Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis

Pradeep Natarajan; Joshua C Bis; Lawrence F Bielak; Amanda J Cox; Marcus Dörr; Mary F Feitosa; Nora Franceschini; Xiuqing Guo; Shih-Jen Hwang; Aaron Isaacs; Min A Jhun; Maryam Kavousi; Ruifang Li-Gao; Leo-Pekka Lyytikäinen; 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 Išgum; J Wouter Jukema; Mika Kähönen; Sharon L R Kardia; Brian G Kral; Lenore J Launer; Joseph Massaro; Roxana Mehran

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 Dörr, Mary F Feitosa, Nora Franceschini, Xiuqing Guo, Shih-Jen Hwang, Aaron Isaacs, Min A Jhun, Maryam Kavousi, Ruifang Li-Gao, Leo-Pekka Lyytikäinen, 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 Išgum, J Wouter Jukema, Mika Kähönen, Sharon L R Kardia, Brian G Kral, Lenore J Launer, Joseph Massaro, Roxana Mehran,

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 (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD.

METHODS AND RESULTS: -We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. 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 CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC (P = 3×10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P = 1×10(-12)) and 1.4% reduced CIMT (P = 4×10(-14)) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for CHD (OR 0.77; P = 1×10(-11)).

CONCLUSIONS: -Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.

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

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Natarajan, P., Bis, J. C., Bielak, L. F., Cox, A. J., Dörr, M., Feitosa, M. F., Franceschini, N., Guo, X., Hwang, S.-J., Isaacs, A., Jhun, M. A., Kavousi, M., Li-Gao, R., Lyytikäinen, L.-P., Marioni, R. E., Schminke, U., Stitziel, N. O., Tada, H., van Setten, 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

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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 (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD.METHODS AND RESULTS: -We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. 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 CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC (P = 3×10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P = 1×10(-12)) and 1.4% reduced CIMT (P = 4×10(-14)) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for CHD (OR 0.77; P = 1×10(-11)).CONCLUSIONS: -Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.",

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 D{\"o}rr 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 Lyytik{\"a}inen 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 I{\v s}gum and Jukema, {J Wouter} and Mika K{\"a}h{\"o}nen and Kardia, {Sharon L R} and Kral, {Brian G} and Launer, {Lenore J} and Joseph Massaro and Roxana Mehran",

year = "2016",

month = dec,

doi = "10.1161/CIRCGENETICS.116.001572",

language = "English",

volume = "9",

pages = "511--520",

number = "6",

}

Natarajan, P, Bis, JC, Bielak, LF, Cox, AJ, Dörr, M, Feitosa, MF, Franceschini, N, Guo, X, Hwang, S-J, Isaacs, A, Jhun, MA, Kavousi, M, Li-Gao, R, Lyytikäinen, 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, Išgum, I, Jukema, JW, Kähönen, M, Kardia, SLR, Kral, BG, Launer, LJ, Massaro, J, Mehran, R 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 - Dörr, 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 - Lyytikäinen, 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 - Išgum, Ivana

AU - Jukema, J Wouter

AU - Kähönen, Mika

AU - Kardia, Sharon L R

AU - Kral, Brian G

AU - Launer, Lenore J

AU - Massaro, Joseph

AU - Mehran, Roxana

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 (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD.METHODS AND RESULTS: -We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. 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 CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC (P = 3×10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P = 1×10(-12)) and 1.4% reduced CIMT (P = 4×10(-14)) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for CHD (OR 0.77; P = 1×10(-11)).CONCLUSIONS: -Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.

AB - BACKGROUND: -The burden of subclinical atherosclerosis in asymptomatic individuals is heritable and associated with elevated risk of developing clinical coronary heart disease (CHD). We sought to identify genetic variants in protein-coding regions associated with subclinical atherosclerosis and the risk of subsequent CHD.METHODS AND RESULTS: -We studied a total of 25,109 European ancestry and African-American participants with coronary artery calcification (CAC) measured by cardiac computed tomography and 52,869 with common carotid intima media thickness (CIMT) measured by ultrasonography within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. 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 CIMT. APOB p.Arg3527Gln was associated with four-fold excess CAC (P = 3×10(-10)). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P = 1×10(-12)) and 1.4% reduced CIMT (P = 4×10(-14)) in carriers compared with non-carriers. In secondary analyses conditioning on LDL cholesterol concentration, the ε2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ε2 was associated with reduced risk for CHD (OR 0.77; P = 1×10(-11)).CONCLUSIONS: -Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE ε2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities as well as clinical CHD.

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 - 1942-3268

VL - 9

SP - 511

EP - 520

JO - Circulation-Cardiovascular genetics

JF - Circulation-Cardiovascular genetics

IS - 6

ER -

Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis

Abstract

Keywords

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