Genetic Determination of Plasma Cholesterol Efflux Capacity Is Gender-Specific and Independent of HDL-Cholesterol Levels

Abstract

Objective-We investigated the impact of several genetic variants located in genes encoding for proteins involved in biogenesis, maturation, and intravascular remodeling of high density lipoprotein (HDL) particles on plasma efflux capacity. Approach and Results-The capacity of whole-plasma to mediate cholesterol efflux from cholesterol-loaded human THP-1 macrophages was measured in 846 individuals (450 men and 396 women). We demonstrated that rs17231506 (CETP c.-1337 C>T), rs2230806 (ABCA1 p.R219K), rs1799837 (APOA1 c.-75 G>A), rs5086 (APOAII c.-265 T>C), and rs1800588 (LIPC c.-514 C>T) single nucleotide polymorphisms (SNPs) significantly modulate the capacity of whole-plasma to mediate cholesterol efflux from human macrophages in a sex-dependent manner. Such associations were independent of circulating plasma lipid levels (HDL-cholesterol, triglyceride, low density lipoprotein-cholesterol). In women, we identified the APOA1 c.-75 G>A and the LIPC c.-514 C>T variants as major contributors of interindividual variability of plasma efflux capacity, whereas the ABCA1 p.R219K and the APOAII c.-265 T>C SNPs mostly contribute to total variance of plasma efflux capacity in men. Multiple regression analyses revealed that the 7 SNPs tested accounted together for approximately 6% of total plasma efflux capacity. We demonstrated that genetically determined plasma efflux capacity represents a better predictor of macrophage cholesterol removal, as compared with plasma HDL-cholesterol levels. Key Words: cholesterol efflux ◼ high density lipoprotein ◼ macrophages ◼ single nucleotide polymorphisms Conclusions-Genetic

HDL-apolipoprotein A-I exchange is independently associated with cholesterol efflux capacity

“…The ABCA1-BHK model explained more than 50% of the variance in effl ux, with HAE, HDL-C, and gender as the strongest predictors ( ‫ف‬ 75% combined). In both models, gender contributed signifi cantly to the effl ux capacity prediction, in agreement with previous data suggesting that effl ux capacity has a gender-specifi c component ( 53,54 ). The fi nding that HAE is a signifi cant predictor of both J774 and ABCA1-BHK effl ux provides a mechanistic rationale as …”

Gender specific association of ABCA1 gene R219K variant in coronary disease risk through interactions with serum triglyceride elevation in Turkish adults

“…On the other hand, Villard et al (35) reported that R219K polymorphism significantly modulates the capacity of wholeplasma to mediate cholesterol efflux from human macrophages in a sex-dependent manner. Furthermore, Villard et al (35) demonstrated impact of the R219K on plasma total cholesterol, LDL-C and Apo A-I concentrations but not HDL-C and TG concentrations in men or women subjects.…”

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

“…Using a family‐based study design, the heritability of CEC was estimated to be 13% to 31% 7. A previous association study of candidate genes involved in HDL biogenesis and remodeling, performed in 846 individuals, has suggested that genetic determinants of CEC are different in men and women, and independent of HDL‐C levels 8. In the GRAPHIC cohort (N=850 individuals with genotypes and CEC measures available), 7 of the 55 tested HDL‐C–associated variants were nominally associated with CEC (including the LIPC and CETP loci) 7…”