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 SedaghatEirini 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

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40 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	English (US)
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 - Jun 13 2017
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2017 American Heart Association, Inc.

Keywords

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

UN SDGs

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

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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

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

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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.",

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

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month = jun,

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doi = "10.1161/CIRCULATIONAHA.116.022069",

language = "English (US)",

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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.

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

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DO - 10.1161/CIRCULATIONAHA.116.022069

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AN - SCOPUS:85020720919

SN - 0009-7322

VL - 135

SP - 2336

EP - 2353

JO - Circulation

JF - Circulation

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ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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