Genetic regulation of serum phytosterol levels and risk of coronary artery disease.
BACKGROUND
Phytosterols are plant-derived sterols that are taken up from food and can serve as biomarkers of cholesterol uptake. Serum levels are under tight genetic control. We used a genomic approach to study the molecular regulation of serum phytosterol levels and potential links to coronary artery disease (CAD).


RESULTS
A genome-wide association study for serum phytosterols (campesterol, sitosterol, brassicasterol) was conducted in a population-based sample from KORA (Cooperative Research in the Region of Augsburg) (n=1495) with subsequent replication in 2 additional samples (n=1157 and n=1760). Replicated single-nucleotide polymorphisms (SNPs) were tested for association with premature CAD in a metaanalysis of 11 different samples comprising 13 764 CAD cases and 13 630 healthy controls. Genetic variants in the ATP-binding hemitransporter ABCG8 and at the blood group ABO locus were significantly associated with serum phytosterols. Effects in ABCG8 were independently related to SNPs rs4245791 and rs41360247 (combined P=1.6 x 10(-50) and 6.2 x 10(-25), respectively; n=4412). Serum campesterol was elevated 12% for each rs4245791 T-allele. The same allele was associated with 40% decreased hepatic ABCG8 mRNA expression (P=0.009). Effects at the ABO locus were related to SNP rs657152 (combined P=9.4x10(-13)). Alleles of ABCG8 and ABO associated with elevated phytosterol levels displayed significant associations with increased CAD risk (rs4245791 odds ratio, 1.10; 95% CI, 1.06 to 1.14; P=2.2 x 10(-6); rs657152 odds ratio, 1.13; 95% CI, 1.07 to 1.19; P=9.4 x 10(-6)), whereas alleles at ABCG8 associated with reduced phytosterol levels were associated with reduced CAD risk (rs41360247 odds ratio, 0.84; 95% CI, 0.78 to 0.91; P=1.3 x 10(-5)).


CONCLUSIONS
Common variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD.
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig, Germany. teupser@medizin.uni-leipzig.de
Daniel
D
Teupser
Ronny
R
Baber
Uta
U
Ceglarek
Markus
M
Scholz
Thomas
T
Illig
Christian
C
Gieger
Lesca M
LM
Holdt
Alexander
A
Leichtle
Karin H
KH
Greiser
Dominik
D
Huster
Patrick
P
Linsel-Nitschke
Arne
A
Schäfer
Peter S
PS
Braund
Laurence
L
Tiret
Klaus
K
Stark
Dorette
D
Raaz-Schrauder
Georg M
GM
Fiedler
Wolfgang
W
Wilfert
Frank
F
Beutner
Stephan
S
Gielen
Anika
A
Grosshennig
Inke R
IR
König
Peter
P
Lichtner
Iris M
IM
Heid
Alexander
A
Kluttig
Nour E
NE
El Mokhtari
Diana
D
Rubin
Arif B
AB
Ekici
André
A
Reis
Christoph D
CD
Garlichs
Alistair S
AS
Hall
Gert
G
Matthes
Christian
C
Wittekind
Christian
C
Hengstenberg
Francois
F
Cambien
Stefan
S
Schreiber
Karl
K
Werdan
Thomas
T
Meitinger
Markus
M
Loeffler
Nilesh J
NJ
Samani
Jeanette
J
Erdmann
H-Erich
HE
Wichmann
Heribert
H
Schunkert
Joachim
J
Thiery
D000017:ABO Blood-Group System / Q000235:genetics; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D016022:Case-Control Studies; D003324:Coronary Artery Disease / Q000097:blood / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D008074:Lipoproteins / Q000235:genetics; D008297:Male; D015201:Meta-Analysis as Topic; D008660:Metabolism / Q000235:genetics*; D010840:Phytosterols / Q000097:blood* / Q000493:pharmacokinetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D054928:Validation Studies as Topic
C416945:ABCG5 protein, human; C416946:ABCG8 protein, human; D000017:ABO Blood-Group System; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D008074:Lipoproteins; D010840:Phytosterols