Genetics
Mendelian randomization finds no overall causal link between genetically determined CETP and carotid intima-media thickness (J Clin Lipidol 2018)
Original title: Mendelian randomization analysis of cholesteryl ester transfer protein and subclinical atherosclerosis: A population-based study
Since most CETP-inhibitor trials for cardiovascular prevention failed except REVEAL, this population-based study used Mendelian randomization to test whether genetically determined CETP concentration causally affects carotid intima-media thickness (cIMT). Among 5655 participants in the Netherlands Epidemiology of Obesity study (56% women, mean age 56, mean serum CETP 2.47 microgram/mL), a weighted genetic risk score based on three single-nucleotide polymorphisms found no evidence for an overall causal relation between genetically determined CETP and cIMT in the total population. Effects were directionally opposite in men (16 micrometer per microgram/mL increase, 95% CI -8 to 39) and women (-8 micrometer, 95% CI -25 to 9), with suggestive associations in normoglycemic men (26 micrometer, 95% CI -1 to 52) and in prediabetic or diabetic women (48 micrometer, 95% CI -2 to 98), findings the authors say require replication in stratified subgroups defined by cardiometabolic risk profile.
Original abstract
Background: Several trials to prevent cardiovascular disease by inhibiting cholesteryl ester transfer protein (CETP) have failed, except Randomized EValuation of the Effects of Anacetrapib through Lipid-modification. Thus far, it is unclear to what extent CETP is causally related to measures of atherosclerosis.
Objective: The aim of the article was to study the causal relationship between genetically determined CETP concentration and carotid intima-media thickness (cIMT) in a population-based cohort study.
Methods: In the Netherlands Epidemiology of Obesity study, participants were genotyped, and cIMT was measured by ultrasonography. We examined the relation between a weighted genetic risk score for CETP concentration, based on 3 single-nucleotide polymorphisms that have previously been shown to largely determine CETP concentration and cIMT using Mendelian randomization in the total population and in strata by sex, Framingham 10-year risk, (pre)diabetes, high-density lipoprotein cholesterol, triglycerides, and statin use.
Results: We analyzed 5655 participants (56% women) with a mean age of 56 (range 44-66) years, body mass index of 26 (range 17-61) kg/m2, and serum CETP of 2.47 (range 0.68-5.33) μg/mL. There was no evidence for a causal relation between genetically determined CETP and cIMT in the total population, but associations were differently directed in men (16 μm per μg/mL increase in genetically determined CETP; 95% confidence interval: -8, 39) and women (-8 μm; -25, 9). Genetically determined CETP appeared to be associated with cIMT in normoglycemic men (26 μm; -1, 52) and in (pre)diabetic women (48 μm; -2, 98).
Conclusion: In this population-based study, there was no causal relation between genetically determined CETP concentration and cIMT in the total population although we observed directionally differing effects in men and women. Stratified results suggested associations in individuals with different cardiometabolic risk factor profiles, which require replication.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.