Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis

Pradeep Natarajan; Joshua C. Bis; Lawrence F. Bielak; Amanda J. Cox; Marcus Dorr; Mary F. Feitosa; Nora Franceschini; Xiuqing Guo; Shih-Jen Hwang; Aaron Isaacs; Min A. Jhun; Maryam Kavousi; Ruifang Li-Gao; Leo-Pekka Lyytikainen; Riccardo E. Marioni; Ulf Schminke; Nathan O. Stitziel; Hayato Tada; Jessica van Setten; Albert V. Smith; Dina Vojinovic; Lisa R. Yanek; Jie Yao; Laura M. Yerges-Armstrong; Najaf Amin; Usman Baber; Ingrid B. Borecki; J. Jeffrey Carr; Yii-Der Ida Chen; L. Adrienne Cupples; Pim A. de Jong; Harry de Koning; Bob D. de Vos; Ayse Demirkan; Valentin Fuster; Oscar H. Franco; Mark O. Goodarzi; Tamara B. Harris; Susan R. Heckbert; Gerardo Heiss; Udo Hoffmann; Albert Hofman; Ivana Isgum; J. Wouter Jukema; Mika Kahonen; Sharon L. R. Kardia; Brian G. Kral; Lenore J. Launer; Joe Massaro; Roxana Mehran; Braxton D. Mitchell; Thomas H. Mosley Jr; Renee de Mutsert; Anne B. Newman; Khanh-dung Nguyen; Kari E. North; Jeffrey R. O'Connell; Matthijs Oudkerk; James S. Pankow; Gina M. Peloso; Wendy Post; Michael A. Province; Laura M. Raffield; Olli T. Raitakari; Dermot F. Reilly; Fernando Rivadeneira; Frits Rosendaal; Samantha Sartori; Kent D. Taylor; Alexander Teumer; Stella Trompet; Stephen T. Turner; Andre G. Uitterlinden; Dhananjay Vaidya; Aad van der Lugt; Uwe Volker; Joanna M. Wardlaw; Christina L. Wassel; Stefan Weiss; Mary K. Wojczynski; Diane M. Becker; Lewis C. Becker; Eric Boerwinkle; Donald W. Bowden; Ian J. Deary; Abbas Dehghan; Stephan B. Felix; Vilmundur Gudnason; Terho Lehtimaki; Rasika Mathias; Dennis O. Mook-Kanamori; Bruce M. Psaty; Daniel J. Rader; Jerome I. Rotter; James G. Wilson; Cornelia M. van Duijn; Henry Volzke; Sekar Kathiresan; Patricia A. Peyser; Christopher J. O'Donnell

doi:10.1161/CIRCGENETICS.116.001572

Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis

Pradeep Natarajan^*, Joshua C. Bis, Lawrence F. Bielak, Amanda J. Cox, Marcus Dorr, Mary F. Feitosa, Nora Franceschini, Xiuqing Guo, Shih-Jen Hwang, Aaron Isaacs, Min A. Jhun, Maryam Kavousi, Ruifang Li-Gao, Leo-Pekka Lyytikainen, Riccardo E. Marioni, Ulf Schminke, Nathan O. Stitziel, Hayato Tada, Jessica van Setten, Albert V. SmithDina Vojinovic, Lisa R. Yanek, Jie Yao, Laura M. Yerges-Armstrong, Najaf Amin, Usman Baber, Ingrid B. Borecki, J. Jeffrey Carr, Yii-Der Ida Chen, L. Adrienne Cupples, Pim A. de Jong, Harry de Koning, Bob D. de Vos, Ayse Demirkan, Valentin Fuster, Oscar H. Franco, Mark O. Goodarzi, Tamara B. Harris, Susan R. Heckbert, Gerardo Heiss, Udo Hoffmann, Albert Hofman, Ivana Isgum, J. Wouter Jukema, Mika Kahonen, Sharon L. R. Kardia, Brian G. Kral, Lenore J. Launer, Joe Massaro, Roxana Mehran, Braxton D. Mitchell, Thomas H. Mosley Jr, Renee de Mutsert, Anne B. Newman, Khanh-dung Nguyen, Kari E. North, Jeffrey R. O'Connell, Matthijs Oudkerk, James S. Pankow, Gina M. Peloso, Wendy Post, Michael A. Province, Laura M. Raffield, Olli T. Raitakari, Dermot F. Reilly, Fernando Rivadeneira, Frits Rosendaal, Samantha Sartori, Kent D. Taylor, Alexander Teumer, Stella Trompet, Stephen T. Turner, Andre G. Uitterlinden, Dhananjay Vaidya, Aad van der Lugt, Uwe Volker, Joanna M. Wardlaw, Christina L. Wassel, Stefan Weiss, Mary K. Wojczynski, Diane M. Becker, Lewis C. Becker, Eric Boerwinkle, Donald W. Bowden, Ian J. Deary, Abbas Dehghan, Stephan B. Felix, Vilmundur Gudnason, Terho Lehtimaki, Rasika Mathias, Dennis O. Mook-Kanamori, Bruce M. Psaty, Daniel J. Rader, Jerome I. Rotter, James G. Wilson, Cornelia M. van Duijn, Henry Volzke, Sekar Kathiresan, Patricia A. Peyser, Christopher J. O'Donnell^*

