Genetics
Mendelian randomisation upends the textbook story: the causal effects of CETP fall mainly on large HDL and small VLDL, not LDL, hinting anacetrapib works by cutting VLDL (Eur J Hum Genet 2019)
Original title: Mendelian randomization reveals unexpected effects of CETP on the lipoprotein profile
The standard view holds that CETP lowers HDL cholesterol and raises LDL cholesterol, but this study used a Mendelian randomisation approach, with a genetic score for serum CETP concentration built from three variants, to estimate causal effects of CETP on 159 metabolic biomarkers measured by NMR in 5,672 participants of the Netherlands Epidemiology of Obesity study. Higher genetically predicted CETP was causally associated with less large HDL and more small VLDL, with no causal effects on LDL subclasses, replicated in an independent European cohort of about 20,000. In contrast, observational associations using ELISA-measured CETP concentration showed CETP predominantly tracking with more VLDL, IDL and LDL, a discrepancy the authors attribute to these particle classes carrying most circulating CETP and masking its true causal effect on HDL. CETP inhibitors such as anacetrapib may lower cardiovascular risk through reducing small VLDL specifically, rather than through LDL as conventionally assumed.
Original abstract
According to the current dogma, cholesteryl ester transfer protein (CETP) decreases high-density lipoprotein (HDL)-cholesterol (C) and increases low-density lipoprotein (LDL)-C. However, detailed insight into the effects of CETP on lipoprotein subclasses is lacking. Therefore, we used a Mendelian randomization approach based on a genetic score for serum CETP concentration (rs247616, rs12720922 and rs1968905) to estimate causal effects per unit (µg/mL) increase in CETP on 159 standardized metabolic biomarkers, primarily lipoprotein subclasses. Metabolic biomarkers were measured by nuclear magnetic resonance (NMR) in 5672 participants of the Netherlands Epidemiology of Obesity (NEO) study. Higher CETP concentrations were associated with less large HDL (largest effect XL-HDL-C, P = 6 × 10-22) and more small VLDL components (largest effect S-VLDL cholesteryl esters, P = 6 × 10-6). No causal effects were observed with LDL subclasses. All these effects were replicated in an independent cohort from European ancestry (MAGNETIC NMR GWAS; n ~20,000). Additionally, we assessed observational associations between ELISA-measured CETP concentration and metabolic measures. In contrast to results from Mendelian randomization, observationally, CETP concentration predominantly associated with more VLDL, IDL and LDL components. Our results show that CETP is an important causal determinant of HDL and VLDL concentration and composition, which may imply that the CETP inhibitor anacetrapib decreased cardiovascular disease risk through specific reduction of small VLDL rather than LDL. The contrast 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.