Genetic Regulation of Serum Phytosterol Levels and Risk of Coronary Artery Disease.
Teupser, Daniel MD; Baber, Ronny MSc; Ceglarek, Uta PhD; Scholz, Markus PhD; Illig, Thomas PhD; Gieger, Christian PhD; Holdt, Lesca M. MD; Leichtle, Alexander MD; Greiser, Karin H. MD; Huster, Dominik MD; Linsel-Nitschke, Patrick MD; Schafer, Arne PhD; Braund, Peter S. MSc; Tiret, Laurence PhD; Stark, Klaus PhD; Raaz-Schrauder, Dorette MD; Fiedler, Georg M. MD; Wilfert, Wolfgang MSc; Beutner, Frank MD; Gielen, Stephan MD; Grohennig, Anika MSc [latin sharp s]; Konig, Inke R. PhD; Lichtner, Peter PhD; Heid, Iris M. PhD; Kluttig, Alexander PhD; El Mokhtari, Nour E. MD; Rubin, Diana MD; Ekici, Arif B. PhD; Reis, Andre MD; Garlichs, Christoph D. MD; Hall, Alistair S. MD; Matthes, Gert MD; Wittekind, Christian MD; Hengstenberg, Christian MD; Cambien, Francois MD, PhD; Schreiber, Stefan MD; Werdan, Karl MD; Meitinger, Thomas MD, MSc; Loeffler, Markus MD; Samani, Nilesh J. FRCP; Erdmann, Jeanette PhD; Wichmann, H.-Erich MD, PhD; Schunkert, Heribert MD; Thiery, Joachim MD
Circulation: Cardiovascular Genetics.
3(4):331-339, August 2010.
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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=1.6x10-50 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.
(C) 2010 American Heart Association, Inc.