Loss of Cardioprotective Effects at the <i>ADAMTS7</i> Locus as a Result of Gene-Smoking Interactions

Abstract

We identified novel gene-smoking interaction for a variant upstream of the <i>ADAMTS7</i> gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (<i>P</i>=1.3×10^-16) in comparison with 5% in ever-smokers (<i>P</i>=2.5×10^-4), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction <i>P</i> value=8.7×10^-5). The protective T allele at rs7178051 was also associated with reduced <i>ADAMTS7</i> expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of <i>ADAMTS7.</i> CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced <i>ADAMTS7</i> expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular <i>ADAMTS7</i> expression may contribute to the loss of CHD protection in smokers.