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

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.