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Loss of Cardio-Protective Effects at the ADAMTS7 Locus Due to Gene-Smoking Interactions.

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posted on 21.08.2017 by Danish Saleheen, Wei Zhao, Robin Young, Christopher P. Nelson, WeangKee 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 Sedaghat, Eirini Marouli, Kati Kristiansson, Jing Hua Zhao, Robert 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 O'Donnell, Erik Ingelsson, Mary F. Feitosa, Jeanette Erdmann, Donald W. Bowden, Colin N. A. Palmer, Vilmundur Gudnason, Ulf de Faire, Pierre Zalloua, Nicholas Wareham, John R. Thompson, Kari Kuulasmaa, George Dedoussis, Markus Perola, Abbas Dehghan, John C. Chambers, Jaspal Kooner, Hooman Allayee, Panos Deloukas, Ruth McPherson, Kari Stefansson, Heribert Schunkert, Sekar Kathiresan, Martin Farrall, Philippe Marcel Frossard, Daniel J. Rader, Nilesh J. Samani, Muredach P. Reilly, EPIC-CVD, PROMIS, CARDIoGRAMplusC4D
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 ADAMTS7Conclusions -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.

Funding

Dr Saleheen has received funding from the National Institutes of Health, the Fogarty International, the Wellcome Trust, the British Heart Foundation, Pfizer, Genentech, Regeneron, and Eli Lilly pharmaceuticals. This work was supported in part by R01-HL-111694 and K24-HL-107643 from the National Institutes of Health to Dr Reilly. PROMIS: Genotyping in PROMIS was funded by the Wellcome Trust, UK, and Pfizer. Fieldwork in the PROMIS study was supported through funds available to investigators at the Center for Non-Communicable Diseases, Pakistan, and the University of Cambridge, UK. EPIC-CVD Consortium: CHD case ascertainment and validation, genotyping, and clinical chemistry assays in EPIC-CVD were principally supported by grants awarded to the University of Cambridge from the European Union (EU) Framework Program 7 (HEALTH-F2-2012-279233), the United Kingdom (UK) Medical Research Council (G0800270) and British Heart Foundation (SP/09/002), the UK National Institute for Health Research Cambridge Biomedical Research Center, and the European Research Council (268834). Scientists at the EPIC-CVD Coordinating Center have also been supported by grants from the US National Institutes of Health, Merck, Novartis, GlaxoSmithKline, and Pfizer. Funding sources for contributing sites can be found in the online-only Data Supplement. http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.116.022069/-/DC1

History

Citation

Circulation, 2017, 135(24), pp. 2336-2353

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular Sciences

Version

AM (Accepted Manuscript)

Published in

Circulation

Publisher

American Heart Association, Lippincott, Williams & Wilkins

issn

0009-7322

eissn

1524-4539

Acceptance date

21/03/2017

Copyright date

2017

Available date

01/11/2017

Publisher version

http://circ.ahajournals.org/content/135/24/2336

Notes

The full author list is available on page 2349. The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.116.022069/-/DC1. Circulation is available at http://circ.ahajournals.org.;The file associated with this record is under embargo until 6 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.

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en

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