Open AccessGenetic Variation at the ADAMTS 7 Locus is Associated With Reduced Severity of Coronary Artery Disease
Author(s) -
Chan Kenneth,
Pu Xiangyuan,
Sandesara Pratik,
Poston Robin N.,
Simpson Iain A.,
Quyyumi Arshed A.,
Ye Shu,
Patel Riyaz S.
Publication year - 2017
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.117.006928
Subject(s) - medicine , odds ratio , coronary artery disease , confidence interval , coronary atherosclerosis , cardiology , single nucleotide polymorphism , locus (genetics) , allele , pathology , gastroenterology , genotype , genetics , biology , gene
Background Genome‐wide association studies identified ADAMTS 7 as a risk locus for coronary artery disease ( CAD ). Functional studies suggest that ADAMTS 7 may promote cellular processes in atherosclerosis. We sought to examine the association between genetic variation at ADAMTS 7 and measures of atherosclerosis using histological, angiographic, and clinical outcomes data. Methods and Results The lead CAD ‐associated single‐nucleotide polymorphism rs3825807 at the ADAMTS 7 locus was genotyped. The G allele (reduced ADAMTS 7 function) was associated with a smaller fibrous cap ( P =0.017) and a smaller percentage area of α‐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 [Em CAB ; 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; Em CAB : 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; Em CAB , P <0.001), lower Sullivan Extent score (Southampton Atherosclerosis Study, P =0.029; Em CAB , 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. Conclusions Genetic variation at the ADAMTS 7 locus is associated with several complementary CAD phenotypes, supporting the emerging role of ADAMTS 7 in atherosclerosis and may represent a potential drug target.