Physicians' Academy for Cardiovascular Education

CETP is associated with atherosclerosis only in specific subpopulations

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

Christen T, Trompet S, Noordam R, et al. - J Clin Lipidol. 2017; published online ahead of print


In data of observational studies, lower concentrations of cholesteryl ester transfer protein (CETP) are associated with a reduced CVD risk [1]. However, lowering CETP levels pharmacologically failed to reduce CVD risk, except for in the Randomized EValuation of the Effects of Anacetrapib through Lipid-modification (REVEAL) trial [2]. Studies examining the association of CETP with CVD risk showed that gender, HDL-C, TG, insulin resistance, and the use of statins or fibrates modulate the effects of CETP on CVD risk, suggesting that CETP inhibition might decrease CVD risk only in specific subgroups of the population [3,4].

In this mendelian randomization analysis of the NEO (Netherlands Epidemiology of Obesity) study, the causal effect of genetically determined higher CETP concentration on atherosclerosis was evaluated in the general low-risk population, as well as in specific subgroups. A genetic risk score (GRS) for CETP concentration was used as determinant. The NEO study is a population-based, prospective cohort study of 6671 men and women aged between 45 and 65 years, who have a self-reported BMI ≥27 kg/m2 [5].

Participants from non-European ancestry or with poor genotyping quality (n=927), as well as participants with missing CETP (n=31) and missing carotid intima-media thickness (cIMT) -measurements (n=58) were excluded from this analysis. Three variants within the CETP gene, discovered in a genome-wide association study in this population, namely rs12720922, rs247616, and rs1968905, were used for the present study, of which rs12720922 and rs1968905 were imputed variants. cIMT was used as a measure of subclinical atherosclerosis, and it was assessed by ultrasonography of the common carotid arteries (CCAs).

Main results


Although CETP was not causally related to atherosclerosis, as assessed by cIMT, in the total study population, this relation may be present in men with normal glucose, HDL, and TG concentrations, as well as in women with a high CV risk profile or impaired fasting glucose.


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Find this article online at J Clin Lipidol. 2017