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Two-marker association tests yield new disease associations for coronary artery disease and hypertension.

ABSTRACT: It has been postulated that multiple-marker methods may have added ability, over single-marker methods, to detect genetic variants associated with disease. The Wellcome Trust Case Control Consortium (WTCCC) provided the first successful large genome-wide association studies (GWAS) which included single-marker association analyses for seven common complex diseases. Of those signals detected, only one was associated with coronary artery disease (CAD), and none were identified for hypertension (HTN). Our objective was to find additional genetic associations and pathways for cardiovascular disease by examining the WTCCC data for variants associated with CAD and HTN using two-marker testing methods. We applied two-marker association testing to the WTCCC dataset, which includes ~2,000 affected individuals with each disorder, and a shared pool of ~3,000 controls, all genotyped using Affymetrix GeneChip 500 K arrays. For CAD, we detected single nucleotide polymorphisms (SNP) pairs in three genes showing genome-wide significance: HFE2, STK32B, and DIPC2. The most notable SNP pairs in a non-protein-coding region were at 9p21, a known major CAD-associated region. For HTN, we detected SNP pairs in five genes: GPR39, XRCC4, MYO6, ZFAT, and MACROD2. Four further associated SNP pair regions were at least 70 kb from any known gene. We have shown that novel, multiple-marker, statistical methods can be of use in finding variants in GWAS. We describe many new, associated variants for both CAD and HTN and describe their known genetic mechanisms.

SUBMITTER: Slavin TP

PROVIDER: S-EPMC3576836 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Two-marker association tests yield new disease associations for coronary artery disease and hypertension.

Slavin Thomas P TP Feng Tao T Schnell Audrey A Zhu Xiaofeng X Elston Robert C RC

Human genetics 20110528 6

It has been postulated that multiple-marker methods may have added ability, over single-marker methods, to detect genetic variants associated with disease. The Wellcome Trust Case Control Consortium (WTCCC) provided the first successful large genome-wide association studies (GWAS) which included single-marker association analyses for seven common complex diseases. Of those signals detected, only one was associated with coronary artery disease (CAD), and none were identified for hypertension (HTN ...[more]

PMID: 21626137

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Project description:BackgroundCoronary artery stenosis induces heart diseases including acute coronary syndrome (ACS). Some studies reported the ceramide species are associated with the ACS and major adverse cardia and cerebrovascular events (MACE). However, few studies investigated the association between plasma ceramide levels and the severity of stenosis, together with the onset of diseases. This aim of the present study was to investigate the association betweencertain ceramide species, coronary artery stenosis and acute coronary syndrome.MethodsFive hundred fifty-three patients with definite or suspected CAD were recruited and received angiography. Subjects were assigned into 4 groups according to the severity of coronary artery stenosis. The measurements of 4 plasma ceramide species, namely, Cer (d18:1/16:0), Cer (d18:1/18:0), Cer (d18:1/24:1), Cer (d18:1/24:0) were carried out by Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and the ratio of Cer (d18:1/16:0), Cer (d18:1/18:0) and Cer (d18:1/24:1) to Cer (18:1/24:0), respectively, were calculated as index to evaluate the association between plasma ceramides levels and coronary artery stenosis. Multiple logistic regression analysis was used to establish the prognostic model for the prediction of ACS risk.ResultsAfter the adjustment by multiple clinical risk factors including age, gender, pre-existing myocardial/cerebral infarction, hemoglobin A1c% (HbA1c%), smoking and the diagnosis during index hospitalization, multiple logistic regression analysis showed that the high ratio of Cer (d18:1/24:1) to Cer (d18:1/24:0), female gender, HbA1c%, unstable angina (UAP) and acute myocardial infarction (AMI) diagnosis (compared with atherosclerosis) during index hospitalization were associated with more severe coronary artery stenosis. Furthermore, the prognostic model was established after adjustment of risk factors and the area under curve (AUC) of receiver operating characteristics (ROC) for the prognostic model was 0.732 and 95% CI was 0.642-0.822.ConclusionThe severity of coronary artery stenosis is associated with high ratio of Cer (d18:1/24:1) to Cer (d18:1/24:0), female gender, HbA1c% and AMI. Although the reported prognostic model showed a good discrimination, further investigation on long term MACE is needed to evaluate the role of ceramide for the prediction of MACE risk.

Project description:BACKGROUND:Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. METHODS:We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). RESULTS:Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10(-14) and P=3.40x10(-6), respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2x10(-5) and less than a 50% chance of being falsely positive). In addition to chromosome 9p21.3, two of these loci were successfully replicated (adjusted P<0.05) in the German study: chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P<1.3x10(-6)) and a high probability (>80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). CONCLUSIONS:We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease.

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Two-marker association tests yield new disease associations for coronary artery disease and hypertension.

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Two-marker association tests yield new disease associations for coronary artery disease and hypertension.

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