Reduction of CV risk with CETP inhibition may be due to a specific reduction of small VLDL
Mendelian randomization reveals unexpected effects of CETP on the lipoprotein profile
Introduction and methods
Cholesteryl ester transfer protein (CETP) increases LDL-c, and decreases HDL-c, although there are no detailed data on the effects of CETP on various lipoprotein subclasses . Mendelian randomization data showed that higher HDL-c concentrations do not decrease the risk of myocardial infarction, as was previously believed [2-5].
This study assessed the causal effects of CETP concentration on 159 circulating metabolic measures, primarily lipoprotein subclasses, using a Mendelian randomization approach in a cohort of the Dutch general population . Moreover, the causal effect estimates were compared with observational associations between serum CETP concentration and these measures of lipid metabolism.
For this analysis, data from 5,672 individuals included in the Netherlands Epidemiology of Obesity (NEO) study , a population-based prospective cohort study of men and women aged 45 to 65 years, were used. DNA was isolated from venous blood samples, and genotyping was performed in participants from European ancestry. From the whole-genome data, three independent genetic variants were extracted that have been previously identified in relationship to CETP concentration in the NEO study population .
The CETP-increasing alleles are rs247616-C, rs12720922-A and rs1968905-G. Based on these three polymorphisms, a weighted genetic score per participant was calculated . A high-throughput proton nuclear magnetic resonance (NMR) metabolomics platform  was used to quantify 159 lipid and metabolite measures. This method provides quantification of lipoprotein subclass profiling with lipid concentrations within 14 lipoprotein subclasses. The following lipoprotein subclasses were quantiﬁed: total cholesterol, total lipids, phospholipids, free cholesterol, cholesteryl esters and triglycerides.
- The mean (SD) concentration of CETP was 2.47 (0.65) μg/mL, of LDL-c 3.56 (0.96) mmol/L and of and HDL-c 1.57 (0.46) mmol/L.
- The association with the CETP genetic score was statistically significant for 46 metabolic measures (P<0.00134).
- CETP concentration most strongly affected very large, large and medium HDL subclasses. With a 1 μg/mL increase in CETP, all components of these lipoprotein subclasses decreased, with the exception of the triglyceride content in medium HDL, which showed a positive association (effect ± SE: 0.272±0.055; P=9×10^–7).
- The largest effect was found for the cholesterol component in very large HDL (effect ± SE: –0.517±0.053; P=6×10^–22).
- CETP concentration was not associated with LDL subclass components, whereas higher CETP concentrations were associated with more small and very small VLDL.
- The largest increasing effect was found for cholesteryl esters in small VLDL (effect ± SE: 0.276 ± 0.061; P=6×10^–6). There were no pronounced differences in the effect sizes between the various components within VLDL subclasses.
- The largest effect sizes for observational associations were found for free cholesterol in very small VLDL (effect ± SE: 0.476 ± 0.030; P=2×10^–55) and phospholipids in very small VLDL (effect ± SE: 0.472 ± 0.030; P=2×10^–56).Overall, the directions of the effects were not very consistent between observational and genetic associations
This Mendelian randomization study shows that CETP is an important causal determinant of HDL and VLDL concentration and composition. These results suggest that reduction of CV risk with CETP inhibition may be due to a specific reduction of small VLDL rather than LDL, as is the current dogma since the REVEAL trial data with anacetrapib. Moreover, the inconsistency between genetic and observational associations might be explained by a high capacity of VLDL, IDL and LDL subclasses to carry CETP, thereby concealing causal effects on HDL.