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.
Teupser
Daniel
D
Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig, Germany. teupser@medizin.uni-leipzig.de
Baber
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Ceglarek
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U
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Christian
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GM
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Inke R
IR
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Heid
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IM
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El Mokhtari
Nour E
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CD
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AS
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Wittekind
Christian
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Hengstenberg
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Cambien
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Werdan
Karl
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Loeffler
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Nilesh J
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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