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

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

doi:10.1161/CIRCULATIONAHA.116.022069

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

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

College of Medicine and Health Sciences

University of Pennsylvania
Center for Non-Communicable Diseases
University of Cambridge
University of Leicester
Vanderbilt University
University of Oxford
Icahn School of Medicine at Mount Sinai
University of Pennsylvania Philadelphia
University of Ottawa Heart Institute
Columbia University Medical Center
University of Southern California School of Medicine
Imperial College London
Ealing Hospital National Health Service (NHS) Trust
Karolinska Inst., Novum, KFC, P.
Helsinki University Central Hospital (HUCH)
Barts and The London School of Medicine and Dentistry
Erasmus Medical Center
Harokopio University of Athens
Boston University
National Institute for Health and Welfare
University of Cambridge School of Clinical Medicine
Centre de Recherche des Cordeliers
University of Iceland
Duke University Medical Center
Icelandic Heart Association
Ninewells Hospital and Medical School
University of Helsinki
Medical Center Boulevard
University of Lübeck
Partner Site Hamburg/Kiel/Lübeck
University of Heidelberg
Deutsches Herzzentrum München
University of Leeds, School of Medicine
Synlab Academy
Washington University School of Medicine in St. Louis
Massachusetts General Hospital
University Hospital
Medical University of Graz
National Heart, Lung, and Blood Institute (NHLBI)
Uppsala University
Stanford School of Medicine
Lebanese American University
Broad Institute
Imperial College NHS Trust
King Abdulaziz University
deCODE genetics
National Heart and Lung Institute
Harvard Medical School

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

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 <1.0×10^-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.

Original language	British English
Pages (from-to)	2336-2353
Number of pages	18
Journal	Circulation
Volume	135
Issue number	24
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.116.022069
State	Published - 13 Jun 2017

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

ADAMTS7 protein
coronary artery disease
gene-environment interaction
genome-wide association study
smoking

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10.1161/CIRCULATIONAHA.116.022069

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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., ... 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

@article{08ea8da8649f4533aa1cfc1d8415ed4e,

title = "Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions",

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 <1.0×10-3 (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.",

keywords = "ADAMTS7 protein, coronary artery disease, gene-environment interaction, genome-wide association study, smoking",

author = "Danish Saleheen and Wei Zhao and Robin Young and Nelson, \{Christopher P.\} and Weangkee Ho and Ferguson, \{Jane F.\} and Asif Rasheed and Kristy Ou and Nurnberg, \{Sylvia T.\} and Bauer, \{Robert C.\} and Anuj Goel and Ron Do and Stewart, \{Alexandre F.R.\} and Jaana Hartiala and Weihua Zhang and Gudmar Thorleifsson and Strawbridge, \{Rona J.\} and Juha Sinisalo and Stavroula Kanoni and Sanaz Sedaghat and Eirini Marouli and Kati Kristiansson and Zhao, \{Jing Hua\} and Robert Scott and Dominique Gauguier and Shah, \{Svati H.\} and Smith, \{Albert Vernon\} and \{Van Zuydam\}, Natalie and Cox, \{Amanda J.\} and Christina Willenborg and Thorsten Kessler and Lingyao Zeng and Province, \{Michael A.\} and Andrea Ganna and Lars Lind and Pedersen, \{Nancy L.\} and White, \{Charles C.\} and Anni Joensuu and Kleber, \{Marcus Edi\} and Hall, \{Alistair S.\} and Winfried M{\"a}rz and Veikko Salomaa and Christopher O'Donnell and Erik Ingelsson and Feitosa, \{Mary F.\} and Jeanette Erdmann and Bowden, \{Donald W.\} and Palmer, \{Colin N.A.\} and Vilmundur Gudnason and Faire, \{Ulf De\} and Pierre Zalloua and Nicholas Wareham and Thompson, \{John R.\} and Kari Kuulasmaa and George Dedoussis and Markus Perola and Abbas Dehghan and Chambers, \{John C.\} and Jaspal Kooner and Hooman Allayee and Panos Deloukas and Ruth McPherson and Kari Stefansson and Heribert Schunkert and Sekar Kathiresan and Martin Farrall and \{Marcel Frossard\}, Philippe and Rader, \{Daniel J.\} and Samani, \{Nilesh J.\} and Reilly, \{Muredach P.\}",

