1. Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions
- Author
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Dominique Gauguier, Ruth McPherson, Anuj Goel, Donald W. Bowden, Nancy L. Pedersen, WeangKee Ho, Danish Saleheen, Nilesh J. Samani, Marcus Edi Kleber, Michael A. Province, Albert V. Smith, Christopher J. O'Donnell, Jeanette Erdmann, Hooman Allayee, Asif Rasheed, Mary F. Feitosa, Vilmundur Gudnason, Jaspal S. Kooner, Christopher P. Nelson, Muredach P. Reilly, Winfried März, George V. Dedoussis, Wei Zhao, Markus Perola, Alexandre F.R. Stewart, Veikko Salomaa, John C. Chambers, Alistair S. Hall, K. Stefansson, Robert C. Bauer, Panos Deloukas, Charles C. White, Daniel J. Rader, Eirini Marouli, Robert A. Scott, Sylvia T. Nurnberg, Stavroula Kanoni, Andrea Ganna, Anni Joensuu, Svati H. Shah, Juha Sinisalo, Gudmar Thorleifsson, Jing Hua Zhao, Lingyao Zeng, Kari Kuulasmaa, Nicholas J. Wareham, Rona J. Strawbridge, Jane F. Ferguson, Philippe M. Frossard, Weihua Zhang, Pierre Zalloua, Kristy Ou, Ulf de Faire, Martin Farrall, Sanaz Sedaghat, Robin Young, Amanda J. Cox, Lars Lind, Christina Willenborg, K. Kristiansson, Erik Ingelsson, Colin N. A. Palmer, Jaana Hartiala, Abbas Dehghan, Natalie van Zuydam, Sekar Kathiresan, John Thompson, Ron Do, Heribert Schunkert, Thorsten Kessler, Epidemiology, Clinicum, Kardiologian yksikkö, Department of Medicine, and Institute for Molecular Medicine Finland
- Subjects
0301 basic medicine ,SUSCEPTIBILITY LOCI ,Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) ,Genome-wide association study ,Locus (genetics) ,smoking ,AMYOTROPHIC-LATERAL-SCLEROSIS ,Coronary artery disease ,03 medical and health sciences ,Muscle cell migration ,Physiology (medical) ,medicine ,Genetic predisposition ,Cardiac and Cardiovascular Systems ,CORONARY-HEART-DISEASE ,Gene–environment interaction ,GENOME-WIDE ASSOCIATION ,Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) ,Gene ,METAANALYSIS ,Genetics ,RISK ,Kardiologi ,genome-wide association study ,business.industry ,MORTALITY ,ADAMTS7 protein ,MEN ,medicine.disease ,3. Good health ,gene-environment interaction ,030104 developmental biology ,3121 General medicine, internal medicine and other clinical medicine ,Etiology ,MUSCLE-CELL MIGRATION ,CIGARETTE-SMOKING ,Cardiology and Cardiovascular Medicine ,business ,coronary artery disease - 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 –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.
- Published
- 2017