Smoking attenuates cardioprotective effects linked to allelic variation at ADAMTS7
Smoking could weaken the genetic protection against coronary heart disease (CHD), with a recent study demonstrating that allelic variation at rs7178051 associated with reduced ADAMTS7 expression provides stronger CHD protection in never-smokers than in ever-smokers.
Exposure of human coronary artery smooth muscle cells to cigarette smoke extract particularly leads to increased vascular ADAMTS7 expression.
Researchers analysed genetic variants at 45 loci previously reported to be associated with CHD risk in a cohort of 60,919 CHD patients and 80,243 controls from 29 gene-smoking interaction studies. Five loci linked to smoking behaviour were also evaluated. A fixed-effects meta-analysis was performed to calculate and pool study-specific gene-smoking interaction effects.
A novel gene-smoking interaction was identified for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 reduced the risk of CHD by 12 percent in never-smokers (p=1.3×10–16) and by only 5 percent in ever-smokers (p=2.5×10–4). The difference reflected a 60-percent loss of CHD protection conferred by the allelic variation in individuals who smoked tobacco (p=8.7×10–5 for interaction).
Moreover, the protective T allele at rs7178051 was associated with a reduction in ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract resulted in an induction of ADAMTS7.
The present data have mechanistic and clinical implications, providing novel insights into the potential mechanisms of CHD in cigarette smokers and pointing towards the directional impact of the ADAMTS7 locus on CHD, researchers noted.
A member of the ADAMTS family of secreted zinc metalloproteases, the ADAMTS7 (A disintegrin and metalloproteinase with thrombospondin motifs-7) has been shown to modulate vascular smooth muscle cell phenotype switching and migration and that this may be mediated via the putative ADAMTS7 substrates expressed in vascular tissue. [PLoS One 2013;8:e71954; Circulation 2015;131:1202-1213; Am J Hum Genet 2013;92:366-374; Circ Res 2009;104:688-698]
“Inhibition of ADAMTS7 is a novel potential therapeutic strategy for CHD that may have particular benefits in individuals who smoke cigarettes,” researchers said.