Mendelian randomization analysis of cholesteryl ester transfer protein and subclinical atherosclerosis: A population-based study

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.