolus doses of drotrecogin alfa are currently not recommended. However, recommendations for the use of drotrecogin alfa may change and current recommendations are not intended to limit the present description of drotrecogin alfa. XIGRIS™ may be reconstituted with Sterile Water for Injection and further diluted with sterile normal saline injection. These solutions must be handled so as to minimize agitation of the solution (Product information. XIGRIS™, Drotecogin alfa (activated), Eli Lilly and Company, November 2001).
EXAMPLES
Example 1: Selection of improved response polymorphisms for activated protein C using a Genome Wide Association Study (GWAS) in the PROWESS cohort
The IRPs (improved response polymorphisms) and IRGs (improved response genotypes) described in this example comprise SNPs that are associated with a differential DrotAA treatment effect. The starting point for our investigation is a genome-wide association study (GWAS), conducted in the PROWESS Cohort (described in detail below) of subjects having an inflammatory condition due to sepsis.
PROWESS is a multicenter, randomized, double-blind, placebo-controlled study evaluating the efficacy of DrotAA in patients with severe sepsis. Eligible patients were enrolled from July 1998 through June 2000 (n=1690). Patients were eligible for the trial if they had a known or suspected infection on the basis of clinical data at the time of screening and if they met the following criteria within a 24-hour period: 3 or more signs of systemic inflammation and at least one sepsis-induced organ dysfunction. Patients begin treatment within 24 hours after they meet the inclusion criteria. Patients are randomly assigned in a 1 : 1 ratio to receive DrotAA or placebo (0.9 percent saline with or without 0.1 percent human serum albumin). Block randomization stratified according to site is used, and all assignments are made through a central randomization center. DrotAA is administered intravenously at a dose of 24 μg/kg/h for a total duration of 96 hours. The patients, investigators, and the sponsor are unaware of the patients' treatment assignments. The institutional review board at each center approves the protocol, and written informed consent is obtained from all participants or their authorized representatives. More detail regarding the protocol and results is reported by Bernard et al., New England Journal of Medicine, 344(10j:699-709 (2001).
The European Medicines Evaluation Agency (EMEA) approved DrotAA for the treatment of adult patients with severe sepsis and multiple organ failure, which is a subset of the PROWESS study population. The US FDA also approve DrotAA for a subset of the study population, specifically for patients with severe sepsis who are at high risk of death {e.g. , APACHE II > 25).
A total of 1446 patient samples are available for the genome wide association study
(GWAS). Genotyping is completed using the Illumina® Human lM-Duo BeadChip.
Two hundred and ninety- three top SNP biomarkers from the GWAS in the
PROWESS Cohort are selected based on three types of analysis:
(1) Logistic Regression Analyses (195 SNPs): a single SNP-by-DrotAA interaction analysis in the PROWESS cohort defining a subgroup showing statistical significance (p < 0.0001).
(2) Predicted functional relevance (58 SNPs): Non-synonymous SNPs that have an absolute risk reduction (ARR; difference in 28 day mortality between control and DrotAA-treated) of 20%, and a frequency of 10% in any genetic model in the complete PROWESS Cohort. Additionally, some SNPs with predicted functional relevance due to location in a gene regulatory region or a coding region are included. In all, 58 such SNPs are included.
(3) SNPs in genes with known relevance to the protein C pathway (40 SNPs): SNPs in candidate genes that also ranked highly in ARR in the PROWESS cohort.
Other criteria such as improved response genotype frequency (generally greater than 20%) and minor allele frequency (generally greater than 10%), and an absolute risk reduction in PROWESS (generally greater than 15%) are also considered when ranking the SNPs.
Table 5 shows the 293 IRP SNPs and the improved response genotypes (IRG) and non-response genotypes (NRG) at each of the SNPs. The absolute risk reduction and interaction P-value for the SNPs is also shown. Details regarding the assumptions made in each type of analysis done for each SNP is given in the notes below Table 5.
Table 5: 293 Improved Response Polymorphisms
Figure imgf000207_0001
SNP Interaction P- Analysis
# RSID of SNP IRG NRG POPn ARR Value Info
18 rsl 1149155 AG AA GG MOD 0.315 6.40X10"5 1
19 rsl 119642 AA GG AG MOD 0.136 8.50X10"5 3
20 rsl l250131 AG AA GG MOD 0.199 4.10X10"5 1
21 rsl 164857 CC CT TT AP 0.408 4.00X10"5 1
22 rsl 1786372 CT CC TT ALL 0.145 9.10X10"5 1
23 rsl 1894266 CT TT CC MOD 0.133 2.40X10"5 3
24 rsl 1984724 CT CC TT ALL 0.247 9.30X10"5 1
25 rsl2025108 AG AA GG AP 0.276 4.50X10"5 1
26 rsl 2159200 AA AG GG AP 0.254 6.00E-07 1
27 rsl2193402 AA CC AC AP 0.179 5.20X10"5 3
28 rsl 2317794 TT CC CT CAUC 0.118 2.20X10"5 1
29 rsl2327456 AT TT AA MOD 0.197 4.40X10"5 3
30 rsl2335840 CC CT TT AP 0.236 4.80X10"5 1
31 rsl2436579 AC CC AA AP 0.266 9.40X10"5 3
32 rsl 2494795 CC CT TT AP 0.224 8.80X10"5 1
33 rsl2513381 AA GG AG MOD 0.162 8.80X10"5 3
34 rsl2529871 GT TT GG MOD 0.145 7.20X10"5 3
35 rsl2573176 AC AA CC MOD 0.265 6.90X10"5 1
36 rsl2618741 CC CT TT CAUC 0.151 6.80X10"5 1
37 rsl265140 CG CC GG MOD 0.203 8.50X10"5 1
38 rsl266382 CT CC TT CAUC 0.169 7.10X10"5 1
39 rsl2680523 CT CC TT ALL 0.282 2.40X10"5 1
40 rsl2918570 CT CC TT MOD 0.173 6.80X10"5 1
41 rsl 294227 CC TT CT MOD 0.18 5.70X10"5 3
42 rsl2951391 CT CC TT MOD 0.263 1.80X10"5 1
43 rsl3153368 CC TT CT ALL 0.138 8.10X10"5 3
44 rsl3190448 AA AC CC MOD 0.166 4.60X10"5 1
45 rsl3247490 AG AA GG AP 0.271 2.80X10"5 1
46 rsl3250662 CT TT CC MOD 0.165 7.90X10"5 3
47 rsl3273073 GG TT GT ALL 0.124 7.20X10"6 3
48 rsl348181 AA AG GG AP 0.242 1.10X10-5 1
49 rsl355597 CC CT TT MOD 0.12 4.70X10"5 3
50 rsl 373649 AG AA GG AP 0.266 4.70X10"5 1
51 rsl411820 CC CT TT MOD 0.149 1.90X10"5 3
52 rsl478842 AA AG GG ALL 0.151 7.80X10"5 3
53 rsl560582 AA AG GG CAUC 0.145 6.10X10"5 1
54 rsl560941 AA GG AG MOD 0.163 8.90X10"5 3
55 rsl605461 AG AA GG AP 0.283 7.70 X10"6 1
56 rsl667223 AA CC AG AP 0.272 3.00X10"5 3
57 rsl6953047 GT GG TT ALL 0.21 6.90X10"5 1 SNP Interaction P- Analysis
# RSID of SNP IRG NRG POPn ARR Value Info
58 rs 17014760 AA GG AG CAUC 0.123 8.30X10"5 3
59 rsl7114618 CC CT TT ALL 0.093 9.20X10"5 1
60 rsl7151969 AA CC AC CAUC 0.105 2.00X10"5 3
61 rsl 7172693 CC CT TT AP 0.184 2.00 X10-7 1
62 rsl7209998 CC CT TT MOD 0.167 4.90X10"5 1
63 rsl7278159 CT TT CC CAUC 0.193 9.80X10"5 3
64 rsl 74948 AG AA GG ALL 0.157 6.90X10"5 1
65 rsl74957 AG AA GG ALL 0.167 3.90X10"5 1
66 rsl7507051 CC CT TT AP 0.272 1.60X10"5 1
67 rsl7781459 AG GG AA CAUC 0.279 7.60X10"5 3
68 rsl7839997 AA AC CC AP 0.183 4.70X10"5 1
69 rsl 823790 AA AG AA AP 0.23 3.90X10"5 3
70 rsl 897833 GT GG TT MOD 0.282 3.90X10"5 1
71 rsl915279 AG AA GG AP 0.339 8.00 X10-7 1
72 rs2024408 CT TT CC AP 0.213 8.40X10"5 3
73 rs2027363 AA GG AG CAUC 0.15 9.50X10"5 3
74 rs2048070 GG AA AG ALL 0.164 0.0027125 2
75 rs2069643 AG AA GG AP 0.285 4.50X10"5 1
76 rs2076977 CT TT CC ALL 0.127 3.60X10"5 3
77 rs2110167 AA GG AG MOD 0.178 1.30X10"5 3
78 rs2159688 AA AG GG MOD 0.19 8.40X10"5 1
79 rs2170169 AG GG AA AP 0.207 9.00X10"5 3
80 rs2178032 CC TT CT AP 0.273 7.70X10"5 3
81 rs2240660 CC TT CT CAUC 0.14 9.30X10"5 3
82 rs2246277 CC TT CT ALL 0.128 4.50X10"5 3
83 rs227397 CC TT CT ALL 0.134 5.90X10"5 3
84 rs2280665 AA GG AG AP 0.281 3.60X10"5 3
85 rs2310160 CC TT CT AP 0.27 8.90X10"5 3
86 rs2322784 CT CC TT CAUC 0.219 3.90X10"5 1
87 rs2341551 AG AA GG CAUC 0.238 9.50X10"5 1
88 rs2394824 AA AG GG CAUC 0.185 4.40X10"5 3
89 rs2501976 CT TT CC CAUC 0.147 3.30X10"5 3
90 rs2531894 AA AG GG AP 0.479 8.30X10"5 1
91 rs2598414 CC TT CT ALL 0.131 2.50X10"5 3
92 rs2653814 GT GG TT MOD 0.215 7.30X10"5 1
93 rs2694418 TT GG GT AP 0.378 5.10X10"5 1
94 rs2695027 AA GG AG MOD 0.163 9.90X10"5 3
95 rs2716555 GG AA AG ALL 0.202 0.0001613 2
96 rs2716601 AA AG GG ALL 0.192 1.00 X10-6 1
97 rs2721952 CT CC TT ALL 0.148 6.50X10"5 1 SNP Interaction P- Analysis
# RSID of SNP IRG NRG POPn ARR Value Info
98 rs2728981 AA AG GG ALL 0.202 9.80X10"5 1
99 rs2729140 AG AA GG AP 0.279 2.40X10"5 1
100 rs2729547 CC TT CT CAUC 0.142 5.00X10"5 3
101 rs2829523 AC CC AA MOD 0.19 7.80X10"5 3
102 rs2942917 AA AG GG MOD 0.159 8.30X10"5 3
103 rs310244 AG AA GG MOD 0.233 5.20X10"5 1
104 rs3118050 CT TT CC AP 0.238 4.70X10"5
105 rs3130454 AG AA GG ALL 0.156 7.40X10"5 1
106 rs321224 CC TT CT AP 0.201 5.80X10"5
107 rs359447 CT CC TT ALL 0.189 2.50X10"5 1
108 rs3813026 AA AG GG AP 0.195 9.20 X10-6 1
109 rs3816253 CC CT TT MOD 0.162 3.90X10"5
110 rs3847794 AG AA GG AP 0.305 6.20X10"5 1
111 rs3963484 AA AG GG ALL 0.161 0.0005785
112 rs4140512 AA AG GG AP 0.242 2.60X10"5 1
113 rs4237265 CT CC TT CAUC 0.165 1.60X10"5 1
114 rs426357 AG AA GG MOD 0.216 2.80X10"5 1
115 rs4322073 CC TT CT CAUC 0.147 9.20X10"5
116 rs4331850 AA AG GG MOD 0.18 5.00X10"5 1
117 rs4369611 AA GG AG MOD 0.172 8.10X10"5
118 rs4525972 AG AA GG ALL 0.144 9.80X10"5 1
119 rs4553010 AG AA GG MOD 0.342 1.30X10"5 1
120 rs4595752 GT GG TT CAUC 0.153 9.30X10"5 1
121 rs4608848 CC CT TT ALL 0.301 5.70X10"5 1
122 rs471814 AA AG GG ALL 0.177 5.40X10"5 1
123 rs4729408 CT CC TT MOD 0.221 8.50X10"6 1
124 rs4876024 CT CC TT AP 0.299 8.00X10"5 1
125 rs4952903 GT TT GG CAUC 0.162 9.30X10"5
126 rs4975300 CC CT TT CAUC 0.137 2.00X10"5 1
127 rs530461 AG AA GG MOD 0.197 6.40X10"5 1
128 rs589258 CT CC TT MOD 0.209 2.70X10"5 1
129 rs6012750 AG AA GG MOD 0.2 2.50X10"5 1
130 rs611003 AA AC CC ALL 0.21 8.00X10"5 1
131 rs626545 GG AA AG MOD 0.28 8.40X10"5 1
132 rs6446731 AG AA GG MOD 0.2 3.20X10"5 1
133 rs6482910 CC TT CT CAUC 0.141 8.20X10"5
134 rs6489851 CT CC TT CAUC 0.224 7.50X10"5 1
135 rs651844 CT CC TT MOD 0.183 7.70X10"5 1
136 rs6549946 AA GG AG AP 0.238 4.00X10"5 3
137 rs6713126 TT CC CT CAUC 0.15 8.30X10"5 1 SNP Interaction P- Analysis
# RSID of SNP IRG NRG POPn ARR Value Info
138 rs6780177 CT CC TT MOD 0.298 3.90X10"5 1
139 rs6864 AC AA CC MOD 0.175 4.40X10"5 1
140 rs6893958 AA AG GG CAUC 0.26 3.50X10"5 1
141 rs6896102 GG GT TT MOD 0.176 1.90X10"5 1
142 rs6909151 AG GG AA AP 0.415 9.40X10"6 3
143 rs6918854 AA GG AG MOD 0.188 1.70X10"5 3
144 rs6922979 AA GG AG MOD 0.165 2.50X10"6 3
145 rs6925087 TT AA AT MOD 0.217 2.50X10"5 1
146 rs6941022 TT CC CT MOD 0.255 4.50X10"6 1
147 rs6953258 CC CT TT ALL 0.21 3.00X10"5 1
148 rs6972943 AG AA GG CAUC 0.186 4.70X10"5 1
149 rs6977578 CC CT TT MOD 0.237 9.20X10"5 1
150 rs6981251 AA AG GG CAUC 0.114 6.10X10"5 1
151 rs6987100 AA AG GG CAUC 0.116 5.00X10"5 1
152 rs7110072 CC CT TT MOD 0.125 6.00X10"5 1
153 rs7120011 TT GG GT CAUC 0.087 9.80X10"5 1
154 rs7134223 TT GG GT ALL 0.084 1.00X10-4 1
155 rs7292804 GG GT TT AP 0.231 1.90X10"5 1
156 rs7305954 CC TT CT MOD 0.142 9.50X10"5 3
