The Association between HDL-C and Subclinical Atherosclerosis Depends on CETP Plasma Concentration: Insights from the IMPROVE Study

The impact of cholesteryl ester transfer protein (CETP) on atherosclerosis is highly debated. This study aimed to investigate the associations between plasma CETP or CETP genotypes and carotid intima-media thickness (cIMT) and the influence of high-density lipoprotein cholesterol (HDL-C) on these associations. Plasma CETP and HDL-C concentrations were measured in 552 subjects free of any pharmacological treatment from the IMPROVE cohort, which includes 3711 European subjects at high cardiovascular risk. CETP single-nucleotide polymorphisms (SNPs) and cIMT measures (cIMT(max); cIMT(mean–max) of bifurcations, common and internal carotids; plaque-free common carotid [PF CC]-IMT(mean)) were available for the full cohort. In drug-free subjects, plasma CETP correlated with HDL-C levels (r = 0.19, p < 0.0001), but not with cIMT variables. When stratified according to HDL-C quartiles, CETP positively correlated with cIMT(max) and cIMT(mean–max), but not with PF CC-IMT(mean), in the top HDL-C quartile only. Positive associations between the CETP concentration and cIMT(max) or cIMT(mean–max) were found in the top HDL-C quartile, whereas HDL-C levels were negatively correlated with cIMT(max) and cIMT(mean–max) when the CETP concentration was below the median (HDL-C × CETP interaction, p = 0.001 and p = 0.003 for cIMT(max) and cIMT(mean–max), respectively). In the full cohort, three CETP SNPs (rs34760410, rs12920974, rs12708968) were positively associated with cIMT(max). rs12444708 exhibited a significant interaction with HDL-C levels in the prediction of cIMT(max). In conclusion, a significant interplay was found between plasma CETP and/or CETP genotype and HDL-C in the prediction of carotid plaque thickness, as indexed by cIMT(max). This suggests that the association of HDL-C with carotid atherosclerosis is CETP-dependent.