Loss of Cardioprotective Effects at theADAMTS7Locus as a Result of Gene-Smoking Interactions.
Saleheen D., Zhao W., Young R., Nelson CP., Ho W., Ferguson JF., Rasheed A., Ou K., Nurnberg ST., Bauer RC., Goel A., Do R., Stewart AFR., Hartiala J., Zhang W., Thorleifsson G., Strawbridge RJ., Sinisalo J., Kanoni S., Sedaghat S., Marouli E., Kristiansson K., Hua Zhao J., Scott R., Gauguier D., Shah SH., Smith AV., van Zuydam N., Cox AJ., Willenborg C., Kessler T., Zeng L., Province MA., Ganna A., Lind L., Pedersen NL., White CC., Joensuu A., Edi Kleber M., Hall AS., März W., Salomaa V., O'Donnell C., Ingelsson E., Feitosa MF., Erdmann J., Bowden DW., Palmer CNA., Gudnason V., Faire UD., Zalloua P., Wareham N., Thompson JR., Kuulasmaa K., Dedoussis G., Perola M., Dehghan A., Chambers JC., Kooner J., Allayee H., Deloukas P., McPherson R., Stefansson K., Schunkert H., Kathiresan S., Farrall M., Marcel Frossard P., Rader DJ., Samani NJ., Reilly MP.
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 aPvalue of <1.0×10-3(Bonferroni correction for 50 tests). RESULTS: We identified novel gene-smoking interaction for a variant upstream of theADAMTS7gene. 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 (interactionPvalue=8.7×10-5). The protective T allele at rs7178051 was also associated with reducedADAMTS7expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction ofADAMTS7.CONCLUSIONS: Allelic variation at rs7178051 that associates with reducedADAMTS7expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascularADAMTS7expression may contribute to the loss of CHD protection in smokers.