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

Danish Saleheen (Lead / Corresponding author), Wei Zhao, Robin Young, Christopher P. Nelson, Weang Kee Ho, Jane F. Ferguson, Asif Rasheed, Kristy Ou, Sylvia T. Nurnberg, Robert C. Bauer, Anuj Goel, Ron Do, Alexandre F. R. Stewart, Jaana Hartiala, Weihua Zhang, Gudmar Thorleifsson, Rona J. Strawbridge, Juha Sinisalo, Stavroula Kanoni, Sanaz SedaghatEirini Marouli, Kati Kristiansson, Jing Hua Zhao, Robert A. Scott, Dominique Gauguier, Svati H. Shah, Albert Vernon Smith, Natalie Van Zuydam, Amanda J. Cox, Christina Willenborg, Thorsten Kessler, Lingyao Zeng, Michael A. Province, Andrea Ganna, Lars Lind, Nancy L. Pedersen, Charles C. White, Anni Joensuu, Marcus Edi Kleber, Alistair S. Hall, Winfried März, Veikko Salomaa, Christopher J. O'Donnell, Erik Ingelsson, Mary F. Feitosa, Jeanette Erdmann, Donald W. Bowden, Colin N. A. Palmer, Vilmundur Gudnason, Ulf de Faire, EPIC-CVD, PROMIS, CARDIoGRAMplusC4D

Research output: Contribution to journalArticlepeer-review

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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-environment 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 associate 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< 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-value: 1.3x10(-16)) compared to 5% in ever-smokers (P-value: 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" compared to "ever-smokers". Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.

Original languageEnglish
Pages (from-to)2336-2353
Number of pages18
Issue number24
Early online date1 May 2017
Publication statusPublished - 13 Jun 2017


  • Gene-environment interaction
  • Coronary artery disease
  • Genome wide association study
  • Smoking


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