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Multiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.

TitleMultiethnic Exome-Wide Association Study of Subclinical Atherosclerosis.
Publication TypeJournal Article
Year of Publication2016
AuthorsNatarajan P, Bis JC, Bielak LF, Cox AJ, Dörr M, Feitosa MF, Franceschini N, Guo X, Hwang S-J, Isaacs A, Jhun MA, Kavousi M, Li-Gao R, Lyytikäinen L-P, Marioni RE, Schminke U, Stitziel NO, Tada H, van Setten J, Smith AV, Vojinovic D, Yanek LR, Yao J, Yerges-Armstrong LM, Amin N, Baber U, Borecki IB, J Carr J, Chen Y-D I, L Cupples A, de Jong PA, de Koning H, de Vos BD, Demirkan A, Fuster V, Franco OH, Goodarzi MO, Harris TB, Heckbert SR, Heiss G, Hoffmann U, Hofman A, Išgum I, J Jukema W, Kähönen M, Kardia SLR, Kral BG, Launer LJ, Massaro J, Mehran R, Mitchell BD, Mosley TH, de Mutsert R, Newman AB, Nguyen K-D, North KE, O'Connell JR, Oudkerk M, Pankow JS, Peloso GM, Post W, Province MA, Raffield LM, Raitakari OT, Reilly DF, Rivadeneira F, Rosendaal F, Sartori S, Taylor KD, Teumer A, Trompet S, Turner ST, Uitterlinden AG, Vaidya D, van der Lugt A, Völker U, Wardlaw JM, Wassel CL, Weiss S, Wojczynski MK, Becker DM, Becker LC, Boerwinkle E, Bowden DW, Deary IJ, Dehghan A, Felix SB, Gudnason V, Lehtimäki T, Mathias R, Mook-Kanamori DO, Psaty BM, Rader DJ, Rotter JI, Wilson JG, van Duijn CM, Völzke H, Kathiresan S, Peyser PA
Secondary AuthorsO'Donnell CJ
Corporate AuthorsCHARGE Consortium
JournalCirc Cardiovasc Genet
Volume9
Issue6
Pagination511-520
Date Published2016 Dec
ISSN1942-3268
KeywordsAfrican Continental Ancestry Group, Apolipoprotein B-100, Apolipoprotein E2, Asymptomatic Diseases, Carotid Artery Diseases, Carotid Intima-Media Thickness, Cholesterol, LDL, Computed Tomography Angiography, Coronary Angiography, Coronary Artery Disease, European Continental Ancestry Group, Exome, Gene Frequency, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Odds Ratio, Oligonucleotide Array Sequence Analysis, Phenotype, Prognosis, Risk Assessment, Risk Factors, Vascular Calcification
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). 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.

DOI10.1161/CIRCGENETICS.116.001572
Alternate JournalCirc Cardiovasc Genet
PubMed ID27872105
PubMed Central IDPMC5418659
Grant ListR01 HL112064 / HL / NHLBI NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
N01 HC025195 / HC / NHLBI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
MR/K026992/1 / MRC_ / Medical Research Council / United Kingdom
P30 DK063491 / DK / NIDDK NIH HHS / United States
ZIA HL006002-10 / ImNIH / Intramural NIH HHS / United States
ZIA HL006002-06 / ImNIH / Intramural NIH HHS / United States
R01 HL117078 / HL / NHLBI NIH HHS / United States
R01 HL119443 / HL / NHLBI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
UL1 TR001881 / TR / NCATS NIH HHS / United States
T32 HL007055 / HL / NHLBI NIH HHS / United States