@article{Natarajan2016, 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. }, author = {Natarajan, Pradeep and Bis, Joshua C. and Bielak, Lawrence F. and Cox, Amanda J. and Dorr, Marcus and Feitosa, Mary F. and Franceschini, Nora and Guo, Xiuqing and Hwang, Shih-Jen and Isaacs, Aaron and Jhun, Min A. and Kavousi, Maryam and Li Gao, Ruifang and Lyytikainen, Leo-Pekka and Marioni, Riccardo E. and Schminke, Ulf and Stitziel, Nathan O. and Tada, Hayato and Van Setten, J. and van Setten, Jessica and Smith, Albert V. and Vojinovic, Dina and Yanek, Lisa R. and Yao, Jie and Yerges Armstrong, Laura M. and Amin, Najaf and Baber, Usman and Borecki, Ingrid B. and Carr, J. Jeffrey and Chen, Yii-Der Ida and Cupples, L. Adrienne and de Jong, Pim A. and De Jong, P. A. and de Koning, Harry and de Vos, Bob D. and De Koning, H. and Demirkan, Ayse and De Vos, B. D. and Fuster, Valentin and Franco, Oscar H. and Goodarzi, Mark O. and Harris, Tamara B. and Heckbert, Susan R. and Heiss, Gerardo and Hoffmann, Udo and Hofman, Albert and Isgum, Ivana and Jukema, J. Wouter and Kähönen, Mika and Kardia, Sharon L. R. and Kahonen, M. and Kral, Brian G. and Launer, Lenore J. and Mehran, Roxana and Mitchell, Braxton D. and Massaro, Joseph and de Mutsert, Renée and Mosley, Thomas H. and Newman, Anne B. and De Mutsert, R. and Nguyen, Khanh-Dung and North, Kari E. and O’Connell, Jeffrey R. and Oudkerk, Matthijs and Pankow, James S. and O'Connell, Jeffrey R. and Peloso, Gina M. and Post, Wendy and Province, Michael A. and Raffield, Laura M. and Raitakari, Olli T. and Reilly, Dermot F. and Rivadeneira, Fernando and Rosendaal, Frits and Sartori, Samantha and Taylor, Kent D. and Teumer, Alexander and Trompet, Stella and Turner, Stephen T. and Uitterlinden, André G. and van der Lugt, Aad and Vaidya, Dhananjay and Van Der Lugt, A. and Volker, Uwe and Wardlaw, Joanna M. and Wassel, Christina L. and Weiss, Stefan and Wojczynski, Mary K. and Becker, Diane M. and Becker, Lewis C. and Boerwinkle, Eric and Bowden, Donald W. and Deary, Ian J. and Dehghan, Abbas and Felix, Stephan B. and Gudnason, Vilmundur and Lehtimaki, Terho and Mathias, Rasika and Mook Kanamori, Dennis O. and Psaty, Bruce M. and Rader, Daniel J. and Rotter, Jerome I. and van Duijn, Cornelia M. and Wilson, James G. and Van Duijn, C. M. and Volzke, Henry and Kathiresan, Sekar and Peyser, Patricia A. and O'Donnell, Christopher J. and Charge, Consortium and O’Donnell, Christopher J.}, doi = {10.1161/circgenetics.116.001572}, journal = {Circulation: Cardiovascular Genetics}, month = {dec}, pages = {511-520}, title = {Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis}, url = {http://dspace.library.uu.nl:8080/handle/1874/343046}, volume = {9}, year = {2016} }