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 & 80 others Dina Vojinovic, Lisa 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, Joe Massaro, Roxana Mehran, Braxton D. Mitchell, Thomas H. Mosley, Renée De Mutsert, Anne B. Newman, Khanh Dung Nguyen, Kari E. North, Jeffrey R. O'Connell, Matthijs Oudkerk, James S. Pankow, Gina M. Peloso, Wendy S 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 Völker, Joanna M. Wardlaw, Christina L. Wassel, Stefan Weiss, Mary K. Wojczynski, Diane M Becker, Lewis Becker, Eric Boerwinkle, Donald W. Bowden, Ian J. Deary, Abbas Dehghan, Stephan B. Felix, Vilmundur Gudnason, Terho Lehtimäki, Rasika Mathias, Dennis O. Mook-Kanamori, Bruce M. Psaty, Daniel J. Rader, Jerome I. Rotter, James G. Wilson, Cornelia M. Van Duijn, Henry Völzke, Sekar Kathiresan, Patricia A. Peyser, Christopher J. O'Donnell

Research output: Contribution to journalArticle

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=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 carotid intima-media thickness (P=4×10- 14) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ϵ2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ϵ2 was associated with reduced risk for coronary heart disease (odds ratio 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 coronary heart disease.

Original languageEnglish (US)
Pages (from-to)511-520
Number of pages10
JournalCirculation: Cardiovascular Genetics
Volume9
Issue number6
DOIs
StatePublished - Dec 1 2016

Fingerprint

Exome
Atherosclerosis
Coronary Vessels
Carotid Intima-Media Thickness
Coronary Disease
Meta-Analysis
LDL Cholesterol
Open Reading Frames
Exons
Ultrasonography
Epidemiology
Alleles
Odds Ratio
Tomography
Genome
Research
Proteins

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

Cite this

Natarajan, P., Bis, J. C., Bielak, L. F., Cox, A. J., Dörr, M., Feitosa, M. F., ... 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

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

In: Circulation: Cardiovascular Genetics, Vol. 9, No. 6, 01.12.2016, p. 511-520.

