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Genetic Variation at the ADAMTS7 Locus is Associated With Reduced Severity of Coronary Artery Disease.

ABSTRACT: Genome-wide association studies identified ADAMTS7 as a risk locus for coronary artery disease (CAD). Functional studies suggest that ADAMTS7 may promote cellular processes in atherosclerosis. We sought to examine the association between genetic variation at ADAMTS7 and measures of atherosclerosis using histological, angiographic, and clinical outcomes data.The lead CAD-associated single-nucleotide polymorphism rs3825807 at the ADAMTS7 locus was genotyped. The G allele (reduced ADAMTS7 function) was associated with a smaller fibrous cap (P=0.017) and a smaller percentage area of ?-actin (smooth muscle cell marker) in the intima (P=0.017), but was not associated with calcification or plaque thickness, following ex vivo immunohistochemistry analysis of human coronary plaques (n=50; mean age 72.2±11.3). In two independent cohorts (Southampton Atherosclerosis Study [n=1359; mean age 62.5±10.3; 70.1% men] and the Emory Cardiovascular Biobank [EmCAB; n=2684; mean age 63.8±11.3; 68.7% men]), the G allele was associated with 16% to 19% lower odds of obstructive CAD (Southampton Atherosclerosis Study: odds ratio, 0.81; 95% confidence interval, 0.67-0.98; EmCAB: odds ratio, 0.84; 95% confidence interval, 0.75-0.95) with similar effects for multivessel, left anterior descending, and proximal CAD. Furthermore, each copy of the G allele was associated with lower angiographic severity Gensini score (Southampton Atherosclerosis Study, P=0.026; EmCAB, P<0.001), lower Sullivan Extent score (Southampton Atherosclerosis Study, P=0.029; EmCAB, P<0.001), and a 23% lower risk of incident revascularization procedures (EmCAB: hazard ratio, 0.76; 95% confidence interval, 0.59-0.98). There were no associations with all-cause mortality or incident myocardial infarction.Genetic variation at the ADAMTS7 locus is associated with several complementary CAD phenotypes, supporting the emerging role of ADAMTS7 in atherosclerosis and may represent a potential drug target.

SUBMITTER: Chan K

PROVIDER: S-EPMC5721775 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Genetic Variation at the <i>ADAMTS7</i> Locus is Associated With Reduced Severity of Coronary Artery Disease.

Chan Kenneth K Pu Xiangyuan X Sandesara Pratik P Poston Robin N RN Simpson Iain A IA Quyyumi Arshed A AA Ye Shu S Patel Riyaz S RS

Journal of the American Heart Association 20171031 11

<h4>Background</h4>Genome-wide association studies identified ADAMTS7 as a risk locus for coronary artery disease (CAD). Functional studies suggest that ADAMTS7 may promote cellular processes in atherosclerosis. We sought to examine the association between genetic variation at ADAMTS7 and measures of atherosclerosis using histological, angiographic, and clinical outcomes data.<h4>Methods and results</h4>The lead CAD-associated single-nucleotide polymorphism rs3825807 at the ADAMTS7 locus was gen ...[more]

PMID: 29089340

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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

Genetic Variation at the ADAMTS7 Locus is Associated With Reduced Severity of Coronary Artery Disease.

Publications

Genetic Variation at the <i>ADAMTS7</i> Locus is Associated With Reduced Severity of Coronary Artery Disease.

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