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Get Free AccessThe 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.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).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.
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 Vojinović, 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 J. de Koning, Bob D. de Vos, Ayşe Demirkan, Valentı́n 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 M. Massaro, Roxana Mehran, Braxton D. Mitchell, Thomas H. Mosley, Renée de Mutsert, Anne B. Newman, Khanh-Dung H. 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 R. Rosendaal, Samantha Sartori, Kent D. Taylor, Alexander Teumer, Stella Trompet, Stephen T. Turner, André 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 C. Becker, Eric Boerwinkle, Donald W. Bowden, Ian J. Deary, Abbas Dehghan, Stephan B. Felix, Vilmundur Guðnason, Terho Lehtimäki, Rasika A. 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 (2016). Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis. Circulation Cardiovascular Genetics, 9(6), pp. 511-520, DOI: 10.1161/circgenetics.116.001572.
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Type
Article
Year
2016
Authors
100
Datasets
0
Total Files
0
Language
English
Journal
Circulation Cardiovascular Genetics
DOI
10.1161/circgenetics.116.001572
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