Genetic variation at the ADAMTS7 locus is associated with reduced severity of coronary artery disease

Abstract

Background--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. Methods and Results--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 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 [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. Conclusions--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.