157 rs7409 CC TT CT ALL 0.124 5.90X10"5 3
158 rs7425164 CC CT TT AP 0.284 6.40X10"5 1
159 rs7444603 AA CC AC AP 0.236 3.20X10"5 3
160 rs7523607 AA CC AC MOD 0.157 6.70X10"5 3
161 rs7544877 CT TT CC MOD 0.14 6.80X10"5 3
162 rs7551773 AG GG AA MOD 0.219 2.80X10"6 3
163 rs7572996 AG AA GG AP 0.273 7.80X10"5 1
164 rs7582779 AG GG AA CAUC 0.124 9.50X10"5 3
165 rs7617493 CT CC TT CAUC 0.154 8.10X10"5 1
166 rs7641222 AC AA CC CAUC 0.16 6.90X10"5 1
167 rs7673752 AC AA CC AP 0.269 6.90X10"5 1
168 rs7702195 CT CC TT ALL 0.137 9.20X10"5 1
169 rs7795499 CC TT CT MOD 0.199 1.80X10"5 3
170 rs7815122 GG GT TT CAUC 0.121 5.50X10"5 1
171 rs7867693 AG AA GG AP 0.475 3.20X10"5 1
172 rs7970821 CC TT CT CAUC 0.164 2.50X10"5 3
173 rs7974223 AA AG GG AP 0.403 3.40X10"5 1
174 rs7979573 AG GG AA AP 0.235 2.40X10"5 3
175 rs7986188 AA GG AG CAUC 0.143 3.70X10"5 3
176 rs8028880 CC CT TT CAUC 0.201 1.00X10-4 1
177 rs8041979 AG AA GG MOD 0.211 9.30X10"5 1 SNP Interaction P- Analysis
# RSID of SNP IRG NRG POPn ARR Value Info
178 rs835481 cc CT TT AP 0.683 1.50X10"5 1
179 rs922902 CG GG CC CAUC 0.156 5.90X10"5 3
180 rs9291224 CC TT CT CAUC 0.132 7.10X10"5 3
181 rs9296272 CC TT CT CAUC 0.152 8.70X10"5 3
182 rs9372243 AG GG AA AP 0.352 7.10X10"5 3
183 rs9373836 TT CC CT CAUC 0.112 3.00X10"4 1
184 rs9460540 AG GG AA CAUC 0.133 1.60X10"6 3
185 rs9554684 CT CC TT CAUC 0.186 9.90X10"5 1
186 rs9587280 CT TT CC MOD 0.124 6.90X10"5 3
187 rs958738 AA GG AG MOD 0.185 4.00X10"6 3
188 rs966775 AA AG GG AP 0.242 1.60X10"5 1
189 rs9815663 CT TT CC ALL 0.154 8.80X10"5 3
190 rs993691 CC TT CT CAUC 0.165 2.40X10"5 3
191 rs9962772 AC CC AA AP 0.185 5.10X10"5 3
192 rsl2380611 CC CT TT CAUC 0.257 4.10X10"5 1
193 rsl2423283 TT CC CT CAUC 0.115 8.00X10"5 1
194 rsl 813758 GT GG TT CAUC 0.147 2.40X10"5 1
195 rs2665981 AA GG AG ALL 0.119 6.40X10"5 3
196 rsl0165340 CT CC TT ALL 0.194 0.0362075 2
197 rsl042277 CC CT TT ALL 0.185 0.0110753 2
198 rsl0486391 GG AA AG ALL 0.202 0.0046185 2
199 rsl0812532 GG GT TT TG ALL 0.157 0.0703898 2
200 rsl l585501 AC AA CC ALL 0.169 0.0477115 2
201 rsl 1645653 CC TT CT ALL 0.101 0.0018848 2
202 rs 1421940 AA AC CC ALL 0.27 0.0007521 2
203 rs1445943 AA CC AC ALL 0.122 0.0003402 2
204 rsl457238 AA AG GG ALL 0.221 0.0084635 2
205 rsl53141 GG AA AG ALL 0.183 0.0185842 2
206 rsl7318470 CT CC TT ALL 0.232 0.0003887 2
207 rsl991013 TT CC CT ALL 0.171 0.005632 2
208 rs2222202 AA AG GG ALL 0.152 0.0562453 2
209 rs2257096 GG AA AG ALL 0.169 0.0329532 2
210 rs2515481 GG AA AG ALL 0.152 0.0580587 2
211 rs2756901 CC CT TT ALL 0.17 0.001803 2
212 rs2916755 AA AG GG ALL 0.151 0.1338035 2
213 rs3024496 GG AA AG ALL 0.153 0.0503108 2
214 rs3176876 GG AA AG ALL 0.185 0.0246937 2
215 rs3176877 AA AT TT ALL 0.186 0.0114639 2
216 rs3212435 TT GG GT ALL 0.181 0.0790313 2
217 rs3212439 TT CC CT ALL 0.122 0.0024543 2 SNP Interaction P- Analysis
# RSID of SNP IRG NRG POPn ARR Value Info
218 rs3212461 GG TT GT ALL 0.115 0.0011478 2
219 rs3212464 AA GG AG ALL 0.114 0.0018234 2
220 rs3212481 CC CT TT ALL 0.122 0.0035128 2
221 rs3212640 CC CG GG ALL 0.165 0.009176 2
222 rs3733138 AG AA GG ALL 0.158 0.1295563 2
223 rs3768777 GG AA AG ALL 0.139 0.0011145 2
224 rs3917019 AA AG GG ALL 0.182 0.0417436 2
225 rs4777049 CC CT TT ALL 0.156 0.0626506 2
226 rs4941183 GG AA AG ALL 0.161 0.0307006 2
227 rs4987821 CT CC TT ALL 0.159 0.0662885 2
228 rs6119410 CT CC TT ALL 0.182 0.0667687 2
229 rs641153 AG AA GG ALL 0.158 0.0502088 2
230 rs6755175 AG AA GG ALL 0.164 0.0245673 2
231 rs7032817 TT CC CT ALL 0.154 0.1267729 2
232 rsl0230573 AA AG GG ALL 0.203 0.0065302 2
233 rsl042327 TT CC CT ALL 0.201 0.00072 2
234 rsl0950521 CC CT TT ALL 0.208 0.0318094 2
235 rsl l6187 AA AG GG ALL 0.202 0.027099 2
236 rsl258236 AG AA GG ALL 0.202 0.0202021 2
237 rsl363560 CC CT TT ALL 0.203 0.0445694 2
238 rs 137794 AA AG GG ALL 0.215 0.0001474 2
239 rsl386440 AA AG GG ALL 0.296 0.0017309 2
240 rsl563632 GG AA AG ALL 0.26 0.0028106 2
241 rsl7395296 AA AG GG ALL 0.222 0.0011551 2
242 rsl7724627 CC CT TT ALL 0.203 0.0147295 2
243 rsl 805100 AA AG GG ALL 0.186 0.0037091 15
244 rs2016224 GG AA AG ALL 0.205 0.013276 2
245 rs2020860 CT CC TT ALL 0.202 0.0458854 2
246 rs2073619 AG AA GG ALL -0.107 4.59X10"5 2
247 rs2073721 AG AA GG ALL 0.145 0.0031686 16
248 rs2276932 AG AA GG ALL 0.216 0.0119172 2
249 rs2827845 AG AA GG ALL -0.1 0.0003938 2
250 rs2941483 AA AG GG ALL -0.114 0.0001568 2
251 rs2989946 AG AA GG ALL 0.156 0.0001256 4
252 rs3746766 GG AA AG ALL 0.211 0.0112974 2
253 rs3848668 AG AA GG ALL 0.22 0.0289594 2
254 rs397250 GG AA AG ALL 0.212 0.0195317 2
255 rs4149338 AA AG GG ALL 0.231 0.0046458 2
256 rs4267943 AA AG GG ALL 0.207 0.0126591 2
257 rs4354185 AA AG GG ALL 0.254 0.0008996 2 SNP Interaction P- Analysis
# RSID of SNP IRG NRG POPn ARR Value Info
258 rs4371530 TT CC CT ALL 0.218 0.0114489 2
259 rs4715631 TT CC CT ALL 0.209 0.0189541 2
260 rs4757548 AA AG GG ALL 0.225 0.0006754 2
261 rs5847 TT CC CT ALL -0.109 0.0002262 2
262 rs711173 CC CT TT ALL 0.207 0.0168698 2
263 rs7535528 AA AG GG ALL 0.207 0.0113453 2
264 rs7610425 CC CT TT ALL 0.222 0.0064342 2
265 rs7861460 GG GT TT ALL 0.247 0.0007118 2
266 rs7940667 AC AA CC ALL 0.204 0.0124081 2
267 rs7992 TT CC CT ALL 0.213 0.0184248 2
268 rs8128 AA AC CC ALL 0.176 0.0029846 12
269 rs397686 CC AA AC ALL 0.21 0.0235153 2
270 rs4936280 TT CC CT ALL 0.217 0.0420013 2
271 rs8878 AA AG GG ALL 0.201 0.005181 2
272 rs684923 TT CC CT ALL 0.205 0.0028516 2
273 rs640098 AA AG GG ALL 0.224 0.0021078 2
274 rs3751501 AA AG GG ALL 0.204 0.0036014 2
275 rs3179969 AA AG GG ALL 0.217 0.0189543 2
276 rsl 1159859 GG GC CC ALL 0.169 0.0477796 20
277 rs 12436642 AA AG GG ALL 0.169 0.0477796 21
278 rsl2436982 AA AG GG ALL 0.176 0.2586335 8
279 rsl342836 GG AA AG ALL 0.185 0.0025867 7
280 rs1344747 AA AT TT ALL 0.169 0.0477796 22
281 rsl7188228 CC CT TT ALL 0.195 0.1583078 10
282 rsl950806 TT CC CT ALL 0.217 0.096128 2
283 rs2274737 CC CT TT ALL 0.159 0.3274403 13
284 rs3742484 AT TT AA 23
285 rs3742486 AG AA GG ALL 0.196 0.0038284 2
286 rs3783889 TT AA AT ALL 0.217 0.0189543 17
287 rs3814855 AA AG GG ALL 0.159 0.3274403 14
288 rs61977053 AA AC CC ALL 0.227 0.0412643 5
289 rs61984684 CC CT TT ALL 0.176 0.2586335 9
290 rs625006 GG AA AG ALL 0.213 0.0013429 2
291 rs8017689 CC CT TT ALL 0.217 0.0189543 18
292 rs8020072 CC CT TT ALL 0.181 0.1895562 19
293 rs930181 TT CC CT ALL 0.169 0.0477796 2
Analysis Info Key
1 ARR and IntPval Data from PROWESS logistic outputs for chosen model (no
assumption)
2 ARR Support data taken from PROWESS data and IntPval computed based on the assumption of 50:50 treatmen placebo distribution within genotype group
IntPval from PROWESS logistic outputs in the complement of chosen model and ARR obtained from the predicted data of the chosen model
ARR support data taken from PROWESS data and IntPval computed based on the assumption of 50:50 treatmentplacebo distribution within genotype group and mortality of 30.8% in placebo group
ARR support data taken from PROWESS data and IntPval computed based on the assumption of 50:50 treatmentplacebo distribution within genotype group using proxy SNP rsl2433464 in CEU RSquared 0.917 with chosen SNP rs61977053
ARR support data taken from PROWESS data and IntPval computed based on the assumption of 50:50 treatmentplacebo distribution within genotype group using proxy SNP rsl2725455 in CEU RSquared 1 with chosen SNP rsl342836
ARR support data taken from PROWESS data and IntPval computed based on the assumption of 50:50 treatmentplacebo distribution within genotype group using proxy SNP rsl7260380 in CEU RSquared 0.956 with chosen SNP rsl2436982
ARR support data taken from PROWESS data and IntPval computed based on the assumption of 50:50 treatmentplacebo distribution within genotype group using proxy SNP rs 17260380 in CEU RSquared 1 with chosen SNP rs61984684
ARR support data taken from PROWESS data and IntPval computed based on the assumption of 50:50 treatmentplacebo distribution within genotype group using proxy SNP rsl956406 in CEU RSquared 1 with chosen SNP rsl7188228
ARR support data taken from PROWESS data and IntPval computed based on the assumption of 50:50 treatmentplacebo distribution within genotype group using proxy SNP rs222498 in CEU RSquared 0.983 with chosen SNP rs8128
ARR support data taken from PROWESS data and IntPval computed based on the assumption of 50:50 treatmentplacebo distribution within genotype group using proxy SNP rs2295135 in CEU RSquared 0.958 with chosen SNP rs2274737
ARR support data taken from PROWESS data and IntPval computed based on the assumption of 50:50 treatmentplacebo distribution within genotype group using proxy SNP rs2295135 in CEU RSquared 1 with chosen SNP rs3814855
ARR support data taken from PROWESS data and IntPval computed based on the assumption of 50:50 treatmentplacebo distribution within genotype group using proxy SNP rs2941477 in CEU RSquared 1 with chosen SNP rs 1805100
ARR support data taken from PROWESS data and IntPval computed based on the assumption of 50:50 treatmentplacebo distribution within genotype group using proxy SNP rs3132528 in CEU RSquared 1 with chosen SNP rs2073721
ARR support data taken from PROWESS data and IntPval computed based on the assumption of 50:50 treatmentplacebo distribution within genotype group using proxy SNP rs3179969 in CEU RSquared 0.963 with chosen SNP rs3783889
ARR support data taken from PROWESS data and IntPval computed based on the assumption of 50:50 treatmentplacebo distribution within genotype group using proxy SNP rs3179969 in CEU RSquared 0.963 with chosen SNP rs8017689
ARR support data taken from PROWESS data and IntPval computed based on the assumption of 50:50 treatmentplacebo distribution within genotype group using proxy SNP rs8021690 in CEU RSquared 1 with chosen SNP rs8020072
ARR support data taken from PROWESS data and IntPval computed based on the assumption of 50:50 treatmentplacebo distribution within genotype group using proxy SNP rs930181 in CEU RSquared 0.926 with chosen SNP rsl 1159859
ARR support data taken from PROWESS data and IntPval computed based on the assumption of 50:50 treatmentplacebo distribution within genotype group using proxy SNP rs930181 in CEU RSquared 1 with chosen SNP rsl2436642
22 ARR support data taken from PROWESS data and IntPval computed based on the assumption of 50:50 treatmen placebo distribution within genotype group using proxy SNP rs930181 in CEU RSquared 1 with chosen SNP rs 1344747
23 CEU RSquared 0.6 with ACINI rs3751501 AND no other proxy in Illumina 1M dual array with CEU RSquared >= 0.8 to assess expected outcome
Example 2: Replication study of improved response polymorphisms in an additional patient cohort
To further rank the IRP SNPs in terms of predictive value, the top SNP markers from the PROWESS GWAS are further tested in a replication cohort. The SPH and VASST cohorts, described below, are combined to act as a single replication cohort for the top SNP biomarkers from the PROWESS GWAS.
