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

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. CONCLUSIONS—Genetic variants located within genes encoding proteins involved in HDL metabolism significantly impact plasma efflux capacity independently of variation in plasma HDL-cholesterol levels.