^*Corresponding author for this work

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

Abstract

Background-The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. Methods and Results-We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima-media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima-media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3x10(-10)). The APOE epsilon 2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1x10(-12)) and 1.4% reduced carotid intima-media thickness (P=4x10(-14)) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the epsilon 2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of epsilon 2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1x10(-11)). Conclusions-Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE epsilon 2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.

Original language	English
Pages (from-to)	511-520
Journal	Circulation : Cardiovascular Genetics
Volume	9
Issue number	6
DOIs	https://doi.org/10.1161/CIRCGENETICS.116.001572
Publication status	Published - Dec 2016

Keywords

carotid intima-media thickness
coronary artery calcification
exome
genome-wide association study
genomics

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10.1161/CIRCGENETICS.116.001572

Cite this

Natarajan, P., Bis, J. C., Bielak, L. F., Cox, A. J., Dorr, M., Feitosa, M. F., Franceschini, N., Guo, X., Hwang, S.-J., Isaacs, A., Jhun, M. A., Kavousi, M., Li-Gao, R., Lyytikainen, L.-P., Marioni, R. E., Schminke, U., Stitziel, N. O., Tada, H., van Setten, J., ... O'Donnell, C. J. (2016). Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis. Circulation : Cardiovascular Genetics, 9(6), 511-520. https://doi.org/10.1161/CIRCGENETICS.116.001572

@article{02e48887eab64449bc81fde0ed0f766a,

title = "Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis",

abstract = "Background-The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. Methods and Results-We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima-media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima-media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3x10(-10)). The APOE epsilon 2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1x10(-12)) and 1.4% reduced carotid intima-media thickness (P=4x10(-14)) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the epsilon 2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of epsilon 2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1x10(-11)). Conclusions-Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE epsilon 2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.",

keywords = "carotid intima-media thickness, coronary artery calcification, exome, genome-wide association study, genomics",

author = "Pradeep Natarajan and Bis, {Joshua C.} and Bielak, {Lawrence F.} and Cox, {Amanda J.} and Marcus Dorr and Feitosa, {Mary F.} and Nora Franceschini and Xiuqing Guo and Shih-Jen Hwang and Aaron Isaacs and Jhun, {Min A.} and Maryam Kavousi and Ruifang Li-Gao and Leo-Pekka Lyytikainen and Marioni, {Riccardo E.} and Ulf Schminke and Stitziel, {Nathan O.} and Hayato Tada and {van Setten}, Jessica and Smith, {Albert V.} and Dina Vojinovic and Yanek, {Lisa R.} and Jie Yao and Yerges-Armstrong, {Laura M.} and Najaf Amin and Usman Baber and Borecki, {Ingrid B.} and Carr, {J. Jeffrey} and Chen, {Yii-Der Ida} and Cupples, {L. Adrienne} and {de Jong}, {Pim A.} and {de Koning}, Harry and {de Vos}, {Bob D.} and Ayse Demirkan and Valentin Fuster and Franco, {Oscar H.} and Goodarzi, {Mark O.} and Harris, {Tamara B.} and Heckbert, {Susan R.} and Gerardo Heiss and Udo Hoffmann and Albert Hofman and Ivana Isgum and Jukema, {J. Wouter} and Mika Kahonen and Kardia, {Sharon L. R.} and Kral, {Brian G.} and Launer, {Lenore J.} and Joe Massaro and Roxana Mehran and Mitchell, {Braxton D.} and Jr, {Thomas H. Mosley} and {de Mutsert}, Renee and Newman, {Anne B.} and Khanh-dung Nguyen and North, {Kari E.} and O'Connell, {Jeffrey R.} and Matthijs Oudkerk and Pankow, {James S.} and Peloso, {Gina M.} and Wendy Post and Province, {Michael A.} and Raffield, {Laura M.} and Raitakari, {Olli T.} and Reilly, {Dermot F.} and Fernando Rivadeneira and Frits Rosendaal and Samantha Sartori and Taylor, {Kent D.} and Alexander Teumer and Stella Trompet and Turner, {Stephen T.} and Uitterlinden, {Andre G.} and Dhananjay Vaidya and {van der Lugt}, Aad and Uwe Volker and Wardlaw, {Joanna M.} and Wassel, {Christina L.} and Stefan Weiss and Wojczynski, {Mary K.} and Becker, {Diane M.} and Becker, {Lewis C.} and Eric Boerwinkle and Bowden, {Donald W.} and Deary, {Ian J.} and Abbas Dehghan and Felix, {Stephan B.} and Vilmundur Gudnason and Terho Lehtimaki and Rasika Mathias and Mook-Kanamori, {Dennis O.} and Psaty, {Bruce M.} and Rader, {Daniel J.} and Rotter, {Jerome I.} and Wilson, {James G.} and {van Duijn}, {Cornelia M.} and Henry Volzke and Sekar Kathiresan and Peyser, {Patricia A.} and O'Donnell, {Christopher J.}",