The St. Paul's Hospital cohort (SPH) is a registry from one hospital in Vancouver, British Columbia, Canada. Over the period from July 2000 through January 2004, all patients over the age of 18 admitted into the intensive care unit at SPH are screened and admitted into the cohort study if they met 2 of 4 systemic inflammatory response syndrome (SIRS) criteria and a blood sample is available for genotype analyses. In total, 1024 patients with severe sepsis are recruited into the registry. Severe sepsis is defined as the presence of a known or suspected infection and at least one new organ failure. This cohort is used for multiple genomic studies and therefore DNA availability is extremely limited. Thus the number of patients that are included for the replication analyses is 265, of which only 38 are treated with DrotAA.
VASST is a large multicenter randomized controlled clinical trial to investigate the efficacy of vasopressin versus norepinephrine in patients with septic shock. It was conducted from July 2001 through April 2006 at 27 centers in Canada, Australia, and the US. Patients included in the VASST trial are older than 16 years of age and had septic shock that is resistant to fluids. More specifically, patients had to have 2 of 4 SIRS criteria plus known or suspected infection, hypotension, vasopressor requirement, and one other new acute organ dysfunction. St. Paul's Hospital participated in the VASST study. Patients that are enrolled into both VASST and the SPH cohort are included only once in the combined dataset. In total, 779 patients are enrolled in the VASST study, but only 473 could be included for the replication analyses, of which 103 are treated with DrotAA.
Therefore, the combined replication cohort included 738 patients, of which 141 are treated with DrotAA. As would be expected in these cohorts that did not randomize patients to treatment with or without DrotAA, the baseline characteristics of the 141 DrotAA-treated patients and the 597 nonDrotAA-treated patients are significantly different. The DrotAA- treated patients are younger with greater severity of disease (Table 5).
These imbalances would confound assessments of efficacy based on mortality.
Therefore, to overcome this treatment selection bias, a suitable control group consisting of up to three nonDrotAA-treated patients for every DrotAA-treated patient is selected using the methods described below. Very good balance is achieved between the DrotAA-treated patients and the matched untreated (control) patients. Table 6 below shows the baseline characteristics for the replication cohort before and after the selection of matched patients. The final replication cohort includes 130 DrotAA patients and 286 matched controls
(nonDrotAA-treated) .
Clinical data from both the SPH and VASST cohorts is anonymized at St. Paul's Hospital prior to transfer to us.
The eligibility criteria for the combined SPH & VASST replication cohort are as follows:
1) Age >18 years
Severe sepsis (must meet a, b, and c below)
a. Suspected or proven infection
b. Systemic Inflammatory Response Syndrome (SIRS) (must meet 2 of 4
criteria)
i. Temperature <36 or >38 °C
ii. Heart rate >90 beats/minute
iii. Respiratory rate >20 breaths/minute or PaC02 <32 mm Hg) or on
mechanical ventilation
iv. White blood cell count <4,000/mm3 or >12,000/mm3 c. At least one organ dysfunction due to sepsis based on definition of clinically significant organ dysfunction from Brussels Score, which are modified slightly for practical reasons
i. Cardiovascular dysfunction [must meet one of (1), (2), or (3) below]:
1. Use of a vasopressor
2. Systolic blood pressure (SBP) <90 mmHg and pH <7.3
3. Mean arterial pressure (MAP) <70 mmHg and pH <7.3 ii. Pulmonary dysfunction: Pa02/Fi02 <300 mmHg
iii. Central Nervous System dysfunction: Glasgow Coma Scale <12 iv. Coagulation dysfunction: platelets <80,000/mm v. Renal dysfunction: creatinine >2.0 mg/dL (>170 μηιοΙ/L) vi. Hepatic dysfunction: bilirubin > 2.0 mg/dL (>33 μmol/L)
2) High risk of death (one of a or b below)
a. APACHE II >25
b. Multiple organ dysfunction - two or more clinically significant organ dysfunctions (as defined above)
3) Platelet counts >30,000/mm3
Genotyping
DNA is extracted from whole blood and genotyped using the Illumina 1M Duo microarray for VASST patients and Sequenom Iplex technology for SPH patients.
Genetic data quality control is performed for each patient sample and for each genetic marker. Given that two genotyping techniques are used, two sets of quality criteria are specified below.
Genotyping in the VASST cohort
The following quality criteria are met for all SNPs genotyped on the Illumina lm Duo microarray:
1. DNA sample must have at least an 90% genotyping success rate (data for 90% of markers are successful).
2. Hardy- Weinberg equilibrium (HWE) -values >10"10. SNPs that have HWE -values between 10"10 and 10"15 are included in the analysis, but are examined at an individual level, and scientific judgment is used in assessing if the SNPs should be included in any further analyses (looking at raw intensity data to determine if small -value is real or if it depicts an assay failure).
3. Missing rate < 5% (call rate less than or equal to 5% for each marker).
4. Patient gender is verified using X chromosome heterozygosity. If discordance exists the patients is excluded from further analysis.
5. A genetic distance is determined between all samples based on SNPs that overlap with the SPH genotyping effort and then a distance matrix is built. For identical samples, it is expected that the smallest genetic distance (with highest agreement) will be observed on the diagonal in the matrix. If an unintentional duplicate is found (genetic distance < 5% or smaller than that of the maximal distance of verified intentional duplicates), the duplicates are excluded from further analyses. Genotyping in the SPH Cohort
The following quality criteria are met for all SNPs genotyped using Sequenom Iplex technology:
1. DNA sample must have at least an 90% genotyping success rate (data for 90% of markers are successful).
2. HWE P values of >10"5. SNPs that have HWE P- values between 10"5 and 10"10 are included in the analysis, but are examined at an individual level, and scientific judgment is used in assessing if the SNPs should be included in any further analyses (look at raw data to determine if small -value is real or if it depicts an assay failure).
3. Missing rate < 5% (call rate was less than or equal to 5% for each marker)
4. A genetic distance is determined between all samples and then a distance matrix is built. For identical samples, it is expected that the smallest genetic distance (with highest agreement) would be observed on the diagonal in the matrix. If an
unintentional duplicate is found (genetic distance < 5% or smaller than that of the maximal distance of verified intentional duplicates), the duplicates are excluded from further analyses.
Selection of Matched Patients
Methods to control for confounding include regression methods where key variables are used as adjustment factors. A design-based approach of matching is used. In order to use observational data to make comparisons of mortality among treated subjects to mortality among untreated subjects, either design-based or analysis-based methods are necessary to control for any characteristics that differ systematically across the groups. A standard design- based option selects a sample of untreated subjects (controls) that match treated subjects on key measured clinical and demographic characteristics. A design-based approach of matching is chosen because it allows tight control for key measures, produces a control sample that is directly comparable to the treated sample, and permits efficient use of resources since only a sub-sample of all possible controls are needed for detailed evaluation.
A well-matched control group is critical in reducing treatment selection bias. It is possible that genotype will be prognostic for survival independent of treatment with DrotAA. Therefore to ascertain the predictive quality of the genomic biomarker with respect to the DrotAA treatment effect, the mortality in well-matched controls is estimated for each genotype subcategory so that the difference in mortality due to DrotAA treatment can be calculated. Within each cohort, control patients are selected programmatically to match the DrotAA-treated patients using an algorithm that matches on baseline demographic and disease characteristics that may have influenced the decision to give DrotAA or that may impact survival. The optimal matching method, described in more detail below, uses a calculated Mahalanobis distance with calipers applied for the two most important individual clinical covariates, age and APACHE II score, and for propensity score which is calculated using 10 covariates (described below). The caliper for age is set at 5 years. The caliper for APACHE II is set at 2 points. The propensity score caliper is set at the value that represents +/- 0.6 standard deviations to define subgroups of approximately 20% of the sample within which a match must be made. The process of applying calipers ensures that matched sets is tightly controlled and effectively removes indication bias from subsequent analyses.
A propensity score (the likelihood for having received DrotAA treatment) is derived using the same covariates as included in the distance calculation but is calculated by combining patients from both cohorts. This means that covariates are included if the data are available in both cohorts. The covariates included are:
• Age
• APACHE II
• Cardiovascular failure
• Respiratory failure
· Mechanical ventilation status
• Renal failure
• Hematologic failure
• Surgical status
• Geographic location
· Cohort (SPH or VASST)
Model Statement for Propensity Score
DrotAA ~ age + APACHE II + cardiovascular organ failure + respiratory organ failure + mechanical ventilation status + renal organ failure + hematologic organ failure + surgical status + geographic location + cohort, family = binomial The number of matched control patients is variable, up to a maximum of 3. This increases the precision in the estimation of the difference between treated and matched control patients. To control for differences in the St Paul's and VASST cohort the selection of matched control patients is done independently.
Matched control patients are selected for all eligible DrotAA-treated patients using an optimal matching methodology. This is done using optimal matching, which in contrast to greedy matching (where treated patients are matched in sequence; nearest neighbor) considers average distance across matched units, therefore resulting in the smallest possible total within-pair distance. Within each study cohort, the match is made using a single
Mahalanobis distance calculated between all treated and untreated patients. The Mahalanobis distance is calculated for all covariates that are predefined as having either influenced the decision to give DrotAA or that may have impacted survival. Due to some differences between the cohorts with respect to available clinical data, the calculation of the Mahalanobis distance varies slightly for the two cohorts, as summarized in Table 6.
