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

Abstract

BackgroundMacrophage 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 ResultsWe 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,APOA1/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 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).ConclusionsOur 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.

Structure-function relationships of HDL in diabetes and coronary heart disease

“…Also in line with these and our findings, a recent genomewide association study found CEC apoB-free plasma associated with variants in genes encoding proteins involved in the formation and metabolism of HDL rather than for minor and nonclassical protein components of HDL (40). Beyond classical genes of HDL metabolism such as the APOLP1 and APOLP2 loci, CETP, LIPC, or LPL, 2 loci including the PLB1 and ENPP7 genes -which encode for enzymes degrading phosphatidylcholines and sphingomyelins -were the only ones associated with CEC apoB-free plasma (40). Thus, general physicochemical properties such as number, size, and fluidity of particles rather than specific components appear to determine CEC HDL .…”

“…Likewise, Lusis and colleagues found apoA-I and medium-sized HDL, rather than any minor HDL proteins, to be the most important explanatory factors of differences in CEC HDL from different mouse strains (39). Also in line with these and our findings, a recent genomewide association study found CEC apoB-free plasma associated with variants in genes encoding proteins involved in the formation and metabolism of HDL rather than for minor and nonclassical protein components of HDL (40). Beyond classical genes of HDL metabolism such as the APOLP1 and APOLP2 loci, CETP, LIPC, or LPL, 2 loci including the PLB1 and ENPP7 genes -which encode for enzymes degrading phosphatidylcholines and sphingomyelins -were the only ones associated with CEC apoB-free plasma (40).…”

Six years’ experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias

“…recessive Tangier disease, LCAT deficiency or apo A-I deficiency) [57]. As with severe hypertriglyceridemia, polygenic factors like heterozygous rare variants with incomplete penetrance and extreme polygenic SNP scores, were much more common among individuals with very low HDL cholesterol [56]. Also, we detected heterozygous large-scale deletions of ABCA1 in four patients with severely lowered HDL cholesterol, the first report of ABCA1 CNVs in the context of this phenotype [39].…”

“…We report our clinical and research experience with LipidSeq, a targeted hybrid panel designed for clinical resequencing of genomic loci known to be associated with dyslipidemia and related metabolic traits and disorders. Since 2014, the results from this panel have contributed to 39 publications reporting original scientific findings, including seven on FH [32,43,44,[46][47][48][49], seven on hypertriglyceridemia [42,45,[50][51][52][53][54], four on extremes of HDL cholesterol [39,[55][56][57], and 21 case reports [40,41,[58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76]. We have published an additional 15 reviews and methods articles related to this work [4, 5, 7, 11-13, 20, 34, 77-83].…”

Reconstructing the blood metabolome and genotype using long-range chromatin interactions

“…For example, APOE, which has been associated with modulation of total cholesterol 34 [28][29][30][31] supporting their links with cholesterol. b) ACSM5 pairs as an eGene with rs11647589, rs6497490, and rs1394678, which were associated with 3-phenylpropionate, X-11478 (an unknown metabolite), and indolepropionate respectively.…”