year = "2016",

month = dec,

doi = "10.1161/CIRCGENETICS.116.001572",

language = "English",

volume = "9",

pages = "511--520",

journal = "Circulation : Cardiovascular Genetics",

issn = "1942-325X",

publisher = "LIPPINCOTT WILLIAMS & WILKINS",

number = "6",

}

Natarajan, P, Bis, JC, Bielak, LF, Cox, AJ, Dorr, M, Feitosa, MF, Franceschini, N, Guo, X, Hwang, S-J, Isaacs, A, Jhun, MA, Kavousi, M, Li-Gao, R, Lyytikainen, L-P, Marioni, RE, Schminke, U, Stitziel, NO, Tada, H, van Setten, J, Smith, AV, Vojinovic, D, Yanek, LR, Yao, J, Yerges-Armstrong, LM, Amin, N, Baber, U, Borecki, IB, Carr, JJ, Chen, Y-DI, Cupples, LA, de Jong, PA, de Koning, H, de Vos, BD, Demirkan, A, Fuster, V, Franco, OH, Goodarzi, MO, Harris, TB, Heckbert, SR, Heiss, G, Hoffmann, U, Hofman, A, Isgum, I, Jukema, JW, Kahonen, M, Kardia, SLR, Kral, BG, Launer, LJ, Massaro, J, Mehran, R, Mitchell, BD, Jr, THM, de Mutsert, R, Newman, AB, Nguyen, K, North, KE, O'Connell, JR, Oudkerk, M, Pankow, JS, Peloso, GM, Post, W, Province, MA, Raffield, LM, Raitakari, OT, Reilly, DF, Rivadeneira, F, Rosendaal, F, Sartori, S, Taylor, KD, Teumer, A, Trompet, S, Turner, ST, Uitterlinden, AG, Vaidya, D, van der Lugt, A, Volker, U, Wardlaw, JM, Wassel, CL, Weiss, S, Wojczynski, MK, Becker, DM, Becker, LC, Boerwinkle, E, Bowden, DW, Deary, IJ, Dehghan, A, Felix, SB, Gudnason, V, Lehtimaki, T, Mathias, R, Mook-Kanamori, DO, Psaty, BM, Rader, DJ, Rotter, JI, Wilson, JG, van Duijn, CM, Volzke, H, Kathiresan, S, Peyser, PA & O'Donnell, CJ 2016, 'Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis', Circulation : Cardiovascular Genetics, vol. 9, no. 6, pp. 511-520. https://doi.org/10.1161/CIRCGENETICS.116.001572

TY - JOUR

T1 - Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis

AU - Natarajan, Pradeep

AU - Bis, Joshua C.

AU - Bielak, Lawrence F.

AU - Cox, Amanda J.

AU - Dorr, Marcus

AU - Feitosa, Mary F.

AU - Franceschini, Nora

AU - Guo, Xiuqing

AU - Hwang, Shih-Jen

AU - Isaacs, Aaron

AU - Jhun, Min A.

AU - Kavousi, Maryam

AU - Li-Gao, Ruifang

AU - Lyytikainen, Leo-Pekka

AU - Marioni, Riccardo E.

AU - Schminke, Ulf

AU - Stitziel, Nathan O.

AU - Tada, Hayato

AU - van Setten, Jessica

AU - Smith, Albert V.