note = "Funding Information: 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). Publisher Copyright: {\textcopyright} 2017 American Heart Association, Inc.",

year = "2017",

month = jun,

day = "13",

doi = "10.1161/CIRCULATIONAHA.116.022069",

language = "British English",

volume = "135",

pages = "2336--2353",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins",

number = "24",

}

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, Zhao, JH, 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, Kleber, ME, 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 2017, 'Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions', Circulation, vol. 135, no. 24, pp. 2336-2353. https://doi.org/10.1161/CIRCULATIONAHA.116.022069

TY - JOUR

T1 - Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions

AU - Saleheen, Danish

AU - Zhao, Wei

AU - Young, Robin

AU - Nelson, Christopher P.

AU - Ho, Weangkee

AU - Ferguson, Jane F.

AU - Rasheed, Asif

AU - Ou, Kristy

AU - Nurnberg, Sylvia T.

AU - Bauer, Robert C.

AU - Goel, Anuj

AU - Do, Ron

AU - Stewart, Alexandre F.R.

AU - Hartiala, Jaana

AU - Zhang, Weihua

AU - Thorleifsson, Gudmar

AU - Strawbridge, Rona J.

AU - Sinisalo, Juha

AU - Kanoni, Stavroula

AU - Sedaghat, Sanaz

AU - Marouli, Eirini

AU - Kristiansson, Kati

AU - Zhao, Jing Hua

AU - Scott, Robert

AU - Gauguier, Dominique

AU - Shah, Svati H.

AU - Smith, Albert Vernon

AU - Van Zuydam, Natalie

AU - Cox, Amanda J.

AU - Willenborg, Christina

AU - Kessler, Thorsten

AU - Zeng, Lingyao

AU - Province, Michael A.

AU - Ganna, Andrea

AU - Lind, Lars

AU - Pedersen, Nancy L.

AU - White, Charles C.

AU - Joensuu, Anni

AU - Kleber, Marcus Edi

AU - Hall, Alistair S.

AU - März, Winfried

AU - Salomaa, Veikko

AU - O'Donnell, Christopher

AU - Ingelsson, Erik

AU - Feitosa, Mary F.

AU - Erdmann, Jeanette

AU - Bowden, Donald W.

AU - Palmer, Colin N.A.

AU - Gudnason, Vilmundur

AU - Faire, Ulf De

AU - Zalloua, Pierre

AU - Wareham, Nicholas

AU - Thompson, John R.

AU - Kuulasmaa, Kari

AU - Dedoussis, George

AU - Perola, Markus

AU - Dehghan, Abbas

AU - Chambers, John C.

AU - Kooner, Jaspal

AU - Allayee, Hooman

AU - Deloukas, Panos

AU - McPherson, Ruth

AU - Stefansson, Kari

AU - Schunkert, Heribert

AU - Kathiresan, Sekar

AU - Farrall, Martin

AU - Marcel Frossard, Philippe

AU - Rader, Daniel J.

AU - Samani, Nilesh J.

AU - Reilly, Muredach P.

N1 - Funding Information: 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). Publisher Copyright: © 2017 American Heart Association, Inc.

PY - 2017/6/13

Y1 - 2017/6/13

N2 - 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.

AB - 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.

KW - ADAMTS7 protein

KW - coronary artery disease

KW - gene-environment interaction

KW - genome-wide association study

KW - smoking

UR - https://www.scopus.com/pages/publications/85020720919

U2 - 10.1161/CIRCULATIONAHA.116.022069

DO - 10.1161/CIRCULATIONAHA.116.022069

M3 - Article

C2 - 28461624

AN - SCOPUS:85020720919

SN - 0009-7322

VL - 135

SP - 2336

EP - 2353

JO - Circulation

JF - Circulation

IS - 24

ER -

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

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Keywords

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