Genetic variants influencing circulating lipid levels and risk of coronary artery disease

Arterioscler Thromb Vasc Biol. 2010 Nov;30(11):2264-76. doi: 10.1161/ATVBAHA.109.201020. Epub 2010 Sep 23.

Abstract

Objective: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides.

Methods and results: We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10(-8) to 3.1×10(-10)). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10(-3) to 1.2×10(-9)).

Conclusions: We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Asian Continental Ancestry Group
  • Cholesterol, HDL / blood
  • Cholesterol, HDL / genetics*
  • Cholesterol, LDL / blood
  • Cholesterol, LDL / genetics*
  • Coronary Artery Disease / genetics*
  • European Continental Ancestry Group
  • Genetic Variation
  • Genome-Wide Association Study
  • Humans
  • Lipid Metabolism / genetics*
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Triglycerides / blood
  • Triglycerides / genetics*

Substances

  • Cholesterol, HDL
  • Cholesterol, LDL
  • Triglycerides