Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis

Pradeep Natarajan; Joshua C. Bis; Lawrence F. Bielak; Amanda J. Cox; Marcus Dorr; Mary F. Feitosa; Nora Franceschini; Xiuqing Guo; Shih-Jen Hwang; Aaron Isaacs; Min A. Jhun; Maryam Kavousi; Ruifang Li-Gao; Leo-Pekka Lyytikainen; 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 Isgum; J. Wouter Jukema; Mika Kahonen; Sharon L. R. Kardia; Brian G. Kral; Lenore J. Launer; Joe Massaro; Roxana Mehran; Braxton D. Mitchell; Thomas H. Mosley; Renee 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 Volker; 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 Lehtimaki; Rasika Mathias; Dennis O. Mook-Kanamori; Bruce M. Psaty; Daniel J. Rader; Jerome I. Rotter; James G. Wilson; Cornelia M. van Duijn; Henry Volzke; Sekar Kathiresan; Patricia A. Peyser; Christopher J. O'Donnell; CHARGE Consortium

doi:10.1161/CIRCGENETICS.116.001572

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Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis

Journal article

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Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis

Pradeep Natarajan, Joshua C. Bis, Lawrence F. Bielak, Amanda J. Cox, Marcus Dorr, Mary F. Feitosa, Nora Franceschini, Xiuqing Guo, Shih-Jen Hwang, Aaron Isaacs, …

Circulation. Cardiovascular genetics, Vol.9(6), pp.511-520

12/2016

DOI: https://doi.org/10.1161/CIRCGENETICS.116.001572

PMID: 27872105

Abstract

Cardiac & Cardiovascular Systems

Cardiovascular System & Cardiology

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

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=3x10(-10)). The APOE epsilon 2 allele (p.Arg176Cys) was associated with both 22.3% reduced CAC (P=1x10(-12)) and 1.4% reduced carotid intima-media thickness (P=4x10(-14)) in carriers compared with noncarriers. In secondary analyses conditioning on low-density lipoprotein cholesterol concentration, the epsilon 2 protective association with CAC, although attenuated, remained strongly significant. Additionally, the presence of epsilon 2 was associated with reduced risk for coronary heart disease (odds ratio 0.77; P=1x10(-11)). Conclusions-Exome-wide association meta-analysis demonstrates that protein-coding variants in APOB and APOE associate with subclinical atherosclerosis. APOE epsilon 2 represents the first significant association for multiple subclinical atherosclerosis traits across multiple ethnicities, as well as clinical coronary heart disease.

