Variants at the APOE /C1/C2/C4 Locus Modulate Cholesterol Efflux Capacity Independently of High-Density Lipoprotein Cholesterol

J Am Heart Assoc. 2018 Aug 21;7(16):e009545. doi: 10.1161/JAHA.118.009545.

Abstract

Background Macrophage cholesterol efflux to high-density lipoproteins ( HDLs ) is the first step of reverse cholesterol transport. The cholesterol efflux capacity ( CEC ) of HDL particles is a protective risk factor for coronary artery disease independent of HDL cholesterol levels. Using a genome-wide association study approach, we aimed to identify pathways that regulate CEC in humans. Methods and Results We measured CEC in 5293 French Canadians. We tested the genetic association between 4 CEC measures and genotypes at >9 million common autosomal DNA sequence variants. These analyses yielded 10 genome-wide significant signals ( P<6.25×10-9) representing 7 loci. Five of these loci harbor genes with important roles in lipid biology ( CETP , LIPC , LPL , APOA 1/C3/A4/A5, and APOE /C1/C2/C4). Except for the APOE /C1/C2/C4 variant ( rs141622900, P nonadjusted=1.0×10-11; P adjusted=8.8×10-9), the association signals disappear when correcting for HDL cholesterol and triglyceride levels. The additional 2 significant signals were near the PPP 1 CB / PLB 1 and RBFOX 3/ ENPP 7 genes. In secondary analyses, we considered candidate functional variants for 58 genes implicated in HDL biology, as well as 239 variants associated with blood lipid levels and/or coronary artery disease risk by genome-wide association study . These analyses identified 27 significant CEC associations, implicating 5 additional loci ( GCKR , LIPG , PLTP , PPARA , and TRIB 1). Conclusions Our genome-wide association study identified common genetic variation at the APOE /C1/C2/C4 locus as a major determinant of CEC that acts largely independently of HDL cholesterol. We predict that HDL -based therapies aiming at increasing CEC will be modulated by changes in the expression of apolipoproteins in this gene cluster.

Keywords: HDL efflux; genome‐wide association study; high‐density lipoprotein cholesterol.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Apolipoprotein C-I / genetics
  • Apolipoprotein C-II / genetics
  • Apolipoproteins C / genetics*
  • Apolipoproteins E / genetics*
  • Canada
  • Case-Control Studies
  • Cholesterol / metabolism*
  • Cholesterol, HDL / metabolism*
  • Coronary Artery Disease / genetics*
  • Coronary Artery Disease / metabolism
  • Female
  • Genetic Variation
  • Genome-Wide Association Study
  • Humans
  • Macrophages / metabolism*
  • Male
  • Middle Aged

Substances

  • APOC1 protein, human
  • APOC4 protein, human
  • Apolipoprotein C-I
  • Apolipoprotein C-II
  • Apolipoproteins C
  • Apolipoproteins E
  • Cholesterol, HDL
  • Cholesterol