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 journalArticleAcademicpeer-review

36 Citations (Web of Science)


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 languageEnglish
Pages (from-to)511-520
JournalCirculation : Cardiovascular Genetics
Issue number6
Publication statusPublished - Dec 2016


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

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