CETP is associated with atherosclerosis only in specific subpopulations

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

Literature - 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

  • According to the GRS, CETP was not causally related to cIMT in the total study population (n=5655).
  • Causal relationships were seen between CETP and cIMT of 16 µm (95%CI: -8 to 39) difference in cIMT per µg/mL genetically determined CETP in men and -8 µm (95%CI: -25 to 9) in women.
  • Stratified analyses show that in men with a low 10-year Framingham risk, 1 µg/mL genetically determined CETP was related to 12 µm (95% CI: -12 to 36) thicker cIMT, whereas in men with a 10-year risk ≥10%, the relation was 24 µm (95% CI: -25 to 72) per µg/mL CETP.
  • In men without (pre)diabetes, 1 µg/mL CETP was related with 26 µm (95% CI: -1 to 52) thicker cIMT per µg/mL, and with -24 µm (95% CI: -66 to 18) in men with (pre)diabetes.
  • In men with normal HDL and TG concentrations, or not using statins, the associations ranged between 19 and 21 µm per µg/mL genetically determined CETP concentration, whereas in men with low HDL-C, CETP was inversely related to cIMT (-20 µm per µg/mL CETP; 95% CI: -67 to 27).
  • One µg/mL genetically determined CETP correlated with a -17 µm (95% CI: -36 to 1) difference in cIMT in women with a low 10-year Framingham risk, whereas in women with a 10-year Framingham risk ≥10%, this relation was 23 µm (95% CI: -14 to 59) per µg/mL genetically determined CETP.
  • In women with (pre)diabetes, 1 µg/mL genetically determined CETP was related with a 48 µm (95% CI: -2 to 98) thicker cIMT, and with -13 µm (95% CI: -31 to 5) difference in cIMT in women without (pre)diabetes.
  • In women with normal HDL-C, fasting TG, or not using statins, the relations ranged between -9 and -14 µm per µg/mL CETP. In premenopausal women, 1 µg/mL genetically determined CETP was related with a -25 µm (95% CI: -59 to 8) difference in cIMT, and -0 (-19 to 18) in postmenopausal women.


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.


1. Boekholdt SM, Kuivenhoven JA, Wareham NJ, et al. Plasma levels of cholesteryl ester transfer protein and the risk of future coronary artery disease in apparently healthy men and women: the prospective EPIC (European Prospective Investigation into Cancer and nutrition)-Norfolk population study. Circulation. 2004;110:1418–1423.

2. Group HTRC. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med. 2017;377:1217–1227.

3. Kakko S, Tamminen M, Paivansalo M, et al. Cholesteryl ester transfer protein gene polymorphisms are associated with carotid atherosclerosis in men. Eur J Clin Invest. 2000;30:18–25.

4. Postmus I, Warren HR, Trompet S, et al. Meta-analysis of genome wide association studies of HDL cholesterol response to statins. J Med Genet. 2016;53:835–845.

5. de Mutsert R, den Heijer M, Rabelink TJ, et al. The Netherlands Epidemiology of Obesity (NEO) study: study design and data collection. Eur J Epidemiol. 2013;28:513–523.

Find this article online at J Clin Lipidol. 2017

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