Association of cholesteryl ester transfer protein (CETP) gene polymorphism, high density lipoprotein cholesterol and risk of coronary artery disease: a meta-analysis using a Mendelian randomization approach

Abstract

BackgroundRecent randomized controlled trials have challenged the concept that increased high density lipoprotein cholesterol (HDL-C) levels are associated with coronary artery disease (CAD) risk reduction. The causal role of HDL-C in the development of atherosclerosis remains unclear. To increase precision and to minimize residual confounding, we exploited the cholesteryl ester transfer protein (CETP)-TaqIB polymorphism as an instrument based on Mendelian randomization.MethodsThe Mendelian randomization analysis was performed by two steps. First, we conducted a meta-analysis of 47 studies, including 23,928 cases and 27,068 controls, to quantify the relationship between the TaqIB polymorphism and the CAD risk. Next, the association between the TaqIB polymorphism and HDL-C was assessed among 5,929 Caucasians. We further employed Mendelian randomization to evaluate the causal effect of HDL-C on CAD based on the findings from the meta-analysis.ResultsThe overall comparison of the B2 allele with the B1 allele yielded a significant risk reduction of CAD (P < 0.0001; OR = 0.88; 95% CI: 0.84–0.92) with substantial between-study heterogeneity (I2 = 55.2%; Pheterogeneity <0.0001). The result was not materially changed after excluding the Hardy-Weinberg Equilibrium (HWE)-violation studies. Compared with B1B1 homozygotes, Caucasian carriers of the B2 allele had a 0.25 mmol/L increase in HDL-C level (95% CI: 0.20–0.31; P <0.0001; I2 = 0; Pheterogeneity =0.87). However, a 1 standard deviation (SD) elevation in HDL-C levels due to the TaqIB polymorphism, was marginal associated with CAD risk (OR =0.79; 95% CI: 0.54–1.03; P =0.08).ConclusionsTaken together, our results lend support to the concept that increased HDL-C cannot be translated into a reduction in CAD risk.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-014-0118-1) contains supplementary material, which is available to authorized users.

Effects of low-carbohydrate dietsv. low-fat diets on body weight and cardiovascular risk factors: a meta-analysis of randomised controlled trials

“…In epidemiological studies, HDL-cholesterol levels are inversely related to the risk of CHD (40) , whereas results from studies on treatment that increase HDL-cholesterol levels have so far been disappointing (41) . Further, large Mendelian randomisation studies indicate that increased HDLcholesterol cannot be translated into a reduction in CVD risk (42,43) . Thus, whether an increase in HDL-cholesterol levels is directly related to the reduction in risk of CHD is yet to be demonstrated (15) .…”

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…199,200 Another recent meta-analysis of this Mendelian randomization approach, however, conversely found, that a specific increase in circulating HDL-cholesterol levels due to the Taq1B polymorphism in the CETP gene was not associated with a lower risk of developing CAD. 201 Population studies that investigated CETP plasma concentrations as a biomarker also yielded results that contradict the initial genetic studies: Low rather than high CETP concentrations were associated with increased cardiovascular mortality in a nearly 8 years long follow-up of more than 3000 patients who underwent coronary angiography. 202 In the PROVE IT-TIMI 22 study, plasma CETP levels were not associated with differences in cardiovascular event rates.…”

SPECIFICS OF LIPID METABOLISM AND ATORVASTATIN EFFICACY IN TYPE 2 DIABETES WITH CARRIAGE OF VARIOUS POLYMORPHISMS OF CHOLESTEROL ETHER CARRYING PROTEIN TaqIB GENE

“…Гомозиготы В1В1 характеризуются более высокой активностью СETP, сниженным уров-нем ХС ЛПВП и быстрым прогрессированием атеро-склероза [6]. Гетерозиготы В1В2 занимают промежу-точное положение и имеют средний риск прогресси-рования атеросклероза.…”