Table 6: Variables used in the calculation of the Mahalanobis distance for the SPH and VASST cohorts
Included in Calculation of the
Mahalanobis Distance
Covariate
for Specific Cohort Explanation for Differences SPH Cohort VASST Cohort
Age Yes Yes
APACHE II score Yes Yes
All patients in VASST, a septic
Cardiovascular
Yes No shock study, had cardiovascular failure (yes/no)
failure
Respiratory failure
Yes Yes
(yes/no)
Mechanical
ventilation status Yes Yes
(yes/no)
Renal failure
Yes Yes
(yes/no)
Hematologic failure
Yes Yes
(yes/no)
Surgical status
Yes Yes
(yes/no) Included in Calculation of the
Mahalanobis Distance
Covariate
for Specific Cohort Explanation for Differences SPH Cohort VASST Cohort
Primary site of
infection (lung vs No Yes Data not available for SPH other)
Geographic
location (North All patients in SPH cohort from
No Yes
America vs North America
Australia)
Caucasian ethnicity Ethnicity not available for SPH
No Yes
(yes/no) cohort
Table 7 below describes the matching model covariates after optimal matching is applied in VASST and SPH separately and combined. The tables list 25th percentile, median, 75th percentile as well as the mean and standard deviation for all continuous covariates and percentage and absolute count for dichotomous covariates used in the match. Additional baseline characteristics are also included to assess balance between treated patients and matched controls. A weighted mean difference or a weighted Chi-square statistic is calculated comparing treated to control patients to test for significant differences in covariates before and after the match. Weights are used to account for the multiple controls (either 3, 2, or 1) that are matched to each exposed subject. Control subjects are assigned a weight equal to the reciprocal of the number of controls in the matched set to which they belong. The weighted test statistics are calculated using a linear regression via glm in the "stats" statistical analysis package in R (R Development Team) with a specification of a Gaussian family for continuous outcomes and a binomial family for binary outcomes.
Table 7: Baseline Characteristics of Replication Cohorts Before and After Matching
Before Matching After Matching
Demographic VASST Cohort SPH Cohort VASST & SPH Combined or Disease DrotAA Control P- DrotAA Control P- DrotAA Control" P- Characteristic (n=103) (n=370) value (n=38) (n=227) value (n=130) (n=286) value
Age
1st Quartile/ 47.0/ 53.0/ 0.009 37.0/ 50.0/ 0.072 47.25/ 48.1/ 0.886 Median/ 59.0/ 65.0/ 59.5/ 63.0/ 60.5/ 62.0/
3rd Quartile 70.0 73.0 68.8 73.0 70.0 70.9
57.6 ± 62.0 ± 54.6 ± 61.0 ± 58.4 ± 58.7 ±
Mean ± SD
15.6 15.4 20.1 14.9 15.4 15.3
Women
(Percentage of 35.9% 41.4% 0.320 44.7% 33.5% 0.178 40.0% 36.8% 0.596 Patients)
APACHE II
Score
1st Quartile/ 23.0/ 22.0/ 21.3/ 18.0/ 23.0/ 23.0/
Median/ 3rd 28.0/ 26.0/ 0.253 25.0/ 22.0/ 0.020 27.0/ 26.6/ 0.862 Quartile 32.0 32.0 29.5 27.0 31.0 31.0
27.8 ± 25.7 ± 22.9 ± 27.1 ±
Mean ± SD 27.0 ± 7.4 27.0 ± 5.9
6.2 6.4 7.2 5.8
Medical
(Percentage of 85.4% 76.5% 0.051 89.5% 83.3% 0.332 86.2% 79.4% 0.106 Patients)
Organ Failure
(Percentage of
Patients)
Before Matching After Matching
Demographic VASST Cohort SPH Cohort VASST & SPH Combined or Disease DrotAA Control P- DrotAA Control P- DrotAA Control" P- Characteristic (n=103) (n=370) value (n=38) (n=227) value (n=130) (n=286) value
Cardiovascular 100.0% 100.0% 1. .000 84.2% 82.4% 0.783 95.4% 96.2% 0.418
Respiratory 85.4% 85.4% 0, .994 94.7% 93.0% 0.686 86.9% 86.0% 0.710
Renal 61.2% 46.2% 0, .007 47.4% 46.3% 0.899 59.2% 55.5% 0.172
Hematologic 23.3% 19.5% 0, .391 13.2% 13.7% 0.934 19.2% 15.1% 0.292
CNS 35.9% 45.1% 0, .095 73.7% 55.1% 0.032 45.4% 52.7% 0.093
Hepatic 25.5% 26.6% 0, .832 21.6% 20.7% 0.903 23.2% 24.9% 0.761
Ventilation
(Percentage of 98.1% 93.5% 0, .073 100.0% 89.4% 0.036 99.2% 99.2% 1.000
Patients)
Caucasian
(Percentage of 80.6 % 83.2% 0, .528 NA NA NA NA
Patients)
Weighted values for control group (see Section 10.
No significant difference by DrotAA is observed in either cohorts or the combined cohort.
As noted above, SNP markers that defined genomic subgroups with a differential treatment response measured by mortality in the PROWESS cohort are tested for replication in the SPH+VASST combined cohort. Markers to be tested for replication are defined by two criteria. The 1 st category is obtained by testing for an interaction association between the SNP and treatment (based on 28-day mortality), using unadjusted P- values, in the complete PROWESS cohort and also in the APACHE II >25, MOD >2 and Caucasian only subgroups of PROWESS. SNPs with at least one model showing significance (p<0.0001) are tested for replication in the SPH + VASST cohort. The 2nd category are non-synonymous SNPs with an ARR > 20% and a frequency > 10% in any genetic model in the complete PROWESS cohort and intronic SNPs with predicted functionality {e.g., transcription factor binding site, splice site, miRNA site).
Markers are considered as replicated in the SPH/VASST Cohort if they met any 1 of the following 6 criteria:
1. Greater than 15% ARR in PROWESS, greater than 6.5% ARR in VASST+SPH cohort and greater than 18% frequency in PROWESS,
2. Statistical significance and response in the same direction,
3. Trending (P between 0.05 and 0.1) and response in the same direction,
4. Greater than 15% ARR in PROWESS and greater than 10% ARR in
VASST+SPH cohort, and greater than 10% frequency and functionally {e.g., non- synonymous/splice site) defined,
5. Point estimate of ARR is within 6% of PROWESS estimate, or
6. Point estimate of ARR in VASST+SPH was within confidence interval of point estimate of ARR in PROWESS
Replicated markers
As described in detail below, replicated SNP markers are rs 1042327, rs 10822315, rsl2380611, rsl2529871 , rsl7781459, rsl 805100, rs2016224, rs2073721, rs2989946, rs3179969, rs3751501, rs4354185, rs4371530, rs4525972, rs4936280, rs640098, rs684923, rs6925087, rs7535528, rs7572996, rs7940667, rs8028880, rs8128 and rs958738. The improved response genotypes at those SNP markers are rs684923 (AA), rsl0822315 (GG), rs8028880 (GG), rs958738 (AA GG), rsl2380611 (GG), rsl2529871 (AA), rs6925087 (TT), rsl7781459 (AG GG), rs4525972 (AG), rs7572996 (AG), rs3179969 (AA), rs640098 (AA), rs4371530 (AA), rs2016224 (GG), rs4936280 (AA), rs3751501 (AA AG), rs4354185 (AA), rs7535528 (AA), rs7940667 (AC AA), rsl042327 (AA), rs2989946 (CT), rs2073721 (AG), rsl805100 (AA), and rs8128 (TT).
Table 8 contains absolute measures of the mortality difference (Absolute Risk Reduction - ARR) between DrotAA-treated patients and matched controls for genomic subgroups in the PROWESS cohort. The 95% confidence interval around the ARR is also presented. All of the statistics for ARR are calculated using a linear regression via glm in the "stats" statistical analysis package in R (R Development Team).
Model Statement:
28-day mortality ~ treatment, family=binomial (identity), weighted
A logistic model is fit to 28-day mortality to calculate the interaction P-value. The model presented tests for a therapy by SNP interaction.
The general form of the logistic model is:
28-day mortality ~ SNP + treatment + SNP*treatment
A likelihood ratio test is used to evaluate the statistical significance of therapy-by- SNP interaction effects (2-sided at .05 level) and is based on the full model fit given above and a reduced model where the interaction term is not included. This will be done using the glm function in the stats library of the statistical analysis package in R (R Development Team).
All genotypic subgroups listed in Table 8 have greater than 14% absolute risk reduction in mortality when treated with DrotAA. All genotypic subgroups listed in Table 8 also have significant interaction P-value with the exception of rs7940667 which shows a trend.
Table 8: Mortality Data for genotypic subgroups in the PROWESS cohort.
Figure imgf000226_0001
rs 10822315 GG CAUC 0.344 0.198 0.1 19 0.274 l . l lxlO"05 rs8028880 GG ALL 0.251 0.185 0.094 0.264 0.0006152 rs958738 AA GG MOD 0.534 0.185 0.1 15 0.252 3.40x1ο-06 rsl2380611 GG ALL 0.281 0.176 0.09 0.258 0.0012377 rsl2529871 AA MOD 0.182 0.219 0.097 0.325 0.004276 rs6925087 TT MOD 0.321 0.217 0.132 0.304 1.51xl0"05 rsl7781459 AG GG CAUC 0.225 0.278 0.193 0.363 <1.0xl0-06 rs4525972 AG ALL 0.452 0.144 0.076 0.21 0.0002743 rs7572996 AG APACHE 0.436 0.273 0.171 0.364 3.93x1ο-05 rs3179969 AA ALL 0.129 0.217 0.079 0.341 0.0189543 rs640098 AA ALL 0.146 0.225 0.107 0.335 0.0021078 rs4371530 AA ALL 0.100 0.218 0.081 0.357 0.0114489 rs2016224 GG ALL 0.158 0.205 0.08 0.316 0.013276 rs4936280 AA ALL 0.100 0.217 0.055 0.349 0.0420013 rs3751501 AA AG ALL 0.109 0.204 0.087 0.322 0.0036014 rs4354185 AA ALL 0.120 0.254 0.127 0.378 0.0008996 rs7535528 AA ALL 0.127 0.207 0.079 0.326 0.0113453 rs7940667 AC AA ALL 0.161 0.164 0.044 0.277 0.0602417 rs 1042327 AA ALL 0.228 0.201 0.103 0.292 0.00072 rs2989946 CT ALL 0.360 0.156 0.079 0.234 0.0103317 rs2073721 AG ALL 0.365 0.150 0.075 0.225 0.0030507 rs 1805100 AA ALL 0.229 0.187 0.085 0.28 0.006149 rs8128 TT ALL 0.248 0.181 0.091 0.274 0.0028195
Table 9 contains absolute measures of the mortality difference (Absolute Risk Reduction; ARR) and the weighted mortality difference (Absolute Risk Reduction) between DrotAA-treated patients and matched controls for the genomic subgroups in the VASST+SPH combined cohort. Table 9 demonstrates that selected genotypic subgroups from PROWESS are associated with better DrotAA treatment response based on 28-day mortality in patients with severe sepsis and high risk of death. The weighted ARR is reported as it accounts for the variable matching described in the design. The 95% confidence interval around the weighted ARR is also presented. All of the described statistics are calculated using a linear regression via glm in the "stats" statistical analysis package in R (R Development Team).
Model Statement:
28-day mortality ~ treatment, family=binomial (identity), weighted A conditional logistic model is fit to 28-day mortality. The model is used to test for a therapy by SNP interaction conditioned on the matched sets into which the subjects have been formed. A second adjusted analysis is also run to account for any bias. The general form of the conditional logistic model is:
28-day mortality ~ SNP + treatment + SNP*treatment + strata(MatchedSetID ) The general form of the adjusted conditional logistic model is:
28-day mortality ~ SNP + treatment + SNP*treatment +
strata(MatchedSetID ) + age + APACHE 11+ surgical status + Cardiovascular failure + Mechanical ventilation status + Renal failure + Hematologic failure
where the interaction terms assesses the differential in the treatment effect across genotype subgroups. In the model syntax the use of "strata" is to denote the matched sets. A likelihood ratio test is used to evaluate the statistical significance of therapy-by- SNP interaction effects (2-sided at .05 level) and is based on the full model fit given above and a reduced model where the interaction term is not included. This is done using the clogit function in the survival library of the statistical analysis package in R (R Development Team).
All genotypic subgroups listed in Table 9 have greater than 6.5% absolute risk reduction in mortality when treated with DrotAA. In addition SNPs rs684923 rsl0822315, rs8028880, rs958738, rsl238061 1, rs4525972, rs7572996, rs3179969 and rs2073721 have either a significant interaction with DrotAA or a trend.
Table 9: Mortality Data for genotypic subgroups in the VASST+SPH replication cohort.
Figure imgf000229_0001
Table 10 contains absolute measures of mortality and absolute risk reduction for 5 all genotypic models and cohorts listed in Table 9 for both DrotAA-treated patients and matched control. The Chi-square P-value, which measures the difference in mortality within a genotypic subgroup, is also presented. All of the described statistics are
calculated using a linear regression via glm in the "stats" statistical analysis package in R (R Development Team).
Model Statement:
5 28-day mortality ~ treatment, family=binomial (identity), weighted
Table 10: Mortality Data for genotypic models in the VASST+SPH replication cohort.