AU - Vojinovic, Dina

AU - Yanek, Lisa R.

AU - Yao, Jie

AU - Yerges-Armstrong, Laura M.

AU - Amin, Najaf

AU - Baber, Usman

AU - Borecki, Ingrid B.

AU - Carr, J. Jeffrey

AU - Chen, Yii-Der Ida

AU - Cupples, L. Adrienne

AU - de Jong, Pim A.

AU - de Koning, Harry

AU - de Vos, Bob D.

AU - Demirkan, Ayse

AU - Fuster, Valentin

AU - Franco, Oscar H.

AU - Goodarzi, Mark O.

AU - Harris, Tamara B.

AU - Heckbert, Susan R.

AU - Heiss, Gerardo

AU - Hoffmann, Udo

AU - Hofman, Albert

AU - Isgum, Ivana

AU - Jukema, J. Wouter

AU - Kahonen, Mika

AU - Kardia, Sharon L. R.

AU - Kral, Brian G.

AU - Launer, Lenore J.

AU - Massaro, Joe

AU - Mehran, Roxana

AU - Mitchell, Braxton D.

AU - Jr, Thomas H. Mosley

AU - de Mutsert, Renee

AU - Newman, Anne B.

AU - Nguyen, Khanh-dung

AU - North, Kari E.

AU - O'Connell, Jeffrey R.

AU - Oudkerk, Matthijs

AU - Pankow, James S.

AU - Peloso, Gina M.

AU - Post, Wendy

AU - Province, Michael A.

AU - Raffield, Laura M.

AU - Raitakari, Olli T.

AU - Reilly, Dermot F.

AU - Rivadeneira, Fernando

AU - Rosendaal, Frits

AU - Sartori, Samantha

AU - Taylor, Kent D.

AU - Teumer, Alexander

AU - Trompet, Stella

AU - Turner, Stephen T.

AU - Uitterlinden, Andre G.

AU - Vaidya, Dhananjay

AU - van der Lugt, Aad

AU - Volker, Uwe

AU - Wardlaw, Joanna M.

AU - Wassel, Christina L.

AU - Weiss, Stefan

AU - Wojczynski, Mary K.

AU - Becker, Diane M.

AU - Becker, Lewis C.

AU - Boerwinkle, Eric

AU - Bowden, Donald W.

AU - Deary, Ian J.

AU - Dehghan, Abbas

AU - Felix, Stephan B.

AU - Gudnason, Vilmundur

AU - Lehtimaki, Terho

AU - Mathias, Rasika

AU - Mook-Kanamori, Dennis O.

AU - Psaty, Bruce M.

AU - Rader, Daniel J.

AU - Rotter, Jerome I.

AU - Wilson, James G.

AU - van Duijn, Cornelia M.

AU - Volzke, Henry

AU - Kathiresan, Sekar

AU - Peyser, Patricia A.

AU - O'Donnell, Christopher J.

PY - 2016/12

Y1 - 2016/12

N2 - Background-The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. Methods and Results-We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima-media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima-media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3x10(-10)). The APOE epsilon 2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1x10(-12)) and 1.4% reduced carotid intima-media thickness (P=4x10(-14)) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the epsilon 2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of epsilon 2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1x10(-11)). Conclusions-Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE epsilon 2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.

AB - Background-The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease. We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent coronary heart disease. Methods and Results-We studied a total of 25 109 European ancestry and African ancestry participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52 869 participants with common carotid intima-media thickness measured by ultrasonography within the CHARGE Consortium (Cohorts for Heart and Aging Research in Genomic Epidemiology). Participants were genotyped for 247 870 DNA sequence variants (231 539 in exons) across the genome. A meta-analysis of exome-wide association studies was performed across cohorts for CAC and carotid intima-media thickness. APOB p.Arg3527Gln was associated with 4-fold excess CAC (P=3x10(-10)). The APOE epsilon 2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1x10(-12)) and 1.4% reduced carotid intima-media thickness (P=4x10(-14)) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the epsilon 2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of epsilon 2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1x10(-11)). Conclusions-Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE epsilon 2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.

KW - carotid intima-media thickness

KW - coronary artery calcification

KW - exome

KW - genome-wide association study

KW - genomics

U2 - 10.1161/CIRCGENETICS.116.001572

DO - 10.1161/CIRCGENETICS.116.001572

M3 - Article

C2 - 27872105

SN - 1942-325X

VL - 9

SP - 511

EP - 520

JO - Circulation : Cardiovascular Genetics

JF - Circulation : Cardiovascular Genetics

IS - 6

ER -