Elsevier

Journal of Clinical Lipidology

Volume 12, Issue 1, January–February 2018, Pages 137-144.e1
Journal of Clinical Lipidology

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

https://doi.org/10.1016/j.jacl.2017.10.023Get rights and content

Highlights

  • Cholesteryl ester transfer protein is not causally related to subclinical atherosclerosis in the total population.

  • CETP is related to atherosclerosis in normoglycemic men and (pre)diabetic women.

  • Effects of different direction in subgroups may mask overall associations.

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.

Introduction

Recent studies to improve cardiovascular risk prevention have focused on cholesteryl ester transfer protein (CETP) inhibitors since they increase high-density lipoprotein cholesterol (HDL-C) and decrease non-HDL-c concentrations.1, 2, 3

CETP facilitates the migration of cholesteryl esters from HDL to low-density lipoprotein (LDL) and very-low-density lipoproteins. A high CETP concentration is therefore hypothesized to contribute to an atherogenic lipoprotein profile by increasing (V)LDL cholesterol (LDL-C) and decreasing HDL-C.4 Several observational studies have suggested that lower concentrations of CETP are associated with reduced cardiovascular disease (CVD) risk.5, 6 Most recent efforts to lower CETP concentration pharmacologically with the purpose of reducing CVD risk have been unsuccessful, except for the Randomized EValuation of the Effects of Anacetrapib through Lipid-modification trial, in which CETP inhibition with anacetrapib successfully lowered the risk of major coronary events in high cardiovascular risk patients.7, 8The effect of genetically determined CETP has been subject to considerable discussion in recent literature, but, in general, a detrimental effect of high CETP, if any, appears to be restricted to men2, 4, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 Close inspection of previous studies on the association of CETP with CVD risk suggested that in addition to sex, other factors potentially modulate the effects of CETP on CVD risk, including HDL-C or triglyceride (TG) concentrations, insulin resistance, or the use of statins or fibrates.1, 9, 19, 20, 21 This suggests that CETP inhibition could be effective in specific subgroups of the population. To provide more insights in the role of CETP on cardiovascular risk, we aimed to study the causal effect of genetically determined higher CETP concentration on atherosclerosis in the general low-risk population, as well as specific subgroups, using a genetic risk score (GRS) for CETP concentration as determinant.

Section snippets

Study design and study population

The Netherlands Epidemiology of Obesity (NEO) study is a population-based, prospective cohort study of 6671 men and women aged between 45 and 65 years. The study design and population are described in detail elsewhere.22 All inhabitants with a self-reported body mass index (BMI) of ≥27 kg/m2 and living in the greater area of Leiden, the Netherlands, were eligible to participate in the NEO study. In addition, all inhabitants aged between 45 and 65 years from 1 adjacent municipality (Leiderdorp,

Baseline characteristics

Baseline characteristics of the study population are presented in Table 1, stratified by sex. The mean (SD) age of the participants was 56 (6) years, and 56% were women. The mean BMI was 26 (4) kg/m2, mean CETP concentration was 2.47 (0.65) μg/mL, and the mean cIMT was 616 (92) μm.

Serum CETP concentration and atherosclerosis

In observational analyses in the total population, CETP concentration was weakly associated with cIMT (adjusted coefficient: −1 μm per μg/mL CETP; 95% CI: −6, 5). Table 2 reports stratified analyses with a weak

Discussion

In 5655 men and women, we investigated the causal associations between CETP and measures of subclinical atherosclerosis. We showed that there was a marginal observational association between CETP and subclinical atherosclerosis in the study population, whereas a genetic propensity toward higher CETP concentrations was not associated with cIMT. However, stratified analyses in prespecified subgroups of sex, cardiovascular risk, (pre)diabetes, HDL-C, TGs, and statin use suggested a marginal

Acknowledgments

The authors express their gratitude to all individuals who participate in the Netherlands Epidemiology in Obesity (NEO) study. They are grateful to all participating general practitioners for inviting eligible participants. They furthermore thank P. van Beelen and all research nurses for collecting the data and P. Noordijk and her team for sample handling and storage and I. de Jonge, MSc, for all data management of the NEO study. The genotyping in the NEO study was supported by the Centre

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    The NEO study is supported by the participating Departments, the Division and the Board of Directors of the Leiden University Medical Centre, and by the Leiden University, Research Profile Area “Vascular and Regenerative Medicine.” We acknowledge the support from the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation (CVON2014-02 ENERGISE).

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