Figure imgf000230_0001
Mortality Mortality
Confidence Confidence Absolute
Interval Interval Risk Chi- Lower Upper SNP Number Number Reducti square P-
RSID DrotAA Mortality Bounds Bounds Model Dead Alive on Value rsl2529871 1 0.374 0.286 0.468 AC CC 40 67 0.007 0.909 rsl2529871 0 0.381 0.298 0.469 AC CC 79 141 0.007 0.909 rs6925087 1 0.250 0.108 0.443 TT 6 18 0.105 0.339 rs6925087 0 0.355 0.237 0.486 TT 25 40 0.105 0.339 rs6925087 1 0.390 0.301 0.486 AA AT 41 64 -0.019 0.77 rs6925087 0 0.372 0.289 0.459 AA AT 80 139 -0.019 0.77 rsl7781459 1 0.400 -0.133 0.933 GG 1 2 0 1 rsl7781459 0 0.355 -0.179 0.888 GG 1 2 0 1 rsl7781459 1 0.400 0.212 0.588 AG GG 7 16 0.086 0.483 rsl7781459 0 0.355 0.205 0.504 AG GG 22 29 0.086 0.483 rs4525972 1 0.310 0.201 0.436 AG 18 40 0.11 0.176 rs4525972 0 0.421 0.318 0.529 AG 49 73 0.11 0.176 rs4525972 1 0.414 0.304 0.531 AA GG 29 41 -0.083 0.28 rs4525972 0 0.332 0.241 0.431 AA GG 53 102 -0.083 0.28 rs7572996 1 0.310 0.201 0.436 AG 18 40 0.08 0.318 rs7572996 0 0.390 0.292 0.494 AG 55 77 0.08 0.318 rs7572996 1 0.417 0.307 0.532 AA GG 30 42 -0.082 0.276 rs7572996 0 0.335 0.247 0.431 AA GG 51 103 -0.082 0.276 rs3179969 1 0.143 0.031 0.379 AA 2 12 0.245 0.047 rs3179969 0 0.387 0.242 0.548 AA 15 25 0.245 0.047 rs3179969 1 0.397 0.31 1 0.487 AG GG 46 70 -0.03 0.633 rs3179969 0 0.366 0.284 0.454 AG GG 90 155 -0.03 0.633 rs640098 1 0.211 0.071 0.424 AA 4 15 0.202 0.097 rs640098 0 0.413 0.269 0.567 AA 20 26 0.202 0.097 rs640098 1 0.380 0.292 0.473 AG GG 41 67 -0.015 0.812 rs640098 0 0.364 0.283 0.452 AG GG 85 153 -0.015 0.812 rs4371530 1 0.267 0.092 0.515 AA 4 1 1 0.195 0.195 rs4371530 0 0.462 0.280 0.650 AA 13 14 0.195 0.195 rs4371530 1 0.381 0.294 0.472 AG GG 43 70 -0.027 0.664 rs4371530 0 0.353 0.273 0.439 AG GG 90 158 -0.027 0.664 rs2016224 1 0.154 0.033 0.404 GG 2 1 1 0.169 0.196 Mortality Mortality
Confidence Confidence Absolute
Interval Interval Risk Chi- Lower Upper SNP Number Number Reducti square P-
RSID DrotAA Mortality Bounds Bounds Model Dead Alive on Value rs2016224 0 0.323 0.177 0.497 GG 14 23 0.169 0.196 rs2016224 1 0.369 0.271 0.475 AA AG 31 53 -0.054 0.452 rs2016224 0 0.315 0.227 0.414 AA AG 57 124 -0.054 0.452 rs4936280 1 0.278 0.110 0.505 AA 5 13 0.137 0.295 rs4936280 0 0.415 0.272 0.567 AA 18 26 0.137 0.295 rs4936280 1 0.384 0.297 0.476 AG GG 43 69 -0.032 0.613 rs4936280 0 0.352 0.272 0.439 AG GG 88 154 -0.032 0.613 rs3751501 1 0.375 0.289 0.467 GG 42 70 -0.021 0.734 rs3751501 0 0.354 0.273 0.441 GG 89 158 -0.021 0.734 rs3751501 1 0.333 0.148 0.563 AA AG 6 12 0.11 1 0.423 rs3751501 0 0.444 0.290 0.606 AA AG 17 22 0.11 1 0.423 rs4354185 1 0.292 0.137 0.488 AA 7 17 0.093 0.435 rs4354185 0 0.385 0.248 0.536 AA 18 31 0.093 0.435 rs4354185 1 0.387 0.298 0.481 AG GG 41 65 -0.026 0.687 rs4354185 0 0.361 0.279 0.449 AG GG 87 149 -0.026 0.687 rs7535528 1 0.200 0.067 0.405 AA 4 16 0.081 0.497 rs7535528 0 0.281 0.146 0.450 AA 10 26 0.081 0.497 rs7535528 1 0.394 0.306 0.488 AG GG 43 66 -0.002 0.97 rs7535528 0 0.392 0.308 0.480 AG GG 94 152 -0.002 0.97 rs7940667 1 0.394 0.302 0.487 CC 43 65 -0.023 0.722 rs7940667 0 0.392 0.307 0.478 CC 92 150 -0.023 0.722 rs7940667 1 0.394 0.219 0.570 AA AC 5 17 0.091 0.424 rs7940667 0 0.392 0.254 0.530 AA AC 14 30 0.091 0.424 rsl042327 1 0.321 0.169 0.505 AA 9 19 0.067 0.541 rsl042327 0 0.389 0.266 0.522 AA 25 40 0.067 0.541 rsl042327 1 0.376 0.286 0.473 AG GG 38 63 -0.033 0.609 rsl042327 0 0.343 0.262 0.431 AG GG 80 140 -0.033 0.609 rs2989946 1 0.333 0.199 0.468 AA 10 30 0.116 0.208 rs2989946 0 0.125 0.005 0.245 AA 28 54 0.116 0.208 rs2989946 1 0.333 0.206 0.461 AG GG 23 34 -0.087 0.297 rs2989946 0 0.125 0.022 0.228 AG GG 43 93 -0.087 0.297 Mortality Mortality
Confidence Confidence Absolute
Interval Interval Risk Chi-
Lower Upper SNP Number Number Reducti square P-
RSID DrotAA Mortality Bounds Bounds Model Dead Alive on Value rs2073721 1 0.333 0.201 0.466 AG 8 29 0.1 0.267 rs2073721 0 0.125 0.007 0.243 AG 26 56 0.1 0.267 rs2073721 1 0.333 0.209 0.458 AA GG 25 35 -0.106 0.195 rs2073721 0 0.125 0.025 0.225 AA GG 45 91 -0.106 0.195 rs 1805100 1 0.333 0.139 0.528 AG 8 15 0.083 0.499 rs 1805100 0 0.125 -0.018 0.268 AG 22 34 0.083 0.499 rs 1805100 1 0.333 0.226 0.441 AA GG 25 49 -0.032 0.66 rs 1805100 0 0.125 0.030 0.220 AA GG 48 113 -0.032 0.66 rs8128 1 0.333 0.177 0.490 AA 6 21 0.075 0.463 rs8128 0 0.125 0.000 0.250 AA 21 42 0.075 0.463 rs8128 1 0.333 0.219 0.448 AG GG 26 43 -0.068 0.382 rs8128 0 0.125 0.026 0.224 AG GG 45 96 -0.068 0.382
Linkage Disequilibrium Analysis
Included herein are SNPs found to be associated with 28-day survival or response to DrotAA as well as SNPs determined to be in LD with the former. LD SNPs are
ascertained using the SNAP server V2.2 released by the BROAD Institute
(http://www.broadinstitute.org/mpg/snap/). The LD SNPs are shown above on page 39 to page 196 and SEQ ID NOs: 318 to 7046.
Example 3: 2-SNP combination genotypic subgroups are predictive of response to DrotAA (improved response genotype combinations)
The four 2-SNP combination genotypic subgroups listed in Table 11 are modeled in a collapsed fashion in which patients are defined as having at least 1 of the improved response genotypes from markers 1 or 2 compared to patients with no improved response genotypes. Both combination markers have greater than 15% absolute risk reduction in mortality (range 15.6 to 21.2%) when treated with DrotAA (Table 8). In addition they have a significant interaction with DrotAA. Table 11: Genotypic Model Group Combinations
Figure imgf000234_0001
Table 12 contains the Absolute Risk Reduction, interaction P-value, odds ratio and adjusted interaction P-value and odds ratio between DrotAA-treated patients and matched controls for four 2-SNP combination genomic subgroups in the VASST+SPH combined cohort. All of the described statistics are calculated using a linear regression via glm in the "stats" statistical analysis package in R (R Development Team).
Model Statement:
28-day mortality ~ treatment, family=binomial (identity), weighted
A conditional logistic model is fit to 28-day mortality. The model is used to test for a therapy by SNP interaction conditioned on the matched sets into which the subjects have been formed. A second adjusted analysis is also run to account for any bias. The general form of the conditional logistic model is: 28-day mortality ~ SNP + treatment + SNP*treatment + strata( MatchedSetID )
The general form of the adjusted conditional logistic model is:
28-day mortality ~ SNP + treatment + SNP*treatment + strata( MatchedSetID ) + age + APACHE 11+ surgical status + Cardiovascular failure + Mechanical ventilation status + Renal failure + Hematologic failure where the interaction terms assesses the differential in the treatment effect across genotype subgroups. In the model syntax the use of "strata" is to denote the matched sets. A likelihood ratio test is used to evaluate the statistical significance of therapy-by- SNP interaction effects (2-sided at .05 level) and is based on the full model fit given above and a reduced model where the interaction term is not included. This is done using the clogit function in the survival library of the statistical analysis package in R (R Development Team).
Table 12: Mortality Data for 2 SNP combination genotypic subgroups in the VASST+SPH replication cohort
Figure imgf000235_0001
The 2-SNP combination genotypic subgroups in Table 13 are modeled in an additive fashion in which patients are categorized as having 0, 1 or 2 response genotypes. The four combination markers have greater than 14% absolute risk reduction in mortality (range 14.8 to 21.79%) when treated with DrotAA and containing one response genotype. In addition they have a significant or nearly significant interaction with DrotAA over all genotype categories. Table 13: Mortality Data for 2 SNP combination genotypic subgroups
VASST+SPH replication cohort.
Figure imgf000236_0001
Figures 1 , 2, 3, 4, 5 and 6 display the absolute risk reductions (ARRs), calculated 5 as control mortality minus DrotAA-treated mortality, and the 95% confidence intervals (CIs) for the ARRs for the improved response genotypes at SNPs rs684923, rs4354185, rs 1042327, rs3741501, 3179969 and 640098 respectively. Figure 7 shows the ARR for the 2-SNP improved response genotype combinations at rs rs684923 and rs4354185. Figure 8 shows the ARR for the 2-SNP improved response genotype combinations at 10 rs684923 and rsl042327. Figure 9 shows the ARR for the 2-SNP improved response genotype combinations at rs684923 and rs3751501. Figure 10 shows the ARR for the 2- SNP improved response genotype combinations at rs3179969 and rs640098.

Claims

What is Claimed is:
1. A method of treating an inflammatory condition in a selected subject in need thereof, comprising administering to said selected subject an anti-inflammatory agent or an anti-coagulant agent, in an amount effective to treat said inflammatory condition; and selecting said subject based on a single nucleotide polymorphism (SNP) that is capable of providing a correlation with a phenotype of an improved response to a treatment with an anti-inflammatory agent or an anti-coagulant agent or a second SNP in linkage disequilibrium with said SNP.
