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

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 x 10(-9)) representing 7 loci. Five of these loci harbor genes with important roles in lipid biology (CETP, LIPC, LPL, APOA1/C3/A4/A5, and APOE/C1/C2/C4). Except for the APOE/C1/C2/C4 variant (rs141622900, P-nonadjusted= 1.0x10(-11); P-adjusted=8.8 x 10(-9)), the association signals disappear when correcting for HDL cholesterol and triglyceride levels. The additional 2 significant signals were near the PPP1CB/PLB1 and RBFOX3/ENPP7 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 TRIB1). 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.