Abstract 11937: Cholesteryl Ester Transfer Protein (CETP) and Hepatic Lipase (HL) Gene Polymorphisms Affect HDL-C Concentrations and Particle Size but Not Macrophage Cholesterol Efflux
CETP -629C>A and HL -514C>T polymorphisms are associated with lower CETP and HL transcriptional and enzymatic activities respectively, and higher HDL-C concentrations. We tested the hypothesis that CETP and HL polymorphisms affect HDL concentrations, size and cholesterol efflux capacity; aimed at providing insights into whether CETP and/or HL inhibition would favourably affect HDL function.
Methods: To assess effects of CETP polymorphisms, we studied 150 men (n=50 of CC, CA and AA genotype) homozygous for the common HL allele. For HL polymorphisms, we studied 125 men (n=50 of CC, CT genotype, n=25 of TT genotype) homozygous for the common CETP allele. Lipid and lipoprotein profiles were obtained after 10 hour fast. Lipoprotein sizes and subclasses were determined by Nuclear Magnetic Resonance Spectroscopy. Cholesterol efflux to plasma was assessed in vitro using [3H]-cholesterol laden THP-1 macrophages. In a subset (n=25 per group), macrophage cholesterol efflux capacity was also assessed with plasma depleted of apo-B-containing lipoproteins.
Results: CETP and HL polymorphisms were associated with higher levels of large HDL particles (4.68±2.58 vs 5.72±2.92 vs 6.23±2.70 µmol/L for CETP CC, CA, AA genotypes respectively; P=0.019 and 4.68±2.58 vs 5.79±2.62 vs 6.57±2.90 µmol/L for HL CC, CT, TT genotypes respectively; P=0.013), leading to higher HDL-C and apoA-1 concentrations. Pre-β HDL concentration was lower (P=0.002) in subjects with HL TT genotype. In macrophage cholesterol efflux studies, CETP and HL polymorphisms were not associated with significant differences in percentage cholesterol efflux to plasma or apo-B depleted plasma.
Conclusions: CETP and HL polymorphisms increase HDL-C and apoA-1 concentrations, particularly large HDL. The lack of correlation between these parameters and macrophage cholesterol efflux suggest that large HDL particles are less efficient acceptors for cholesterol efflux. Lower pre-β HDL concentrations observed with the HL TT genotype may adversely impact cholesterol efflux capacity or be a marker of reduced in vivo reverse cholesterol transport. Our findings reinforce the concept that changes in HDL-C concentrations may not translate into effects on cholesterol efflux capacity, a metric of HDL function.
- © 2011 by American Heart Association, Inc.