2. The method of claim 1 , wherein said SNP is a Group A SNP with an improved response genotype selected from the group consisting of rs 1000418 (AA GG), rs 10026134 (AA GG), rs 10275461 (GG), rs 10500982 (AG), rs 10518784 (GT TT), rs 10788160 (AA), rs 10817866 (CT TT), rs 10822315 (CC), rs 10849300 (AA GG), rs 10869665 (CT), rs 10884100 (CT), rs 10895944 (CT TT), rs 10925783 (CC TT), rs 10951131 (AA), rs 10999122 (CT TT), rs 1 1063674 (AG), rs 1108255 (AA), rs 11149155 (AG), rsl 119642 (AA GG), rsl 1250131 (AG), rsl 164857 (CC), rsl 1786372 (CT), rsl 1894266 (CT TT), rsl 1984724 (CT), rs 12025108 (AG), rsl2159200 (AA), rsl2193402 (AA CC), rsl2317794 (TT), rsl2327456 (AT TT), rsl2335840 (CC), rsl2436579 (AC CC), rsl2494795 (CC), rsl2513381 (AA GG), rsl2529871 (GT TT), rsl2573176 (AC), rsl2618741 (CC), rsl265140 (CG), rsl266382 (CT), rsl2680523 (CT), rsl2918570 (CT), rsl294227 (CC TT), rsl2951391 (CT), rsl3153368 (CC TT), rsl 3190448 (AA), rsl 3247490 (AG), rsl 3250662 (CT TT), rsl 3273073 (GG TT), rsl348181 (AA), rsl355597 (CC CT), rsl373649 (AG), rsl411820 (CC CT), rsl478842 (AA AG), rsl560582 (AA), rsl560941 (AA GG), rsl605461 (AG), rsl667223 (AA CC), rsl 6953047 (GT), rsl 7014760 (AA GG), rsl 7114618 (CC), rsl7151969 (AA CC), rsl7172693 (CC), rsl 7209998 (CC), rsl 7278159 (CT TT), rsl 74948 (AG), rsl 74957 (AG), rsl7507051 (CC), rsl7781459 (AG GG), rsl7839997 (AA), rsl823790 (AA AG), rsl 897833 (GT), rsl915279 (AG), rs2024408 (CT TT), rs2027363 (AA GG), rs2048070 (GG), rs2069643 (AG), rs2076977 (CT TT), rs2110167 (AA GG), rs2159688 (AA), rs2170169 (AG GG), rs2178032 (CC TT), rs2240660 (CC TT), rs2246277 (CC TT), rs227397 (CC TT), rs2280665 (AA GG), rs2310160 (CC TT), rs2322784 (CT), rs2341551 (AG), rs2394824 (AA AG), rs2501976 (CT TT), rs2531894 (AA), rs2598414 (CC TT), rs2653814 (GT), rs2694418 (TT), rs2695027 (AA GG), rs2716555 (GG), rs2716601 (AA), rs2721952 (CT), rs2728981 (AA), rs2729140 (AG), rs2729547 (CC TT), rs2829523 (AC CC), rs2942917 (AA AG), rs310244 (AG), rs3118050 (CT TT), rs3130454 (AG), rs321224 (CC TT), rs359447 (CT), rs3813026 (AA), rs3816253 (CC CT), rs3847794 (AG), rs3963484 (AA AG), rs4140512 (AA), rs4237265 (CT), rs426357 (AG), rs4322073 (CC TT), rs4331850 (AA), rs4369611 (AA GG), rs4525972 (AG), rs4553010 (AG), rs4595752 (GT), rs4608848 (CC), rs471814 (AA), rs4729408 (CT), rs4876024 (CT), rs4952903 (GT TT), rs4975300 (CC), rs530461 (AG), rs589258 (CT), rs6012750 (AG), rs611003 (AA), rs626545 (GG), rs6446731 (AG), rs6482910 (CC TT), rs6489851 (CT), rs651844 (CT), rs6549946 (AA GG), rs6713126 (TT), rs6780177 (CT), rs6864 (AC), rs6893958 (AA), rs6896102 (GG), rs6909151 (AG GG), rs6918854 (AA GG), rs6922979 (AA GG), rs6925087 (TT), rs6941022 (TT), rs6953258 (CC), rs6972943 (AG), rs6977578 (CC), rs6981251 (AA), rs6987100 (AA), rs7110072 (CC), rs7120011 (TT), rs7134223 (TT), rs7292804 (GG), rs7305954 (CC TT), rs7409 (CC TT), rs7425164 (CC), rs7444603 (AA CC), rs7523607 (AA CC), rs7544877 (CT TT), rs7551773 (AG GG), rs7572996 (AG), rs7582779 (AG GG), rs7617493 (CT), rs7641222 (AC), rs7673752 (AC), rs7702195 (CT), rs7795499 (CC TT), rs7815122 (GG), rs7867693 (AG), rs7970821 (CC TT), rs7974223 (AA), rs7979573 (AG GG), rs7986188 (AA GG), rs8028880 (CC), rs8041979 (AG), rs835481 (CC), rs922902 (CG GG), rs9291224 (CC TT), rs9296272 (CC TT), rs9372243 (AG GG), rs9373836 (TT), rs9460540 (AG GG), rs9554684 (CT), rs9587280 (CT TT), rs958738 (AA GG), rs966775 (AA), rs9815663 (CT TT), rs993691 (CC TT), rs9962772 (AC CC), rsl2380611 (CC), rsl2423283 (TT), rsl813758 (GT), rs2665981 (AA GG), rsl0165340 (CT), rsl042277 (CC), rsl0486391 (GG), rsl0812532 (GG GT), rsl 1585501 (AC), rsl 1645653 (CC TT), rsl421940 (AA), rsl445943 (AA CC), rsl457238 (AA), rsl53141 (GG), rsl7318470 (CT), rsl991013 (TT), rs2222202 (AA), rs2257096 (GG), rs2515481 (GG), rs2756901 (CC), rs2916755 (AA), rs3024496 (GG), rs3176876 (GG), rs3176877 (AA), rs3212435 (TT), rs3212439 (TT), rs3212461 (GG TT), rs3212464 (AA GG), rs3212481 (CC), rs3212640 (CC), rs3733138 (AG), rs3768777 (GG), rs3917019 (AA), rs4777049 (CC), rs4941183 (GG), rs4987821 (CT), rs61 19410 (CT), rs641153 (AG), rs6755175 (AG), rs7032817 (TT), rsl 0230573 (AA), rsl 042327 (TT), rsl 0950521 (CC), rsl 16187 (AA), rsl 258236 (AG), rsl363560 (CC), rsl37794 (AA AG), rsl386440 (AA), rsl563632 (GG), rsl7395296 (AA AG), rsl7724627 (CC), rsl805100 (AA), rs2016224 (GG), rs2020860 (CT), rs2073619 (AG), rs2073721 (AG), rs2276932 (AG), rs2827845 (AG), rs2941483 (AA), rs2989946 (AG), rs3746766 (GG), rs3848668 (AG), rs397250 (GG), rs4149338 (AA), rs4267943 (AA), rs4354185 (AA), rs4371530 (TT), rs4715631 (TT), rs4757548 (AA), rs5847 (TT), rs711173 (CC), rs7535528 (AA), rs7610425 (CC), rs7861460 (GG), rs7940667 (AC), rs7992 (TT), rs8128 (AA), rs397686 (CC), rs4936280 (TT), rs8878 (AA), rs684923 (TT), rs640098 (AA), rs3751501 (AA AG), rs3179969 (AA), rsl 1159859 (GG), rsl2436642 (AA), rsl2436982 (AA), rsl342836 (GG), rsl344747 (AA), rsl7188228 (CC), rsl950806 (TT), rs2274737 (CC), rs3742484 (AT TT), rs3742486 (AG), rs3783889 (TT), rs3814855 (AA), rs61977053 (AA), rs61984684 (CC), rs625006 (GG), rs8017689 (CC), rs8020072 (CC), rs930181 (TT), and combinations thereof.
3. The method of claim 1 , wherein said SNP is a Group A SNP selected from the group consisting of rsl042327, rsl0822315, rsl238061 1, rsl2529871, rsl7781459, rsl805100, rs2016224, rs2073721, rs2989946, rs3179969, rs3751501, rs4354185, rs4371530, rs4525972, rs4936280, rs640098, rs684923, rs6925087, rs7535528, rs7572996, rs7940667, rs8028880, rs8128, rs958738, and combinations thereof.
4. The method of claim 2, wherein said SNP is a Group B SNP in linkage disequilibrium with said Group A SNP selected from the group consisting of rsl 042327, rsl0822315, rsl2380611 , rsl2529871, rsl7781459, rsl 805100, rs2016224, rs2073721 , rs2989946, rs3179969, rs3751501, rs4354185, rs4371530, rs4525972, rs4936280, rs640098, rs684923, rs6925087, rs7535528, rs7572996, rs7940667, rs8028880, rs8128, rs958738, and combinations thereof.
5. The method of claim 2, wherein the genotype of said Group A SNP is selected from the group consisting of rs684923 (AA), rsl0822315 (GG), rs8028880 (GG), rs958738 (AA GG), rsl2380611 (GG), rsl2529871 (AA), rs6925087 (TT), rsl7781459 (AG GG), rs4525972 (AG), rs7572996 (AG), rs3179969 (AA), rs640098 (AA), rs4371530 (AA), rs2016224 (GG), rs4936280 (AA), rs3751501 (AA AG), rs4354185 (AA), rs7535528 (AA), rs7940667 (AC AA), rs 1042327 (AA), rs2989946 (CT), rs2073721 (AG), rs 1805100 (AA), rs8128 (TT), and combinations thereof.
6. The method of claim 1 , wherein said SNP is selected from the group consisting of one polymorphic site, a pair of polymorphic sites, three polymorphic sites, four polymorphic sites, and five or more polymorphic sites.
7. The method of claim 5, wherein said pair of polymorphic sites is selected from the group consisting of rs684923 and rs4354185, rs684923 and rsl042327, rs684923 and rs3751501, and rs3179969 and rs640098.
8. The method of claim 7, wherein the genotype of said pair of polymorphic sites is selected from the group consisting of rs684923AA and rs4354185AG, rs684923AA and rs4354185GG, rs684923AG and rs4354185AA, rs684923GG and rs4354185AA, rs684923AA and rs4354185AA, rs684923AA and rsl042327AG, rs684923AA and rsl042327GG, rs684923AG and rsl042327AA, rs684923GG and rsl042327AA, rs684923AA and rsl042327AA, rs684923AA and rs3751501AG, rs684923AA and rs3751501GG, rs684923AG and rs3751501 AA, rs684923GG and rs3751501 AA, rs684923AA and rs3751501AA, rs684923GG and rs3751501AG, rs684923AG and rs3751501AG, rs3179969AA and rs640098AG, rs3179969AA and rs640098GG, rs3179969AG and rs640098AA, rs3179969GG and rs640098AA, and rs3179969AA and rs640098AA.
9. The method of Claim 8, wherein the selected subject has been determined to have an improved response genotype at one or both of rs684923 and rs4354185.
10. The method of Claim 8, wherein the selected subject has been determined to have an improved response genotype at one or both of rs684923 and rs 1042327.
11. The method of Claim 8, wherein the selected subject has been determined to have an improved response genotype at one or both of rs684923 and rs3751501.
12. The method of Claim 8, wherein the selected subject has been determined to have an improved response genotype at one or both of rs3179969 and rs640098.
13. The method of claim 1 , wherein said SNP is within a hap lo type window.
14. The method of claim 13, wherein said haplotype window comprises a Group A SNP and a Group B SNP that are in linkage disequilibrium with an r value of at least 0.8.
15. The method of claim 13, wherein said haplotype window comprises sequence within 12,000 basepairs (bp) of said Group A SNP.
16. The method of claim 1 , wherein said anti-inflammatory agent or anti-coagulant agent is activated protein C, protein C, or an activator of protein C.
17. The method of claim 16, wherein said activated protein C is drotrecogin alfa- recombinant human activated protein C or GED-aPC.
18. The method of claim 16, wherein said anti-inflammatory agent or anti-coagulant agent is protein C.
19. The method of claim 1 , wherein said inflammatory condition is selected from the group consisting of severe sepsis; sepsis; septicemia; pneumonia; septic shock; systemic inflammatory response syndrome (SIRS); Acute Respiratory Distress Syndrome (ARDS); acute lung injury; aspiration pneumonitis; infection; pancreatitis; bacteremia; peritonitis; abdominal abscess; inflammation due to trauma; inflammation due to surgery; chronic inflammatory disease; ischemia; ischemia-reperfusion injury of an organ or tissue; tissue damage due to disease; tissue damage due to chemotherapy or radiotherapy; reactions to ingested, inhaled, infused, injected, or delivered substances; glomerulonephritis; bowel infection; opportunistic infections; major surgery or dialysis; immunocompromised immune system; immunosuppressive agents; HIV/ AIDS; suspected endocarditis; fever; fever of unknown origin; cystic fibrosis; diabetes mellitus; chronic renal failure; acute renal failure; acute kidney injury (AKI); oliguria; acute renal dysfunction; glomerulonephritis; interstitial-nephritis; acute tubular necrosis (ATN); oliguric ATN; non-oliguric ATN; bronchiectasis; chronic obstructive lung disease; chronic bronchitis; emphysema; asthma; febrile neutropenia; meningitis; septic arthritis; urinary tract infection;
necrotizing fasciitis; other suspected Group A streptococcus infections; splenectomy; recurrent or suspected enterococcus infection; other medical and surgical conditions associated with increased risk of infection; Gram positive sepsis; Gram negative sepsis; culture negative sepsis; fungal sepsis; meningococcemia; post-pump syndrome; cardiac stun syndrome; myocardial infarction; stroke; congestive heart failure; cardiogenic shock; post-cardiopulmonary bypass low cardiac output syndrome; low cardiac output syndrome post-myocardial infarction; disseminated intravascular coagulation (DIC); sepsis-induced coagulopathy; hepatitis; epiglottitis; E. coli 0157:H7; malaria; gas gangrene; toxic shock syndrome; pre-eclampsia; eclampsia; HELLP syndrome; mycobacterial tuberculosis; Pneumocystis carinii pneumonia; Leishmaniasis; hemolytic uremic syndrome/thrombotic thrombocytopenic purpura; Dengue hemorrhagic fever; pelvic inflammatory disease; Legionella; Lyme disease; Influenza A; Epstein-Barr virus; encephalitis; inflammatory diseases and autoimmunity including Rheumatoid arthritis, osteoarthritis, progressive systemic sclerosis and systemic lupus erythematosus; inflammatory bowel disease;
idiopathic pulmonary fibrosis; sarcoidosis; hypersensitivity pneumonitis; systemic vasculitis; Wegener's granulomatosis; transplants including heart, liver, lung, kidney, and bone marrow; graft-versus-host disease; transplant rejection; sickle cell anemia; nephrotic syndrome; toxicity of agents such as OKT3; cytokine therapy; hepato rental syndrome (HRS); and cirrhosis.
20. The method of claim 19, wherein the inflammatory condition is associated with the group consisting of SIRS, sepsis, severe sepsis, septic shock, acute renal failure, and cardiogenic shock.
21. The method of claim 1 , wherein said selected subject has an APACHE II score of > 25 or at least two organ system failures.
