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; Leichtle, A; Greiser, KH; Huster, D; Linsel-Nitschke, P; Schafer, 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, CD; Hall, AS; Matthes, G; Wittekind, C; Hengstenberg, C; Cambien, F; Schreiber, S; Werdan, K; Meitinger, T; Loeffler, M; Samani, NJ; Erdmann, J; Wichmann, HE; Schunkert, H; Thiery, J     «

Teupser, D; Baber, R; Ceglarek, U; Scholz, M; Illig, T; Gieger, C; Holdt, LM; Leichtle, A; Greiser, KH; Huster, D; Linsel-Nitschke, P; Schafer, 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, CD; Hall, AS; Matthes, G; Wittekind, C; Hengstenberg, C; Cambien, F; Schreiber, S; Werdan, K; Meitinger, T; Loeffler, M; Samani, NJ; Er...     »

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

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).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 Augsb...     »