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 P value of <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=1.3×10-16) in comparison with 5% in ever-smokers (P=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 than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.
Bibliographical noteFunding Information:
This work was supported in part by R01-HL-111694 and K24-HL-107643 from the National Institutes of Health to Dr Reilly. PROMIS: Genotyping in PROMIS was funded by the Wellcome Trust, UK, and Pfizer. Fieldwork in the PROMIS study was supported through funds available to investigators at the Center for Non-Communicable Diseases, Pakistan, and the University of Cambridge, UK. EPIC-CVD Consortium: CHD case ascertainment and validation, genotyping, and clinical chemistry assays in EPIC-CVD were principally supported by grants awarded to the University of Cambridge from the European Union (EU) Framework Program 7 (HEALTH-F2-2012-279233), the United Kingdom (UK) Medical Research Council (G0800270) and British Heart Foundation (SP/09/002), the UK National Institute for Health Research Cambridge Biomedical Research Center, and the European Research Council (268834).
© 2017 American Heart Association, Inc.
- ADAMTS7 protein
- coronary artery disease
- gene-environment interaction
- genome-wide association study