Common variants of multiple genes that control reverse cholesterol transport together explain only a minor part of the variation of HDL cholesterol levels.
It is assumed that the combined effects of multiple common genetic variants explain a large part of variation of high-density lipoprotein cholesterol (HDL-C) plasma levels, but little evidence exists to corroborate this assumption. It was our objective to study the contribution of multiple common genetic variants of HDL-C-related genes to variation of HDL-C plasma levels. A well-characterized cohort of 546 Caucasian men with documented coronary artery disease was genotyped for common functional variants in genes that control reverse cholesterol transport: ATP-binding cassette transporter A1, apolipoprotein A-I and apolipoprotein-E, cholesteryl ester transfer protein, hepatic lipase, lecithin : cholesterol-acyl transferase, lipoprotein lipase, and scavenger receptor class B type 1. Multivariate linear regression showed that these variants, in conjunction, explain 12.4% (95% confidence interval: 6.9-17.9%) of variation in HDL-C plasma levels. When the covariates smoking and body mass index were taken into account, the explained variation increased to 15.3% (9.4-21.2%), and when 10 two-way interactions were incorporated, this percentage rose to 25.2% (18.9-31.5%). This study supports the hypothesis that multiple, mildly penetrant, but highly prevalent genetic variants explain part of the variation of HDL-C plasma levels, albeit to a very modest extent. Multiple environmental and genetic influences on HDL-C plasma levels still have to be elucidated.
Department of Cardiology, Academic Medical Center, Amsterdam, the Netherlands. s.m.boekholdt@amc.uva.nl
S M
SM
Boekholdt
O W
OW
Souverein
M W T
MW
Tanck
G K
GK
Hovingh
J A
JA
Kuivenhoven
R I G
RI
Peters
H
H
Jansen
P M H
PM
Schiffers
E E
EE
van der Wall
P A
PA
Doevendans
P H
PH
Reitsma
A H
AH
Zwinderman
J J P
JJ
Kastelein
J W
JW
Jukema
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000483:Alleles; D016632:Apolipoprotein A-I / Q000235:genetics; D001057:Apolipoproteins E / Q000235:genetics; D001693:Biological Transport, Active / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood*; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000235:genetics / Q000378:metabolism; D014644:Genetic Variation; D005838:Genotype; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D008049:Lipase / Q000235:genetics; D008071:Lipoprotein Lipase / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics; D051122:Scavenger Receptors, Class B / Q000235:genetics
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D006023:Glycoproteins; C504173:LIPC protein, human; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D008049:Lipase; D008071:Lipoprotein Lipase