Loss of Cardioprotective Effects at the Locus as a Result of Gene-Smoking Interactions.
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-lifestyle 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 be associated 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 value of
RESULTS: We identified novel gene-smoking interaction for a variant upstream of the gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (=1.3×10) in comparison with 5% in ever-smokers (=2.5×10), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction value=8.7×10). The protective T allele at rs7178051 was also associated with reduced 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 CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular expression may contribute to the loss of CHD protection in smokers.
|Year of Publication||
2017 Jun 13
|PubMed Central ID||
P30 ES007048 / ES / NIEHS NIH HHS / United States
T32 HL007954 / HL / NHLBI NIH HHS / United States
R01 HL133169 / HL / NHLBI NIH HHS / United States
R01 HL111694 / HL / NHLBI NIH HHS / United States
K24 HL107643 / HL / NHLBI NIH HHS / United States
Wellcome Trust / United Kingdom