Genetic Variants Influencing Circulating Lipid Levels and Risk of Coronary Artery Disease
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Published:2010-11
Issue:11
Volume:30
Page:2264-2276
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ISSN:1079-5642
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Container-title:Arteriosclerosis, Thrombosis, and Vascular Biology
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language:en
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Short-container-title:ATVB
Author:
Waterworth Dawn M.1, Ricketts Sally L.1, Song Kijoung1, Chen Li1, Zhao Jing Hua1, Ripatti Samuli1, Aulchenko Yurii S.1, Zhang Weihua1, Yuan Xin1, Lim Noha1, Luan Jian'an1, Ashford Sofie1, Wheeler Eleanor1, Young Elizabeth H.1, Hadley David1, Thompson John R.1, Braund Peter S.1, Johnson Toby1, Struchalin Maksim1, Surakka Ida1, Luben Robert1, Khaw Kay-Tee1, Rodwell Sheila A.1, Loos Ruth J.F.1, Boekholdt S. Matthijs1, Inouye Michael1, Deloukas Panagiotis1, Elliott Paul1, Schlessinger David1, Sanna Serena1, Scuteri Angelo1, Jackson Anne1, Mohlke Karen L.1, Tuomilehto Jaako1, Roberts Robert1, Stewart Alexandre1, Kesäniemi Y. Antero1, Mahley Robert W.1, Grundy Scott M.1, McArdle Wendy1, Cardon Lon1, Waeber Gérard1, Vollenweider Peter1, Chambers John C.1, Boehnke Michael1, Abecasis Gonçalo R.1, Salomaa Veikko1, Järvelin Marjo-Riitta1, Ruokonen Aimo1, Barroso Inês1, Epstein Stephen E.1, Hakonarson Hakon H.1, Rader Daniel J.1, Reilly Muredach P.1, Witteman Jacqueline C.M.1, Hall Alistair S.1, Samani Nilesh J.1, Strachan David P.1, Barter Philip1, van Duijn Cornelia M.1, Kooner Jaspal S.1, Peltonen Leena1, Wareham Nicholas J.1, McPherson Ruth1, Mooser Vincent1, Sandhu Manjinder S.1,
Affiliation:
1. From the Genetics Division, GlaxoSmithKline R&D, King of Prussia, Pa (D.M.W., K.S., X.Y., N.L., L. Cardon, V.M.); Department of Public Health and Primary Care, Strangeways Research Laboratory (S.L.R., S.A., E.H.Y., R.L., K.-T.K., M.S.S.) and Department of Public Health and Primary Care (S.A.R.), University of Cambridge, Cambridge, United Kingdom; Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (L. Chen, R.R., A. Stewart, R.M.); Medical Research Council...
Abstract
Objective—
Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides.
Methods and Results—
We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10
−8
to 3.1×10
−10
). These include a potentially functional SNP in the
SLC39A8
gene for HDL-C, an SNP near the
MYLIP/GMPR
and
PPP1R3B
genes for LDL-C, and at the
AFF1
gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the
CELSR2
,
APOB
,
APOE-C1-C4-C2
cluster,
LPL
,
ZNF259-APOA5-A4-C3-A1
cluster and
TRIB1
loci were also associated with CAD risk (probability values, 1.1×10
−3
to 1.2×10
−9
).
Conclusion—
We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
351 articles.
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