22. The method of claim 1 , wherein said improved response comprises one or more of the benefits selected from the group consisting of:
(a) a survival benefit comprising an increased period of survival, an increased survival during hospital stay, or an increased survival over a period ranging from 28 to 90 days post-treatment;
(b) a renal benefit comprising an increase in days alive and free of renal dysfunction (using Brussels, SOFA, or other scores), an increase in days alive and free of renal support, an increase in days alive and free of renal failure, the prevention of a need for renal support (hemodialysis, peritoneal dialysis, or continuous renal replacement therapy (CRRT)), or a reversal of renal dysfunction; (c) a pulmonary benefit comprising an increase in days alive and free of pulmonary dysfunction (using Brussels, SOFA, or other scores), an increase in days alive and free of ventilation, or an increase in days alive and free of acute lung injury;
(d) a cardiovascular benefit comprising an increase in days alive and free of cardiovascular dysfunction (using Brussels, SOFA, or other scores), an increase in days alive and free of vasopressors, an increase in days alive and free of renal dysfunction (using Brussels, SOFA, or other scores), or an increase in days alive and free of inotropic agents; and
(e) a central nervous system benefit comprising an increase in days alive and free of neurologic dysfunction (using Brussels, SOFA, or other scores), a reversal of stroke, a reversal reversal of cerebral vascular accident (CVA), a prevention of stroke, a prevention of cerebrovascular accident, a reversal of cerebral ischemic event, a reversal of transient ischemic event (TIA), a prevention of cerebral ischemic event, or a prevention of transient ischemic event.
23. A method of indentifying a subject having an improved response to a treatment with activated protein C comprising:
determining the genotype of the subject at a Group A SNP, a Group B SNP, or a Group A and a Group B SNP, wherein said determining is done using a sample of nucleic acid obtained from the subject and performing one or more of the following techniques:
(a) restriction fragment length analysis;
(b) nucleic acid sequencing;
(c) micro-sequencing assay;
(d) hybridization;
(e) invader assay;
(f) gene chip hybridization assays;
(g) oligonucleotide ligation assay;
(h) ligation-rolling circle amplification;
(i) 5' nuclease assay;
(j) polymerase proofreading methods; (k) allele specific PCR;
(1) matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectroscopy;
(m) ligase chain reaction assay;
(n) enzyme-amplified electronic transduction; and
(o) single base pair extension assay; and
wherein an improved response genotype at a Group A, Group B, or Group A and Group B SNP is indicative of a subject having an improved response to said treatment.
24. The method of claim 23, wherein said SNP is Group A SNP selected from the group consisting of rsl042327, rsl0822315, rsl238061 1, rsl2529871, rsl7781459, rsl805100, rs2016224, rs2073721, rs2989946, rs3179969, rs3751501, rs4354185, rs4371530, rs4525972, rs4936280, rs640098, rs684923, rs6925087, rs7535528, rs7572996, rs7940667, rs8028880, rs8128, rs958738, and combinations thereof.
25. The method of claim 24, wherein said SNP is a Group B SNP in linkage disequilibrium with said Group A SNP selected from the group consisting of rs 1042327, rsl0822315, rsl2380611 , rsl2529871, rsl7781459, rsl 805100, rs2016224, rs2073721 , rs2989946, rs3179969, rs3751501, rs4354185, rs4371530, rs4525972, rs4936280, rs640098, rs684923, rs6925087, rs7535528, rs7572996, rs7940667, rs8028880, rs8128, rs958738, and combinations thereof.
26. The method of claim 24, further comprising administering to said identified subject activated protein C in an amount effective to treat said inflammatory condition
27. A method of indentifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising determining the genotype of the subject at a Group A SNP, a Group B SNP, or a Group A and Group B SNP by hybridization wherein an improved response genotype at a Group A SNP, a Group B SNP, or a Group A and Group B SNP is indicative of a subject having an improved response to said treatment.
28. A method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising: annealing a primer to template DNA from said subject, wherein said primer anneals 5' to a Group A (SNP) site or adjacent to a Group B SNP site in linkage disequilibrium with said Group A SNP;
synthesizing a complementary DNA strand to said template DNA;
incorporating an allele-specific nucleotide in said complementary DNA strand; and identifying said allele-specific nucleotide.
29. The method of claim 24, wherein said identifying is performed by observing fluorescence, measuring mass charge, or binding affinity.
30. A method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising:
annealing a labeled primer to template DNA from said subject, wherein said primer is immediately adjacent to a Group A SNP or a Group B SNP and includes at its 3' nucleotide end, the residue complementary to said Group A SNP or said Group B SNP ; synthesizing a complementary DNA strand to said template DNA; and
identifying said allele-specific nucleotide.
31. The method of claim 30, wherein said identifying is performed by observing fluorescence, measuring mass charge, or binding affinity of said labeled primer.
32. A method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising:
annealing a primer to template DNA from said subject, wherein said primer anneals next to a Group A SNP or a Group B SNP;
synthesizing DNA complementary to said template DNA, wherein said synthesizing incorporates said SNP site;
hybridizing a probe comprising a Group A SNP or a Group B SNP-specific nucleotide to said synthesized DNA;
washing said hybridized probe - DNA complex so that any probe stuck to DNA with mismatched DNA basepairs are washed away; and identifying said SNP-specific nucleotide based on which hybridized probe - DNA complexes remain after washing.
33. The method of claim 32, wherein said identifying is performed by observing fluorescence, measuring mass charge, or binding based on affinity of said labeled primer.
34. A method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising:
annealing a primer to template DNA from said subject, wherein said primer anneals adjacent to a Group A SNP or a Group B SNP;
synthesizing DNA complementary to said template DNA, wherein said synthesizing incorporates a nucleotide complementary to said SNP site nucleotide;
hybridizing a probe comprising a Group A SNP-specific nucleotide or a Group B SNP- specific nucleotide to said synthesized DNA with a fluorescent label and a quencher before said synthesizing; and
identifying said subject genotype at said SNP site based on whether said hybridized probe releases said fluorescent label after said synthesizing.
35. A method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising:
annealing a SNP-specific probe ending with a nucleotide complementary to a nucleotide at a Group A SNP or Group B SNP to template DNA from said subject;
annealing a ligation probe that binds to said template DNA immediately adjacent to said SNP site in said SNP-specific probe;
adding ligase; and
synthesizing a covalent bond between said probes.
36. The method of claim 35, wherein said ligation probe comprises an affinity tag and said allele-specific probe comprises a fluorescent label.
37. A method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising: annealing a SNP-specific probe ending with a nucleotide complementary to a nucleotide at a Group A SNP or Group B SNP to template DNA from said subject, wherein said SNP-specific probe further comprises a sequence complementary to sequence on the other side of the SNP site;
adding ligase;
synthesizing a covalent bond between the ends of said probe; and
amplifying said ligated probe.
38. A method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising cleaving a covalent bond at a SNP site of a single nucleotide polymorphism or a single nucleotide polymorphism site in linkage disequilibrium thereto that is recognized by a restriction enzyme.
39. A method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising:
annealing an invader probe that is fully complementary to a Group A SNP or Group B SNP on just one side of the SNP site of DNA from said subject;
annealing a second SNP-specific probe complementary to the SNP site and the other side of said Group A SNP or Group B SNP , said second SNP-specific probe further comprising a reporter label and a quencher label on opposite sides of said second SNP- specific probe;
adding a cleavase enzyme; and
cleaving said reporter or said quencher from said second SNP-specific probe.
40. A method of identifying a subject having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising:
annealing a SNP-specific primer that is fully complementary to a Group A SNP or a Group B SNP to template DNA from said subject;
amplifying said template DNA; melting double-stranded template DNA into single-stranded DNA strands;
running said single-stranded DNA on a gel under nondenaturing conditions; and identifying a genotype at said allele, wherein alleles with different genotypes have different mobilities.
41. The method of claim 20, wherein said single-stranded DNA is labeled with a radioisotope or fluorescence.
42. Two or more oligonucleotides of about 25 to about 400 nucleotides that hybridize specifically to a Group A SNP or a Group B SNP contained in a human having an improved response to a treatment with activated protein C, protein C, or an activator of protein C, wherein said two or more oligonucleotides are capable of determining the presence or absence of an improved response genotype in said target sequence selected from one of the selected IRGs.
43. A kit comprising two or more oligonucleotides of about 25 to about 400 nucleotides that are capable of being used to determine the presence or absence of an improved response genotype in a human target DNA selected from a Group A SNP or a Group B SNP, and instructions on how to use said two or more oligonucleotides to determine the presence or absence of an improved response genotype in said human target sequence selected from one of the selected IRGs.
44. A method of treating an inflammatory condition in a selected subject in need thereof, comprising administering to said selected subject an activated protein C, protein C, or an activator of protein C, in an amount effective to treat the inflammatory condition, wherein the selected subject has been determined to have an improved response genotype at a polymorphic site selected from the group consisting of the IRP SNPs or a
polymorphic site in linkage disequilibrium therewith, and the improved response genotype indicates that the selected subject would benefit from treatment with activated protein C, protein C, or an activator of protein C.
45. A method of identifying a subject not having an improved response to a treatment with activated protein C, protein C, or an activator of protein C comprising: determining the genotype of the subject at a Group A or Group B SNP, wherein said determining is done using a sample of nucleic acid obtained from the subject; and performing one or more of the following techniques:
(a) restriction fragment length analysis;
(b) nucleic acid sequencing;
(c) micro-sequencing assay;
(d) hybridization;
(e) invader assay;
(f) gene chip hybridization assays;
(g) oligonucleotide ligation assay;
(h) ligation-rolling circle amplification;
(i) 5' nuclease assay;
(j) polymerase proofreading methods;
(k) allele specific PCR;
(1) matrix assisted laser desorption ionization time of flight (MALDI-TOF) mass spectroscopy;
(m) ligase chain reaction assay;
(n) enzyme-amplified electronic transduction; and
(o) single base pair extension assay,
wherein a non-response genotype at a Group A SNP, a Group B SNP, or a Group A and a Group B SNP is indicative of a subject having a non-improved response to said treatment.
46. The method of claim 45, wherein said SNP is a Group A SNP selected from the group consisting of rsl042327, rsl0822315, rsl238061 1, rsl2529871, rsl7781459, rsl805100, rs2016224, rs2073721, rs2989946, rs3179969, rs3751501, rs4354185, rs4371530, rs4525972, rs4936280, rs640098, rs684923, rs6925087, rs7535528, rs7572996, rs7940667, rs8028880, rs8128, rs958738, and combinations thereof.
47. The method of claim 46, wherein said SNP is a Group B SNP in linkage disequilibrium with said Group A SNP selected from the group consisting of rs 1042327, rsl0822315, rsl2380611 , rsl2529871, rsl7781459, rsl 805100, rs2016224, rs2073721 , rs2989946, rs3179969, rs3751501, rs4354185, rs4371530, rs4525972, rs4936280, rs640098, rs684923, rs6925087, rs7535528, rs7572996, rs7940667, rs8028880, rs8128, rs958738, and combinations thereof.
48. A method for predicting the benefit of treatment with an activated protein C, protein C, or an activator of protein C comprising:
determining the genotype of the subject at a Group A SNP, a Group B SNP, or a Group A and Group B SNP, wherein said determining is done using a sample of nucleic acid obtained from the subject and
performing one or more of the following techniques:
(a) restriction fragment length analysis;
(b) nucleic acid sequencing;
(c) micro-sequencing assay;
(d) hybridization;
(e) invader assay;
(f) gene chip hybridization assays;
(g) oligonucleotide ligation assay;
(h) ligation-rolling circle amplification;
(i) 5' nuclease assay;
(j) polymerase proofreading methods;
(k) allele-specific PCR;
(1) matrix assisted laser desorption ionization time of flight (MALDI-TOF) mass spectroscopy;
(m) ligase chain reaction assay;
(n) enzyme-amplified electronic transduction; and
(o) single base pair extension assay,
wherein an improved response genotype at a Group A SNP, a Group B SNP, or a Group A and a Group B SNP is indicative of a subject having an improved response to said treatment.
49. The method of claim 48, wherein said SNP is a Group A SNP selected from the group consisting of rsl042327, rsl0822315, rsl238061 1, rsl2529871, rsl7781459, rsl805100, rs2016224, rs2073721, rs2989946, rs3179969, rs3751501, rs4354185, rs4371530, rs4525972, rs4936280, rs640098, rs684923, rs6925087, rs7535528, rs7572996, rs7940667, rs8028880, rs8128, rs958738, and combinations thereof.
50. The method of claim 49, wherein said SNP is a Group B SNP in linkage disequilibrium with said Group A SNP selected from the group consisting of rs 1042327, rsl0822315, rsl2380611 , rsl2529871, rsl7781459, rsl 805100, rs2016224, rs2073721 , rs2989946, rs3179969, rs3751501, rs4354185, rs4371530, rs4525972, rs4936280, rs640098, rs684923, rs6925087, rs7535528, rs7572996, rs7940667, rs8028880, rs8128, rs958738, and combinations thereof.
51. A method of selecting a subject for the treatment of an inflammatory condition with an anti- inflammatory agent or an anti-coagulant agent, comprising the step of identifying a subject having an improved response genotype at a Group A SNP, a Group B SNP, or a Group A and a Group B SNP, wherein the identification of a subject with the improved response genotype is predictive of increased responsiveness to the treatment of the inflammatory condition with the anti-inflammatory agent or the anti-coagulant agent.
