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

Publication ,  Journal Article
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 ...
Published in: Circulation
June 13, 2017

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.

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Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

June 13, 2017

Volume

135

Issue

24

Start / End Page

2336 / 2353

Location

United States

Related Subject Headings

  • Smoking
  • Polymorphism, Single Nucleotide
  • Middle Aged
  • Male
  • Humans
  • Genetic Predisposition to Disease
  • Genetic Loci
  • Gene-Environment Interaction
  • Female
  • Coronary Vessels
 

Citation

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Chicago
ICMJE
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Saleheen, D., Zhao, W., Young, R., Nelson, C. P., Ho, W., Ferguson, J. F., … Reilly, M. P. (2017). Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions. Circulation, 135(24), 2336–2353. https://doi.org/10.1161/CIRCULATIONAHA.116.022069
Saleheen, Danish, Wei Zhao, Robin Young, Christopher P. Nelson, WeangKee Ho, Jane F. Ferguson, Asif Rasheed, et al. “Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions.Circulation 135, no. 24 (June 13, 2017): 2336–53. https://doi.org/10.1161/CIRCULATIONAHA.116.022069.
Saleheen D, Zhao W, Young R, Nelson CP, Ho W, Ferguson JF, et al. Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions. Circulation. 2017 Jun 13;135(24):2336–53.
Saleheen, Danish, et al. “Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions.Circulation, vol. 135, no. 24, June 2017, pp. 2336–53. Pubmed, doi:10.1161/CIRCULATIONAHA.116.022069.
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. Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions. Circulation. 2017 Jun 13;135(24):2336–2353.

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

June 13, 2017

Volume

135

Issue

24

Start / End Page

2336 / 2353

Location

United States

Related Subject Headings

  • Smoking
  • Polymorphism, Single Nucleotide
  • Middle Aged
  • Male
  • Humans
  • Genetic Predisposition to Disease
  • Genetic Loci
  • Gene-Environment Interaction
  • Female
  • Coronary Vessels