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

Danish Saleheen; 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 Sedaghat; Eirini 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

doi:10.1161/CIRCULATIONAHA.116.022069

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

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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-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 language	English
Pages (from-to)	2336-2353
Number of pages	18
Journal	Circulation
Volume	135
Issue number	24
Early online date	1 May 2017
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.116.022069
Publication status	Published - 13 Jun 2017

Keywords

ADAMTS7
Gene-environment interaction
Coronary artery disease
Genome wide association study
Smoking

UN SDGs

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

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10.1161/CIRCULATIONAHA.116.022069

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Saleheen, D., Zhao, W., Young, R., Nelson, C. P., Ho, W. K., 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., ... EPIC-CVD, PROMIS, CARDIoGRAMplusC4D (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{d90c35969ddb48ab9580c3d96bfbe79b,

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-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.",

keywords = "ADAMTS7, Gene-environment interaction , Coronary artery disease, Genome wide association study , Smoking",

author = "Danish Saleheen and Wei Zhao and Robin Young and Nelson, {Christopher P.} and Ho, {Weang Kee} 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 Scott, {Robert A.} 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 O'Donnell, {Christopher J.} and Erik Ingelsson and Feitosa, {Mary F.} and Jeanette Erdmann and Bowden, {Donald W.} and Palmer, {Colin N. A.} and Vilmundur Gudnason and {de Faire}, Ulf and {EPIC-CVD, PROMIS, CARDIoGRAMplusC4D}",

note = "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.",

year = "2017",

month = jun,

day = "13",

doi = "10.1161/CIRCULATIONAHA.116.022069",

language = "English",

volume = "135",

pages = "2336--2353",

journal = "Circulation",

issn = "0009-7322",

publisher = "American Heart Association",

number = "24",

}

Saleheen, D, Zhao, W, Young, R, Nelson, CP, Ho, WK, 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, RA, 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, CJ, Ingelsson, E, Feitosa, MF, Erdmann, J, Bowden, DW, Palmer, CNA, Gudnason, V, de Faire, U & EPIC-CVD, PROMIS, CARDIoGRAMplusC4D 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, Weang Kee

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 A.

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 J.

AU - Ingelsson, Erik

AU - Feitosa, Mary F.

AU - Erdmann, Jeanette

AU - Bowden, Donald W.

AU - Palmer, Colin N. A.

AU - Gudnason, Vilmundur

AU - de Faire, Ulf

AU - EPIC-CVD, PROMIS, CARDIoGRAMplusC4D

N1 - 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.

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-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.

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-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.

KW - ADAMTS7

KW - Gene-environment interaction

KW - Coronary artery disease

KW - Genome wide association study

KW - Smoking

U2 - 10.1161/CIRCULATIONAHA.116.022069

DO - 10.1161/CIRCULATIONAHA.116.022069

M3 - Article

C2 - 28461624

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

Abstract

Keywords

UN SDGs

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