Genetic Regulation of Serum Phytosterol Levels and Risk of Coronary Artery Disease
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°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).
Conclusion—Common variants in ABCG8 and ABO are strongly associated with serum phytosterol levels and show concordant and previously unknown associations with CAD.
- Received September 10, 2009.
- Accepted April 22, 2010.
- Copyright © 2010, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited