Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.

Authors:
Samantha Sartori, PhD
Samantha Sartori, PhD
Icahn School of Medicine at Mount Sinai
Assistant Professor / Biostatistician Epidemiologist
Biostatistics
New York, NY | United States
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 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

Circ Cardiovasc Genet 2016 Dec 21;9(6):511-520. Epub 2016 Nov 21.

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). The APOE ε2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1×10) and 1.4% reduced carotid intima-media thickness (P=4×10) 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).

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.

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Source
http://dx.doi.org/10.1161/CIRCGENETICS.116.001572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418659PMC
December 2016
209 Reads
6 Citations
5.340 Impact Factor

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