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, 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 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 C 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

-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. -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)). -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.