Genetic regulation of serum phytosterol levels and risk of coronary artery disease

Circ Cardiovasc Genet. 2010 Aug;3(4):331-9. doi: 10.1161/CIRCGENETICS.109.907873. Epub 2010 Jun 7.

Abstract

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=9.4x10(-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)).

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ABO Blood-Group System / genetics
  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • ATP Binding Cassette Transporter, Subfamily G, Member 8
  • ATP-Binding Cassette Transporters / genetics
  • Case-Control Studies
  • Coronary Artery Disease / blood
  • Coronary Artery Disease / etiology
  • Coronary Artery Disease / genetics*
  • Coronary Artery Disease / metabolism
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Linkage Disequilibrium
  • Lipoproteins / genetics
  • Male
  • Meta-Analysis as Topic
  • Metabolism / genetics*
  • Phytosterols / blood*
  • Phytosterols / pharmacokinetics*
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Validation Studies as Topic

Substances

  • ABCG5 protein, human
  • ABCG8 protein, human
  • ABO Blood-Group System
  • ATP Binding Cassette Transporter, Subfamily G, Member 5
  • ATP Binding Cassette Transporter, Subfamily G, Member 8
  • ATP-Binding Cassette Transporters
  • Lipoproteins
  • Phytosterols