Large-Scale Analysis of Determinants, Stability, and Heritability of High-Density Lipoprotein Cholesterol Efflux Capacity

Abstract

Supplemental Digital Content is available in the text.

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

“…Except for APOE/C1/C2/C4 and PLTP , association signals at all other loci were only significant in model 1 (Table 4). Focusing on SNPs associated with HDL‐C levels by GWAS, Koekemoer et al previously reported 10 variants nominally associated with CEC in the GRAPHIC cohort 7. In our data set, we confirmed the association between J774‐stimulated CEC measures and variants at the LIPC and CETP loci in model 1, consistent with our genome‐wide significant results (Table S7).…”

“…HDL‐C levels were also strongly correlated with the number or size of HDL particles and apolipoprotein A‐I concentration in cases and controls (Spearman's ρ all >0.6, P all <2.2×10 −16 ). As previously noted,4, 7 HDL‐C levels were positively correlated with CEC using the J774 or BHK models, although the strength of the correlations varied from one phenotype to the other: the correlations were strong with the J774‐basal model (Spearman's ρ control =0.63, ρ case =0.66, P both <2.2×10 −16 ), modest with the J774‐stimulated model (Spearman's ρ control =0.38, ρ case =0.37, P both <2.2×10 −16 ) and the BHK‐stimulated model (Spearman's ρ control =0.43, ρ case =0.34, P both <2.2×10 −16 ), and weak or absent with the J774‐ABCA1–dependent model (Spearman's ρ control =−0.06, ρ case =−0.07, P control =0.07, P case =0.03). Using unsupervised hierarchical clustering, we noted that the BHK‐stimulated assay clustered with the J774‐basal model in controls, but with the J774‐stimulated and J774‐ABCA1–dependent measures in cases (Figure 1).…”

“…However, none of the 10 SNPs was associated with CEC in model 2 (Table S7). The PLTP locus, which is significantly associated with CEC in our data set (Tables 3 and 4), was not associated with this phenotype in the GRAPHIC cohort, nor with HDL‐C levels 7…”

“…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.…”

Relation of High‐Density Lipoprotein Charge Heterogeneity, Cholesterol Efflux Capacity, and the Expression of High‐Density Lipoprotein‐Related Genes in Mononuclear Cells to the HDL‐Cholesterol Level

“…The increased dissociation of lipid‐free apoA‐I from HDL at hypertriglyceridemia was described recently (Jayaraman et al, ). Overall, the atheroprotective effect of preβ‐HDL at hypertriglyceridemia may be suggested thus explaining the discordance between HDL‐C and cholesterol efflux (Koekemoer et al, ). Moreover, the balance between proatherogenic and antiatherogenic effects of TAG may underlie TAG significance as a risk factor of CVD.…”