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Title: Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis
Creators: Pradeep Natarajan - Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA
Joshua C. Bis - University of Washington
Lawrence F. Bielak - Supreme Council Of Health
Amanda J. Cox - Cox & Company
Marcus Dorr - Marcus
Mary F. Feitosa - Supreme Council Of Health
Nora Franceschini - Northern Ohio Recovery Association
Xiuqing Guo - State Administration of Foreign Experts Affairs
Shih-Jen Hwang - Framingham Heart Study
Aaron Isaacs - Maastricht University
Min A. Jhun - Supreme Council Of Health
Maryam Kavousi - Erasmus MC
Ruifang Li-Gao - Leiden University
Leo-Pekka Lyytikainen - Fimlab
Riccardo E. Marioni - University of Edinburgh
Ulf Schminke - College Station Medical Center
Nathan O. Stitziel - Supreme Council Of Health
Hayato Tada - Kanazawa University
Jessica van Setten - College Station Medical Center
Albert V. Smith - Smith Family
Dina Vojinovic - Erasmus MC
Lisa R. Yanek - Johns Hopkins University
Jie Yao - Biomed Research Institute
Laura M. Yerges-Armstrong - Supreme Council Of Health
Najaf Amin - National Academy Foundation
Usman Baber - United States Holocaust Memorial Museum
Ingrid B. Borecki - Regeneron
J. Jeffrey Carr - Jeffrey Modell Foundation
Yii-Der Ida Chen - Biomed Research Institute
L. Adrienne Cupples - Boston University
Pim A. de Jong - College Station Medical Center
Harry de Koning - Koning
Bob D. de Vos - College Station Medical Center
Ayse Demirkan - Erasmus MC
Valentin Fuster - Supreme Council Of Health
Oscar H. Franco - Erasmus MC
Mark O. Goodarzi - College Station Medical Center
Tamara B. Harris - NIA, Lab Epidemiol & Populat Sci, Intramural Res, NIH, Baltimore, MD 21224 USA
Susan R. Heckbert - Susan G. Komen Breast Cancer Foundation
Gerardo Heiss - Supreme Council Of Health
Udo Hoffmann
Albert Hofman - Erasmus MC
Ivana Isgum - College Station Medical Center
J. Wouter Jukema - Leiden University
Mika Kahonen - University of Tampere
Sharon L. R. Kardia - Supreme Council Of Health
Brian G. Kral - Johns Hopkins University
Lenore J. Launer - NIA, Lab Epidemiol & Populat Sci, Intramural Res, NIH, Baltimore, MD 21224 USA
Joe Massaro - Boston University
Roxana Mehran - Supreme Council Of Health
Braxton D. Mitchell - Braxton
Thomas H. Mosley - University of Mississippi
Renee de Mutsert - Leiden University
Anne B. Newman - University of Pittsburgh
Khanh-dung Nguyen - Merck & Co Inc, MRL, Genet & Pharmacogen Dept, Boston, MA USA
Kari E. North - Korea Aerospace Research Institute
Jeffrey R. O'Connell - Supreme Council Of Health
Matthijs Oudkerk - University of Groningen
James S. Pankow - University of Minnesota
Gina M. Peloso - Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA
Wendy Post - Johns Hopkins University
Michael A. Province - Supreme Council Of Health
Laura M. Raffield - Wake Forest Hlth Sci, Diabet Heart Study, Winston Salem, NC USA
Olli T. Raitakari - College Station Medical Center
Dermot F. Reilly - Merck
Fernando Rivadeneira - Hospital Prof. Dr. Fernando Fonseca
Frits Rosendaal - Leiden University
Samantha Sartori - Supreme Council Of Health
Kent D. Taylor - Biomed Research Institute
Alexander Teumer - College Station Medical Center
Stella Trompet - Stella Therapeutics
Stephen T. Turner - Turner Consulting Group
Andre G. Uitterlinden - Erasmus MC
Dhananjay Vaidya - Johns Hopkins University
Aad van der Lugt - Erasmus MC
Uwe Volker - College Station Medical Center
Joanna M. Wardlaw - University of Edinburgh
Christina L. Wassel - Christ University
Stefan Weiss - College Station Medical Center
Mary K. Wojczynski - Supreme Council Of Health
Diane M. Becker - Johns Hopkins University
Lewis C. Becker - Johns Hopkins University
Eric Boerwinkle - Supreme Council Of Health
Donald W. Bowden - Wake Forest Hlth Sci, Diabet Heart Study, Winston Salem, NC USA
Ian J. Deary - University of Edinburgh
Abbas Dehghan - Erasmus MC
Stephan B. Felix - Felix Scholarship
Vilmundur Gudnason - Icelandic Heart Assoc, Kopavogur, Iceland
Terho Lehtimaki - Fimlab
Rasika Mathias - Johns Hopkins University
Dennis O. Mook-Kanamori - Leiden University
Bruce M. Psaty - University of Washington
Daniel J. Rader - Supreme Council Of Health
Jerome I. Rotter - Biomed Research Institute
James G. Wilson - University of Mississippi
Cornelia M. van Duijn - Erasmus MC
Henry Volzke - College Station Medical Center
Sekar Kathiresan - Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA
Patricia A. Peyser - Supreme Council Of Health
Christopher J. O'Donnell - Boston Vet Affairs Healthcare Syst, Div Cardiol, Boston, MA USA
CHARGE Consortium
Publication Details: Circulation. Cardiovascular genetics, Vol.9(6), pp.511-520
Publisher: Lippincott Williams & Wilkins
Number of pages: 57
Date published: 12/2016
Grant note: John S. LaDue Memorial Fellowship in Cardiology, Harvard Medical School Data Supplement 91616079 / NWO VENI grant (VENI) R01HL105756; R01HL120393 / National Heart, Lung, and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) MR/K026992/1 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC)
Identifiers: 99928830402346
Academic Unit: Institute for Sustainability; Surrey Institute for People-Centred AI; School of Biosciences
Language: English
Resource Type: Journal article

Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis

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