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

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Saleheen , D , Zhao , W , Young , R , Nelson , C P , Ho , W , Ferguson , J F , Rasheed , A , Ou , K , Nurnberg , S T , Bauer , R C , Goel , A , Do , R , Stewart , A F R , Hartiala , J , Zhang , W , Thorleifsson , G , Strawbridge , R J , Sinisalo , J , Kanoni , S , Sedaghat , S , Marouli , E , Kristiansson , K , Zhao , J H , Scott , R , Gauguier , D , Shah , S H , Smith , A V , van Zuydam , N , Cox , A J , Willenborg , C , Kessler , T , Zeng , L , Province , M A , Ganna , A , Lind , L , Pedersen , N L , White , C C , Joensuu , A , Kleber , M E , Hall , A S , Maerz , W , Salomaa , V , O'Donnell , C , Ingelsson , E , Feitosa , M F , Erdmann , J , Bowden , D W , Palmer , C N A , Gudnason , V , Perola , M , PROMIS & Cardiogramplusc4D 2017 , ' Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions ' , Circulation , vol. 135 , no. 24 , pp. 2336-+ . https://doi.org/10.1161/CIRCULATIONAHA.116.022069

Title: Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions
Author: Saleheen, Danish; Zhao, Wei; Young, Robin; Nelson, Christopher P.; Ho, WeangKee; Ferguson, Jane F.; Rasheed, Asif; Ou, Kristy; Nurnberg, Sylvia T.; Bauer, Robert C.; Goel, Anuj; Do, Ron; Stewart, Alexandre F. R.; Hartiala, Jaana; Zhang, Weihua; Thorleifsson, Gudmar; Strawbridge, Rona J.; Sinisalo, Juha; Kanoni, Stavroula; Sedaghat, Sanaz; Marouli, Eirini; Kristiansson, Kati; Zhao, Jing Hua; Scott, Robert; Gauguier, Dominique; Shah, Svati H.; Smith, Albert Vernon; van Zuydam, Natalie; Cox, Amanda J.; Willenborg, Christina; Kessler, Thorsten; Zeng, Lingyao; Province, Michael A.; Ganna, Andrea; Lind, Lars; Pedersen, Nancy L.; White, Charles C.; Joensuu, Anni; Kleber, Marcus Edi; Hall, Alistair S.; Maerz, Winfried; Salomaa, Veikko; O'Donnell, Christopher; Ingelsson, Erik; Feitosa, Mary F.; Erdmann, Jeanette; Bowden, Donald W.; Palmer, Colin N. A.; Gudnason, Vilmundur; Perola, Markus; PROMIS; Cardiogramplusc4D
Contributor: University of Helsinki, Clinicum
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
Date: 2017-06-13
Language: eng
Number of pages: 45
Belongs to series: Circulation
ISSN: 0009-7322
URI: http://hdl.handle.net/10138/237005
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-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 <1.0x10(-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= 1.3x10(-16)) in comparison with 5% in ever-smokers (P= 2.5x10(-4)), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value= 8.7x10(-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.
Subject: ADAMTS7 protein
coronary artery disease
gene-environment interaction
genome-wide association study
3121 General medicine, internal medicine and other clinical medicine

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