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Circulation: Cardiovascular Genetics

Year: 2010  |  Volume: 3  |  Issue: 4  |  Page No.: 331 - 339

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

D Teupser, R Baber, U Ceglarek, M Scholz, T Illig, C Gieger, L. M Holdt, A Leichtle, K. H Greiser, D Huster, P Linsel Nitschke, A Schafer, P. S Braund, L Tiret, K Stark, D Raaz Schrauder, G. M Fiedler, W Wilfert, F Beutner, S Gielen, A Grosshennig, I. R Konig, P Lichtner, I. M Heid, A Kluttig, N. E El Mokhtari, D Rubin, A. B Ekici, A Reis, C. D Garlichs, A. S Hall, G Matthes, C Wittekind, C Hengstenberg, F Cambien, S Schreiber, K Werdan, T Meitinger, M Loeffler, N. J Samani, J Erdmann, H. E Wichmann, H Schunkert and J. Thiery

Abstract

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=1.6x10–50 and 6.2x10–25, 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=2.2x10–6; rs657152 odds ratio, 1.13; 95% CI, 1.07 to 1.19; P=9.4x10–6), 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=1.3x10–5).

Conclusion—

Common variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD.

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