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

Teupser, Daniel ; Baber, Ronny ; Ceglarek, Uta ; Scholz, Markus ; Illig, Thomas ; Gieger, Christian

; Holdt, Lesca M. ; Leichtle, Alexander

; Greiser, Karin H. ; Huster, Dominik ; Linsel-Nitschke, Patrick ; Schäfer, Arne ; Braund, Peter S. ; Tiret, Laurence ; Stark, Klaus

; Raaz-Schrauder, Dorette ; Fiedler, Georg M.

; Wilfert, Wolfgang ; Beutner, Frank ; Gielen, Stephan ; Großhennig, Anika ; König, Inke R. ; Lichtner, Peter ; Heid, Iris M. ; Kluttig, Alexander ; El Mokhtari, Nour E. ; Rubin, Diana ; Ekici, Arif B.

; Reis, André

; Garlichs, Christoph D. ; Hall, Alistair S.

; Matthes, Gert ; Wittekind, Christian ; Hengstenberg, Christian ; Cambien, Francois ; Schreiber, Stefan

; Werdan, Karl ; Meitinger, Thomas

; Loeffler, Markus ; Samani, Nilesh J. ; Erdmann, Jeanette

; Wichmann, H.-Erich ; Schunkert, Heribert ; Thiery, Joachim

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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 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 = 9.4 x 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 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)). Conclusion-Common variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD. (Circ Cardiovasc Genet. 2010;3:331-339.)

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