Research output: Contribution to journalArticle

Natarajan, P, Bis, JC, Bielak, LF, Cox, AJ, Dörr, M, Feitosa, MF, Franceschini, N, Guo, X, Hwang, SJ, Isaacs, A, Jhun, MA, Kavousi, M, Li-Gao, R, Lyytikäinen, LP, Marioni, RE, Schminke, U, Stitziel, NO, Tada, H, Van Setten, J, Smith, AV, Vojinovic, D, Yanek, L, Yao, J, Yerges-Armstrong, LM, Amin, N, Baber, U, Borecki, IB, Carr, JJ, Chen, YDI, 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, Mitchell, BD, Mosley, TH, De Mutsert, R, Newman, AB, Nguyen, KD, North, KE, O'Connell, JR, Oudkerk, M, Pankow, JS, Peloso, GM, Post, WS, 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, Völker, U, Wardlaw, JM, Wassel, CL, Weiss, S, Wojczynski, MK, Becker, DM, Becker, L, Boerwinkle, E, Bowden, DW, Deary, IJ, Dehghan, A, Felix, SB, Gudnason, V, Lehtimäki, T, Mathias, R, Mook-Kanamori, DO, Psaty, BM, Rader, DJ, Rotter, JI, Wilson, JG, Van Duijn, CM, Völzke, 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
Natarajan, Pradeep ; Bis, Joshua C. ; Bielak, Lawrence F. ; Cox, Amanda J. ; Dörr, Marcus ; Feitosa, Mary F. ; Franceschini, Nora ; Guo, Xiuqing ; Hwang, Shih Jen ; Isaacs, Aaron ; Jhun, Min A. ; Kavousi, Maryam ; Li-Gao, Ruifang ; Lyytikäinen, Leo Pekka ; Marioni, Riccardo E. ; Schminke, Ulf ; Stitziel, Nathan O. ; Tada, Hayato ; Van Setten, Jessica ; Smith, Albert V. ; Vojinovic, Dina ; Yanek, Lisa ; Yao, Jie ; Yerges-Armstrong, Laura M. ; Amin, Najaf ; Baber, Usman ; Borecki, Ingrid B. ; Carr, J. Jeffrey ; Chen, Yii Der Ida ; Cupples, L. Adrienne ; De Jong, Pim A. ; De Koning, Harry ; De Vos, Bob D. ; Demirkan, Ayse ; Fuster, Valentin ; Franco, Oscar H. ; Goodarzi, Mark O. ; Harris, Tamara B. ; Heckbert, Susan R. ; Heiss, Gerardo ; Hoffmann, Udo ; Hofman, Albert ; Išgum, Ivana ; Jukema, J. Wouter ; Kähönen, Mika ; Kardia, Sharon L R ; Kral, Brian G ; Launer, Lenore J. ; Massaro, Joe ; Mehran, Roxana ; Mitchell, Braxton D. ; Mosley, Thomas H. ; De Mutsert, Renée ; Newman, Anne B. ; Nguyen, Khanh Dung ; North, Kari E. ; O'Connell, Jeffrey R. ; Oudkerk, Matthijs ; Pankow, James S. ; Peloso, Gina M. ; Post, Wendy S ; Province, Michael A. ; Raffield, Laura M. ; Raitakari, Olli T. ; Reilly, Dermot F. ; Rivadeneira, Fernando ; Rosendaal, Frits ; Sartori, Samantha ; Taylor, Kent D. ; Teumer, Alexander ; Trompet, Stella ; Turner, Stephen T. ; Uitterlinden, Andre G. ; Vaidya, Dhananjay ; Van Der Lugt, Aad ; Völker, Uwe ; Wardlaw, Joanna M. ; Wassel, Christina L. ; Weiss, Stefan ; Wojczynski, Mary K. ; Becker, Diane M ; Becker, Lewis ; Boerwinkle, Eric ; Bowden, Donald W. ; Deary, Ian J. ; Dehghan, Abbas ; Felix, Stephan B. ; Gudnason, Vilmundur ; Lehtimäki, Terho ; Mathias, Rasika ; Mook-Kanamori, Dennis O. ; Psaty, Bruce M. ; Rader, Daniel J. ; Rotter, Jerome I. ; Wilson, James G. ; Van Duijn, Cornelia M. ; Völzke, Henry ; Kathiresan, Sekar ; Peyser, Patricia A. ; O'Donnell, Christopher J. / Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis. In: Circulation: Cardiovascular Genetics. 2016 ; Vol. 9, No. 6. pp. 511-520.
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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

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, Joe

AU - Mehran, Roxana

AU - Mitchell, Braxton D.

AU - Mosley, Thomas H.

AU - De Mutsert, Renée

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 S

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 - Völker, Uwe

AU - Wardlaw, Joanna M.

AU - Wassel, Christina L.

AU - Weiss, Stefan

AU - Wojczynski, Mary K.

AU - Becker, Diane M

AU - Becker, Lewis

AU - Boerwinkle, Eric

AU - Bowden, Donald W.

AU - Deary, Ian J.

AU - Dehghan, Abbas

AU - Felix, Stephan B.

AU - Gudnason, Vilmundur

AU - Lehtimäki, 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 - Völzke, Henry

AU - Kathiresan, Sekar

AU - Peyser, Patricia A.

AU - O'Donnell, Christopher J.

PY - 2016/12/1

Y1 - 2016/12/1

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=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 carotid intima-media thickness (P=4×10- 14) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ϵ2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ϵ2 was associated with reduced risk for coronary heart disease (odds ratio 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 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=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 carotid intima-media thickness (P=4×10- 14) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the ϵ2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of ϵ2 was associated with reduced risk for coronary heart disease (odds ratio 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 coronary heart disease.

KW - carotid intima-media thickness

KW - coronary artery calcification

KW - exome

KW - genome-wide association study

KW - genomics

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U2 - 10.1161/CIRCGENETICS.116.001572

DO - 10.1161/CIRCGENETICS.116.001572

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EP - 520

JO - Circulation. Genomic and precision medicine

JF - Circulation. Genomic and precision medicine

SN - 1942-325X

IS - 6

ER -