Genetic variants influencing circulating lipid levels and risk of coronary artery disease.
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.


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)).


CONCLUSIONS
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.
Waterworth
Dawn M
DM
Genetics Division, GlaxoSmithKline R&D, King of Prussia, PA, USA.
Ricketts
Sally L
SL
Song
Kijoung
K
Chen
Li
L
Zhao
Jing Hua
JH
Ripatti
Samuli
S
Aulchenko
Yurii S
YS
Zhang
Weihua
W
Yuan
Xin
X
Lim
Noha
N
Luan
Jian'an
J
Ashford
Sofie
S
Wheeler
Eleanor
E
Young
Elizabeth H
EH
Hadley
David
D
Thompson
John R
JR
Braund
Peter S
PS
Johnson
Toby
T
Struchalin
Maksim
M
Surakka
Ida
I
Luben
Robert
R
Khaw
Kay-Tee
KT
Rodwell
Sheila A
SA
Loos
Ruth J F
RJ
Boekholdt
S Matthijs
SM
Inouye
Michael
M
Deloukas
Panagiotis
P
Elliott
Paul
P
Schlessinger
David
D
Sanna
Serena
S
Scuteri
Angelo
A
Jackson
Anne
A
Mohlke
Karen L
KL
Tuomilehto
Jaako
J
Roberts
Robert
R
Stewart
Alexandre
A
Kesäniemi
Y Antero
YA
Mahley
Robert W
RW
Grundy
Scott M
SM
McArdle
Wendy
W
Cardon
Lon
L
Waeber
Gérard
G
Vollenweider
Peter
P
Chambers
John C
JC
Boehnke
Michael
M
Abecasis
Gonçalo R
GR
Salomaa
Veikko
V
Järvelin
Marjo-Riitta
MR
Ruokonen
Aimo
A
Barroso
Inês
I
Epstein
Stephen E
SE
Hakonarson
Hakon H
HH
Rader
Daniel J
DJ
Reilly
Muredach P
MP
Witteman
Jacqueline C M
JC
Hall
Alistair S
AS
Samani
Nilesh J
NJ
Strachan
David P
DP
Barter
Philip
P
van Duijn
Cornelia M
CM
Kooner
Jaspal S
JS
Peltonen
Leena
L
Wareham
Nicholas J
NJ
McPherson
Ruth
R
Mooser
Vincent
V
Sandhu
Manjinder S
MS
D044466:Asian People; D008076:Cholesterol, HDL / Q000097:blood / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics*; D003324:Coronary Artery Disease / Q000235:genetics*; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood / Q000235:genetics*; D044465:White People
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D014280:Triglycerides