Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions

Abstract

Background Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-environment interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk. Methods We analyzed data on 60,919 CHD cases and 80,243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to associate with CHD risk. We also studied 5 loci associated with smoking behavior. Study specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P-value < 1.0×10−3 (Bonferroni correction for 50 tests). Results We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P-value: 1.3×10−16) compared to 5% in ever-smokers (P-value: 2.5×10−4) translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (Interaction P-value: 8.7×10−5). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 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 ADAMTS7. Conclusions Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in “never-smokers” compared to “ever-smokers”. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.

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

“…Finally, a recent study reported that of the 45 loci known to associate with CAD risk, a variant at ADAMTS7 rs7178051, which is in modest linkage disequilibrium with rs3825807 (LD=0.52), exhibited an important gene‐smoking interaction in 61 000 cases with coronary heart disease and 80 000 controls . The protective effect of ADAMTS7 genetic variation on CAD risk was found to be lower in persons who smoked than in nonsmokers, while exposure of human coronary cell lines to cigarette smoke led to induction of ADAMTS7 activity.…”

“…Genome‐wide association studies have revealed a robust association between genetic variation in the ADAMTS7 (a disintegrin and metalloprotease with thrombospondin motif 7) gene on chromosome 15q25 and clinical phenotypes of coronary artery disease (CAD) . One of the lead single nucleotide polymorphisms (SNPs), rs3825807, is an adenine (A) to guanine (G) substitution located in exon 4 of the ADAMTS7 gene, with the G allele conferring a reduced risk of CAD, and is found to be in linkage disequilibrium with other SNPs such as rs1994016 and rs7178051 commonly studied at the ADAMTS7 loci. This nonsynonymous SNP leads to an amino acid change in the prodomain of the ADAMTS7 protein, a metalloproteinase that plays a role in proteolysis and degradation of extracellular matrix in connective tissues .…”

Big Data’s Role in Precision Public Health

“…Big data offers special contributions to precision public health in enabling a wider view of health variables through linking disparate or novel data ( 44 , 153 , 154 ) and enabling large study populations with volumes of multiomic data to identify “molecular cohorts” ( 155 ).…”

Clinical genomics of the relationship between ADAMTS7 and coronary artery calcification and atherosclerosis

“…The interaction of genes and environment have produced the interesting observation that Allelic variations at rs7178051 that are associated with reduced ADAMTS7 expression confers CAD protection which is stronger in never-smokers than in cigarette smokers [36] . Enhanced vascular ADAMTS7 expression may lead to the loss of protection from CAD which occurs in cigarette smokers leading to the suggestion that inhibition of ADAMTS7 maybe especial helpful for individuals who smoke cigarettes [36] .…”