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Association between the chromosome 9p21 locus and angiographic coronary artery disease burden: a collaborative meta-analysis.

ABSTRACT: This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD.Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability.We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects.We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele.The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.

SUBMITTER: Chan K

PROVIDER: S-EPMC3653306 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Association between the chromosome 9p21 locus and angiographic coronary artery disease burden: a collaborative meta-analysis.

Chan Kenneth K Patel Riyaz S RS Newcombe Paul P Nelson Christopher P CP Qasim Atif A Epstein Stephen E SE Burnett Susan S Vaccarino Viola L VL Zafari A Maziar AM Shah Svati H SH Anderson Jeffrey L JL Carlquist John F JF Hartiala Jaana J Allayee Hooman H Hinohara Kunihiko K Lee Bok-Soo BS Erl Anna A Ellis Katrina L KL Goel Anuj A Schaefer Arne S AS El Mokhtari Nour Eddine NE Goldstein Benjamin A BA Hlatky Mark A MA Go Alan S AS Shen Gong-Qing GQ Gong Yan Y Pepine Carl C Laxton Ross C RC Whittaker John C JC Tang W H Wilson WH Johnson Julie A JA Wang Qing K QK Assimes Themistocles L TL Nöthlings Ute U Farrall Martin M Watkins Hugh H Richards A Mark AM Cameron Vicky A VA Muendlein Axel A Drexel Heinz H Koch Werner W Park Jeong Euy JE Kimura Akinori A Shen Wei-feng WF Simpson Iain A IA Hazen Stanley L SL Horne Benjamin D BD Hauser Elizabeth R ER Quyyumi Arshed A AA Reilly Muredach P MP Samani Nilesh J NJ Ye Shu S

Journal of the American College of Cardiology 20130123 9

<h4>Objectives</h4>This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD.<h4>Background</h4>Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability.<h4>Methods</h4>We established a collaboration ...[more]

PMID: 23352782

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Project description:BackgroundCase-control Genome-Wide Association Studies (GWAS) have identified single nucleotide polymorphisms (SNPs) at the 9p21 locus as risk factors for coronary artery disease (CAD). The locus does not contain a clear candidate gene. Hence, the results of GWAS have raised an intense interest in delineating the basis for the observed association. We analyzed association of 4 SNPs at the 9p21 locus with the severity and progression of coronary atherosclerosis, as determined by serial quantitative coronary angiograms (QCA) in the well-characterized Lipoprotein Coronary Atherosclerosis Study (LCAS) population. The LCAS is a randomized placebo-control longitudinal follow-up study in patients with CAD conducted to test the effects of fluvastatin on progression or regression of coronary atherosclerosis.MethodsExtensive plasma lipid levels were measured at the baseline and 2 1/2 years after randomization. Likewise serial QCA was performed at the baseline and upon completion of the study. We genotyped the population for 4 SNPs, previously identified as the susceptibility SNPs for CAD in GWAS, using fluorogenic 5' nuclease assays. We reconstructed the haplotypes using Phase 2, analyzed SNP and haplotype effects using the Thesias software as well as by the conventional statistical methods.ResultsOnly Caucasians were included since they comprised 90% of the study population (332/371 with available DNA sample). The 4 SNPs at the 9p21 locus were in tight linkage disequilibrium, leading to 3 common haplotypes in the LCAS population. We found no significant association between quantitative indices of severity of coronary atherosclerosis, such as minimal lumen diameter and number of coronary lesions or occlusions and the 9p21 SNPs and haplotypes. Likewise, there was no association between quantitative indices of progression of coronary atherosclerosis and the SNPs or haplotypes. Similarly, we found no significant SNP or haplotype effect on severity and progression of coronary atherosclerosis.ConclusionWe conclude the 4 SNPs at the 9p21 locus analyzed in this study do not impart major effects on the severity or progression of coronary atherosclerosis. The effect size may be very modest or the observed association of the CAD with SNPs at the 9p21 locus in the case-control GWAS reflect involvement of vascular mechanisms not directly related to the severity or progression of coronary atherosclerosis.

Dataset Information

Association between the chromosome 9p21 locus and angiographic coronary artery disease burden: a collaborative meta-analysis.

Publications

Association between the chromosome 9p21 locus and angiographic coronary artery disease burden: a collaborative meta-analysis.

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