Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.
Natarajan, Pradeep MD, MMSc *; Bis, Joshua C. PhD *; Bielak, Lawrence F. DDS, MPH; Cox, Amanda J. PhD; Dorr, Marcus MD; Feitosa, Mary F. PhD; Franceschini, Nora MD, MPH; Guo, Xiuqing PhD; Hwang, Shih-Jen PhD; Isaacs, Aaron PhD; Jhun, Min A PhD; Kavousi, Maryam MD, PhD; Li-Gao, Ruifang MSc; Lyytikainen, Leo-Pekka MD; Marioni, Riccardo E. PhD; Schminke, Ulf MD; Stitziel, Nathan O. MD, PhD; Tada, Hayato MD; van Setten, Jessica PhD; Smith, Albert V. PhD; Vojinovic, Dina MD, MSc; Yanek, Lisa R. MPH; Yao, Jie MD, MS; Yerges-Armstrong, Laura M. PhD; Amin, Najaf PhD; Baber, Usman MD; Borecki, Ingrid B. PhD; Carr, J. Jeffrey MD, MSc; Chen, Yii-Der Ida PhD; Cupples, L. Adrienne PhD; de Jong, Pim A. MD, PhD; de Koning, Harry PhD; de Vos, Bob D. MSc; Demirkan, Ayse PhD; Fuster, Valentin MD, PhD; Franco, Oscar H. MD, PhD; Goodarzi, Mark O. MD, PhD; Harris, Tamara B. MD; Heckbert, Susan R. MD, PhD; Heiss, Gerardo MD, PhD; Hoffmann, Udo MD, PhD; Hofman, Albert MD, PhD; Isgum, Ivana PhD; Jukema, J. Wouter MD, PhD; Kahonen, Mika MD PhD; Kardia, Sharon L.R. PhD; Kral, Brian G. MD, MPH; Launer, Lenore J. PhD; Massaro, Joe PhD; Mehran, Roxana MD; Mitchell, Braxton D. PhD, MPH; Mosley, Thomas H. Jr PhD; de Mutsert, Renee PhD; Newman, Anne B. MD; Nguyen, Khanh-dung PhD; North, Kari E. PhD; O'Connell, Jeffrey R. PhD; Oudkerk, Matthijs MD; Pankow, James S. PhD, MPH; Peloso, Gina M. PhD; Post, Wendy MD, MS; Province, Michael A. PhD; Raffield, Laura M. PhD; Raitakari, Olli T. MD, PhD; Reilly, Dermot F. PhD; Rivadeneira, Fernando MD, PhD; Rosendaal, Frits MD, PhD; Sartori, Samantha PhD; Taylor, Kent D. PhD; Teumer, Alexander PhD; Trompet, Stella PhD; Turner, Stephen T. MD; Uitterlinden, Andre G. PhD; Vaidya, Dhananjay PhD, MPH, MBBS; van der Lugt, Aad MD, PhD; Volker, Uwe PhD; Wardlaw, Joanna M. MD; Wassel, Christina L. PhD, MS; Weiss, Stefan PhD; Wojczynski, Mary K. PhD; Becker, Diane M. ScD, PhD; Becker, Lewis C. MD; Boerwinkle, Eric PhD; Bowden, Donald W. PhD; Deary, Ian J. PhD; Dehghan, Abbas MD, PhD; Felix, Stephan B. MD; Gudnason, Vilmundur MD, PhD; Lehtimaki, Terho MD, PhD; Mathias, Rasika ScD; Mook-Kanamori, Dennis O. MD, PhD; Psaty, Bruce M. MD; Rader, Daniel J. MD; Rotter, Jerome I. MD; Wilson, James G. MD; van Duijn, Cornelia M. PhD; Volzke, Henry MD; Kathiresan, Sekar MD; Peyser, Patricia A. PhD; O'Donnell, Christopher J. MD, MPH; CHARGE Consortium
Circulation: Cardiovascular Genetics.
9(6):511-520, December 2016.
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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.
(C) 2016 American Heart Association, Inc.