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

Teupser D, Baber R, Ceglarek U, Scholz M, Illig T, Gieger C, Holdt LM, Leichtler A, Greiser KH, Huster D, Linsel-Nitschke P, Schäfer A, Braund PS, Tiret L, Stark K, Raaz-Schrauder D, Fiedler GM, Wilfert W, Beutner F, Gielen S, Großhennig A, König IR, Lichtner P, Heid IM, Kluttig A, El Mokhtari NE, Rubin D, Ekici AB, Reis A, Garlichs C, Hall AS, Matthes G, Wittekind C, Hengstenberg C, Cambien F, Schreiber S, Werdan K, Meitinger T, Löffler M, Samani NJ, Erdmann J, Wichmann HE, Schunkert H, Thiery J.

University Leipzig, Leipzig, Germany

Circ Cardiovasc Genet. 2010 Jun 7. [Epub ahead of print]

Abstract

BACKGROUND: -Phytosterols are plant-derived sterols, which 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 phytosterol-serum 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 (n=1495) with subsequent replication in two additional samples (n=1157 and n=1760). Replicated SNPs were tested for association with premature CAD in a meta-analysis of 11 different samples comprising a total of 13,764 CAD cases and 13,630 healthy controls. Genetic variants in the ATP-binding cassette transporter ABCG8 and at the blood group ABO locus were significantly associated with serum phytosterols. Effects in ABCG8 were independently related to SNP rs4245791 and rs41360247 (combined p=1.6x10(-50) and 6.2x10(-25), respectively, n=4412). Serum campesterol was elevated 12 degrees percent for each rs4245791 T-allele. The same allele was associated with 40 percent 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, OR=1.10, 95%CI 1.06-1.14, p=2.2x10(-6); rs657152, OR=1.13; 95%CI 1.07-1.19, p=9.4x10(-6)), whereas alleles at ABCG8 associated with reduced phytosterol levels were associated with reduced CAD risk (rs41360247, OR=0.84, 95%CI 0.78-0.91, p=1.3x10(-5)). CONCLUSIONS: -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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