Genetic Regulation of Serum Phytosterol Levels and Risk of Coronary Artery Disease
| Autor: | François Cambien, Markus Loeffler, Arif B. Ekici, Jeanette Erdmann, Christian Gieger, Iris M. Heid, Christian Hengstenberg, Klaus Stark, Markus Scholz, Karl Werdan, Arne Schäfer, Uta Ceglarek, Gert Matthes, Alistair S. Hall, Thomas Meitinger, Heribert Schunkert, Peter Lichtner, Dominik Huster, Alexander Kluttig, Thomas Illig, Frank Beutner, Daniel Teupser, Stefan Schreiber, Lesca M. Holdt, Nilesh J. Samani, Inke R. König, Karin Halina Greiser, Christoph D. Garlichs, H.-Erich Wichmann, Dorette Raaz-Schrauder, Nour Eddine El Mokhtari, Anika Großhennig, Alexander Benedikt Leichtle, Ronny Baber, Patrick Linsel-Nitschke, Wolfgang Wilfert, Peter S. Braund, André Reis, Christian Wittekind, Stephan Gielen, Diana Rubin, Georg Martin Fiedler, Laurence Tiret, Joachim Thiery |
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| Rok vydání: | 2010 |
| Předmět: |
Male
medicine.medical_specialty Lipoproteins Campesterol Population Genome-wide association study Single-nucleotide polymorphism Coronary Artery Disease Validation Studies as Topic Biology Polymorphism Single Nucleotide Linkage Disequilibrium ABO Blood-Group System chemistry.chemical_compound Meta-Analysis as Topic Risk Factors Internal medicine ABO blood group system Genetics medicine Humans Genetic Predisposition to Disease ATP Binding Cassette Transporter Subfamily G Member 5 Allele education Genetic Association Studies Genetics (clinical) education.field_of_study ATP Binding Cassette Transporter Subfamily G Member 8 Case-control study Phytosterols Odds ratio Metabolism Endocrinology chemistry Case-Control Studies ATP-Binding Cassette Transporters Female Cardiology and Cardiovascular Medicine Genome-Wide Association Study |
| Zdroj: | Circulation: Cardiovascular Genetics. 3:331-339 |
| ISSN: | 1942-3268 1942-325X |
| Popis: | 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 =1.6×10 −50 and 6.2×10 −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 =9.4×10 −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 =2.2×10 −6 ; rs657152 odds ratio, 1.13; 95% CI, 1.07 to 1.19; P =9.4×10 −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 =1.3×10 −5 ). Conclusion— Common variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD. |
| Databáze: | OpenAIRE |
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