52. A method for the treatment of an inflammatory condition with an antiinflammatory agent or an anti-coagulant agent, comprising:
identifying a subject having an improved response genotype at a Group A SNP, a Group B SNP, or a Group A and Group B SNP, and
providing an anti-inflammatory agent or an anti-coagulant agent.
53. The method of claim 52, wherein said anti-inflammatory agent or anti-coagulant agent is activated protein C, protein C, or an activator of protein C.
54. A method for increasing the likelihood of effectiveness of an activated protein C treatment, protein C treatment, or a protein C like compound treatment, the method comprising administering an inflammatory condition treating dose of an activated protein C, protein C or protein C like compound to a subject, wherein said subject is determined to have an improved response genotype at a Group A SNP, a Group B SNP, or a Group A and a Group B SNP.
55. A method for identifying a subject with a decreased likelihood to respond to an anti-inflammatory agent or an anti-coagulant agent comprising determining a genotype of said subject at a polymorphic site, wherein said genotype is a non-response genotype and wherein said polymorphic site is a Group A SNP, a Group B SNP, or a Group A and a Group B SNP.
56. The method of claim 55, wherein said non-response genotype is selected from the group consisting of rsl 000418 (AG), rsl 0026134 (AG), rsl 0275461 (TT TG), rsl 0500982 (AA GG), rsl 0518784 (GG), rsl 0788160 (AG GG), rsl 0817866 (CC), rsl 0822315 (CT TT), rsl 0849300 (AG), rsl 0869665 (CC TT), rsl 0884100 (CC TT), rsl 0895944 (CC), rsl 0925783 (CT), rsl 0951131 (AG GG), rsl 0999122 (CC), rsl 1063674 (AA GG), rsl 108255 (AG GG), rsl 1149155 (AA GG), rsl 119642 (AG), rsl 1250131 (AA GG), rsl 164857 (CT TT), rsl 1786372 (CC TT), rsl 1894266 (CC), rsl 1984724 (CC TT), rsl2025108 (AA GG), rsl2159200 (AG GG), rsl2193402 (AC), rsl2317794 (CC CT), rsl2327456 (AA), rsl2335840 (CT TT), rsl2436579 (AA), rsl2494795 (CT TT), rsl2513381 (AG), rsl2529871 (GG), rsl2573176 (AA CC), rsl2618741 (CT TT), rsl265140 (CC GG), rsl266382 (CC TT), rsl2680523 (CC TT), rsl2918570 (CC TT), rsl294227 (CT), rsl2951391 (CC TT), rsl3153368 (CT), rsl 3190448 (AC CC), rsl 3247490 (AA GG), rsl 3250662 (CC), rsl 3273073 (GT), rsl348181 (AG GG), rsl355597 (TT), rsl373649 (AA GG), rsl411820 (TT), rsl478842 (GG), rsl 560582 (AG GG), rsl 560941 (AG), rsl 605461 (AA GG), rsl 667223 (AG), rsl 6953047 (GG TT), rsl 7014760 (AG), rsl7114618 (CT TT), rsl 7151969 (AC), rsl7172693 (CT TT), rsl 7209998 (CT TT), rsl 7278159 (CC), rsl 74948 (AA GG), rsl 74957 (AA GG), rsl 7507051 (CT TT), rsl 7781459 (AA), rsl 7839997 (AC CC), rsl 823790 (AA), rsl 897833 (GG TT), rsl 915279 (AA GG), rs2024408 (CC), rs2027363 (AG), rs2048070 (AA AG), rs2069643 (AA GG), rs2076977 (CC), rs2110167 (AG), rs2159688 (AG GG), rs2170169 (AA), rs2178032 (CT), rs2240660 (CT), rs2246277 (CT), rs227397 (CT), rs2280665 (AG), rs2310160 (CT), rs2322784 (CC TT), rs2341551 (AA GG), rs2394824 (GG), rs2501976 (CC), rs2531894 (AG GG), rs2598414 (CT), rs2653814 (GG TT), rs2694418 (GG GT), rs2695027 (AG), rs2716555 (AA AG), rs2716601 (AG GG), rs2721952 (CC TT), rs2728981 (AG GG), rs2729140 (AA GG), rs2729547 (CT), rs2829523 (AA), rs2942917 (GG), rs310244 (AA GG), rs31 18050 (CC), rs3130454 (AA GG), rs321224 (CT), rs359447 (CC TT), rs3813026 (AG GG), rs3816253 (TT), rs3847794 (AA GG), rs3963484 (GG), rs4140512 (AG GG), rs4237265 (CC TT), rs426357 (AA GG), rs4322073 (CT), rs4331850 (AG GG), rs436961 1 (AG), rs4525972 (AA GG), rs4553010 (AA GG), rs4595752 (GG TT), rs4608848 (CT TT), rs471814 (AG GG), rs4729408 (CC TT), rs4876024 (CC TT), rs4952903 (GG), rs4975300 (CT TT), rs530461 (AA GG), rs589258 (CC TT), rs6012750 (AA GG), rs611003 (AC CC), rs626545 (AA AG), rs6446731 (AA GG), rs6482910 (CT), rs6489851 (CC TT), rs651844 (CC TT), rs6549946 (AG), rs6713126 (CC CT), rs6780177 (CC TT), rs6864 (AA CC), rs6893958 (AG GG), rs6896102 (GT TT), rs6909151 (AA), rs6918854 (AG), rs6922979 (AG), rs6925087 (AA AT), rs6941022 (CC CT), rs6953258 (CT TT), rs6972943 (AA GG), rs6977578 (CT TT), rs6981251 (AG GG), rs6987100 (AG GG), rs7110072 (CT TT), rs7120011 (GG GT), rs7134223 (GG GT), rs7292804 (GT TT), rs7305954 (CT), rs7409 (CT), rs7425164 (CT TT), rs7444603 (AC), rs7523607 (AC), rs7544877 (CC), rs7551773 (AA), rs7572996 (AA GG), rs7582779 (AA), rs7617493 (CC TT), rs7641222 (AA CC), rs7673752 (AA CC), rs7702195 (CC TT), rs7795499 (CT), rs7815122 (GT TT), rs7867693 (AA GG), rs7970821 (CT), rs7974223 (AG GG), rs7979573 (AA), rs7986188 (AG), rs8028880 (CT TT), rs8041979 (AA GG), rs835481 (CT TT), rs922902 (CC), rs9291224 (CT), rs9296272 (CT), rs9372243 (AA), rs9373836 (CC CT), rs9460540 (AA), rs9554684 (CC TT), rs9587280 (CC), rs958738 (AG), rs966775 (AG GG), rs9815663 (CC), rs993691 (CT), rs9962772 (AA), rsl2380611 (CT TT), rsl2423283 (CC CT), rsl813758 (GG TT), rs2665981 (AG), rsl0165340 (CC TT), rsl042277 (CT TT), rsl0486391 (AA AG), rsl0812532 (TT TG), rsl 1585501 (AA CC), rsl 1645653 (CT), rsl421940 (AC CC), rs1445943 (AC), rsl457238 (AG GG), rsl53141 (AA AG), rsl7318470 (CC TT), rsl 991013 (CC CT), rs2222202 (AG GG), rs2257096 (AA AG), rs2515481 (AA AG), rs2756901 (CT TT), rs2916755 (AG GG), rs3024496 (AA AG), rs3176876 (AA AG), rs3176877 (AT TT), rs3212435 (GG GT), rs3212439 (CC CT), rs3212461 (GT), rs3212464 (AG), rs3212481 (CT TT), rs3212640 (CG GG), rs3733138 (AA GG), rs3768777 (AA AG), rs3917019 (AG GG), rs4777049 (CT TT), rs4941183 (AA AG), rs4987821 (CC TT), rs61 19410 (CC TT), rs641153 (AA GG), rs6755175 (AA GG), rs7032817 (CC CT), rs 10230573 (AG GG), rs 1042327 (CC CT), rs 10950521 (CT TT), rsl 16187 (AG GG), rsl258236 (AA GG), rsl363560 (CT TT), rsl37794 (GG), rs 1386440 (AG GG), rsl 563632 (AA AG), rsl 7395296 (GG), rsl 7724627 (CT TT), rsl 805100 (AG GG), rs2016224 (AA AG), rs2020860 (CC TT), rs2073619 (AA GG), rs2073721 (AA GG), rs2276932 (AA GG), rs2827845 (AA GG), rs2941483 (AG GG), rs2989946 (AA GG), rs3746766 (AA AG), rs3848668 (AA GG), rs397250 (AA AG), rs4149338 (AG GG), rs4267943 (AG GG), rs4354185 (AG GG), rs4371530 (CC CT), rs4715631 (CC CT), rs4757548 (AG GG), rs5847 (CC CT), rs71 1173 (CT TT), rs7535528 (AG GG), rs7610425 (CT TT), rs7861460 (GT TT), rs7940667 (AA CC), rs7992 (CC CT), rs8128 (AC CC), rs397686 (AA AC), rs4936280 (CC CT), rs8878 (AG GG), rs684923 (CC CT), rs640098 (AG GG), rs3751501 (GG), rs3179969 (AG GG), rsl 1159859 (GC CC), rsl2436642 (AG GG), rsl2436982 (AG GG), rsl342836 (AA AG), rsl 344747 (AT TT), rsl7188228 (CT TT), rsl 950806 (CC CT), rs2274737 (CT TT), rs3742484 (AA), rs3742486 (AA GG), rs3783889 (AA AT), rs3814855 (AG GG), rs61977053 (AC CC), rs61984684 (CT TT), rs625006 (AA AG), rs8017689 (CT TT), rs8020072 (CT TT), rs930181 (CC CT), Group B SNPs in linkage disequilibrium thereto, and combinations thereof.
57. The method of claim 55, further comprising obtaining polymorphism sequence information for said subject.
58. The method of claim 55, wherein said genotype is determined using a nucleic acid sample from the subject.
59. The method of claim 58, further comprising obtaining the nucleic acid sample from the subject.
60. The method of claim 55, further comprising selectively not administering an antiinflammatory agent or an anti-coagulant agent, wherein said subject does not have an improved response genotype or improved response genotype combination and said polymorphic site is a Group A SNP, a Group B SNP, or a Group A and a Group B SNP.
61. A method of treating an inflammatory condition in a subject in need thereof, the method comprising administering to the subject an anti-inflammatory agent or an anti- coagulant agent, wherein said subject is determined to have an improved response genotype at a Group A SNP, a Group B SNP, a Group A and Group B SNP, or one or more polymorphic sites in linkage disequilibrium thereto.
62. A method of selecting a subject for the treatment of an inflammatory condition with an anti- inflammatory agent or an anti-coagulant agent, comprising the step of identifying a subject having an improved response genotype a Group A SNP, a Group B SNP, a Group A and Group B SNP, or one or more polymorphic sites in linkage disequilibrium thereto, wherein the identification of a subject with the improved response genotype is predictive of increased responsiveness to the treatment of the inflammatory condition with the anti-inflammatory agent or the anti-coagulant agent.
63. A use of an anti-inflammatory agent or an anti-coagulant agent in the manufacture of a medicament for the treatment of an inflammatory condition, wherein the subjects treated are determined to have an improved response genotype at a Group A SNP, a Group B SNP, a Group A and Group B SNP, or one or more polymorphic sites in linkage disequilibrium thereto.
64. A use of an anti-inflammatory agent or an anti-coagulant agent in the manufacture of a medicament for the treatment of an inflammatory condition in a subset of subjects, wherein the subset of subjects have an improved response genotype at a Group A SNP, a Group B SNP, a Group A and Group B SNP, or one or more polymorphic sites in linkage disequilibrium thereto.
65. A method of treating an inflammatory condition in a subject in need thereof, the method comprising administering to the subject a protein C or protein C like compound, wherein said subject is determined to have an improved response genotype at a Group A SNP, a Group B SNP, a Group A and Group B SNP, or one or more polymorphic sites in linkage disequilibrium thereto.
66. A method for increasing likelihood of effectiveness of a protein C treatment or protein C like compound treatment, the method comprising administering an
inflammatory condition treating dose of the protein C or protein C like compound to a subject, wherein said subject is determined to have an improved response genotype at a Group A SNP, a Group B SNP, a Group A and Group B SNP, or one or more polymorphic sites in linkage disequilibrium thereto.
67. A commercial package containing, as active pharmaceutical ingredient, a protein C or protein C like compound, together with instructions for its use for the curative or prophylactic treatment of an inflammatory condition in a subject, wherein the subject treated has an improved response genotype at a Group A SNP, a Group B SNP, a Group A and Group B SNP, or one or more polymorphic sites in linkage disequilibrium thereto.
68. A method for identifying a subject having one or more improved response genotype(s), the method comprising determining a genotype of said subject at one or more polymorphic sites, wherein said genotype is indicative of the subject's response to an anti-inflammatory agent or an anti-coagulant agent, wherein the polymorphic site(s) are selected from one or more of a Group A SNP, a Group B SNP, a Group A and Group B SNP, or one or more polymorphic sites in linkage disequilibrium thereto.
69. A method for selecting a group of subjects for determining the efficacy of a candidate drug known or suspected of being useful for the treatment of an inflammatory condition, the method comprising determining a genotype at one or more of a Group A SNP, a Group B SNP, a Group A and Group B SNP, or one or more polymorphic sites in linkage disequilibrium thereto, wherein said genotype is indicative of the subject's response to the candidate drug and sorting subjects based on their genotype.
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