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Genetic Regulation of Serum Phytosterol Levels and Risk of Coronary Artery Disease

2010; Lippincott Williams & Wilkins; Volume: 3; Issue: 4 Linguagem: Inglês

10.1161/circgenetics.109.907873

1942-325X

Daniel Teupser, Ronny Baber, Uta Ceglarek, Markus Scholz, Thomas Illig, Christian Gieger, Lesca M. Holdt, Alexander Leichtle, Karin Halina Greiser, Dominik Hüster, Patrick Linsel‐Nitschke, Arne Schäfer, Peter S. Braund, Laurence Tiret, Klaus Stark, Dorette Raaz‐Schrauder, Martin Fiedler, Wolfgang Wilfert, Frank Beutner, Stephan Gielen, Anika Großhennig, Inke R. König, Peter Lichtner, Iris M. Heid, Alexander Kluttig, Nour Eddine El Mokhtari, Deborah C. Rubin, Arif B. Ekici, André Reis, Christoph D. Garlichs, Alistair S. Hall, G Matthes, C Wittekind, Christian Hengstenberg, François Cambien, Stefan Schreiber, Karl Werdan, Thomas Meitinger, Markus Loeffler, Nilesh J. Samani, Jeanette Erdmann, H.‐Erich Wichmann, Heribert Schunkert, Joachim Thiery,

Hormonal Regulation and Hypertension

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). Methods and 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 =1.6×10 −50 and 6.2×10 −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 =9.4×10 −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 =2.2×10 −6 ; rs657152 odds ratio, 1.13; 95% CI, 1.07 to 1.19; P =9.4×10 −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 =1.3×10 −5 ). Conclusion— Common variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD.