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Interaction between cholesteryl ester transfer protein and hepatic lipase encoding genes and the risk of type 2 diabetes: results from the Telde study.

ABSTRACT: BACKGROUND AND AIM: Diabetic dyslipidaemia is common in type 2 diabetes (T2D) and insulin resistance and often precedes the onset of T2D. The Taq1B polymorphism in CETP (B1 and B2 alleles) (rs708272) and the G-250A polymorphism in LIPC (rs2070895) are associated with changes in enzyme activity and lipid concentrations. Our aim was to assess the effects of both polymorphisms on the risk of T2D. METHODS AND RESULTS: In a case-control study from the population-based Telde cohort, both polymorphisms were analysed by PCR-based methods. Subjects were classified, according to an oral glucose tolerance test, into diabetic (N = 115) and pre-diabetic (N = 116); 226 subjects with normal glucose tolerance, matched for age and gender, were included as controls. Chi-square (comparison between groups) and logistic regression (identification of independent effects) were used for analysis. The B1B1 Taq1B CETP genotype frequency increased with worsening glucose metabolism (42.5%, 46.1% and 54.3% in control, IGR and diabetic group; p = 0.042). This polymorphism was independently associated with an increased risk of diabetes (OR: 1.828; IC 95%: 1.12-2.99; p = 0.016), even after adjusting by confounding variables, whereas the LIPC polymorphism was not. Regarding the interaction between both polymorphisms, in the B1B1 genotype carriers, the absence of the minor (A) allele of the LIPC polymorphism increased the risk of having diabetes. CONCLUSION: The presence of the B1B1 Taq1B CETP genotype contributes to the presence of diabetes, independently of age, sex, BMI and waist. However, among carriers of B1B1, the presence of GG genotype of the -250 LIPC polymorphism increases this risk further.

SUBMITTER: Lopez-Rios L

PROVIDER: S-EPMC3207838 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Interaction between cholesteryl ester transfer protein and hepatic lipase encoding genes and the risk of type 2 diabetes: results from the Telde study.

López-Ríos Laura L Nóvoa Francisco J FJ Chirino Ricardo R Varillas Francisco F Boronat-Cortés Mauro M Wägner Ana M AM

PloS one 20111103 11

<h4>Background and aim</h4>Diabetic dyslipidaemia is common in type 2 diabetes (T2D) and insulin resistance and often precedes the onset of T2D. The Taq1B polymorphism in CETP (B1 and B2 alleles) (rs708272) and the G-250A polymorphism in LIPC (rs2070895) are associated with changes in enzyme activity and lipid concentrations. Our aim was to assess the effects of both polymorphisms on the risk of T2D.<h4>Methods and results</h4>In a case-control study from the population-based Telde cohort, both ...[more]

PMID: 22073289

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Project description:In almost 30 years since the introduction of HMG-CoA reductase inhibitors (statins), no other class of lipid modulators has entered the market. Elevation of high-density lipoprotein-cholesterol (HDL-C) via inhibiting cholesteryl ester transfer protein (CETP) is an attractive strategy for reducing the risk of cardiovascular events in high-risk patients. Transfer of triglyceride and cholesteryl ester (CE) between lipoproteins is mediated by CETP; thus inhibition of this pathway can increase the concentration of HDL-C. Torcetrapib was the first CETP inhibitor evaluated in phase III clinical trials. Because of off-target effects, torcetrapib raised blood pressure and increased the concentration of serum aldosterone, leading to higher cardiovascular events and mortality. Torcetrapib showed positive effects on cardiovascular risk especially in patients with a greater increase in HDL-C and apolipoprotein A-1 (apoA-1) levels. The phase III clinical trial of dalcetrapib, the second CETP inhibitor that has entered clinical development, was terminated because of ineffectiveness. Dalcetrapib is a CETP modulator that elevated HDL-C levels but did not reduce the concentration of low-density lipoprotein cholesterol (LDL-C). Both heterotypic and homotypic CE transfer between lipoproteins are mediated by some CETP inhibitors, including torcetrapib, anacetrapib, and evacetrapib, while dalcetrapib only affects the heterotypic CE transfer. Dalcetrapib has a chemical structure that is distinct from other CETP inhibitors, with a smaller molecular weight and a lack of trifluoride moieties. Moreover, dalcetrapib is a pro-drug that must be hydrolyzed to a pharmacologically active thiol form. Two other CETP inhibitors, anacetrapib and evacetrapib, are currently undergoing evaluation in phase III clinical trials. Both molecules have shown beneficial effects by increasing HDL-C and decreasing LDL-C concentration. The success of anacetrapib and evacetrapib remains to be confirmed upon the completion of phase III clinical trials in 2017 and 2015, respectively. Generally, the concentration of HDL-C has been considered a biomarker for the activity of CETP inhibitors. However, it is not clear whether a fundamental relationship exists between HDL-C levels and the risk of coronary artery diseases. The most crucial role for HDL is cholesterol efflux capacity in which HDL can reverse transport cholesterol from foam cells in atherosclerotic plaques. In view of the heterogeneity in HDL particle size, charge, and composition, the mere concentration of HDL-C may not be a good surrogate marker for HDL functionality. Recent clinical studies have reported that increased HDL functionality inversely correlates with the development of atherosclerotic plaque. Future development of CETP inhibitors may therefore benefit from the use of biomarkers of HDL functionality.

Dataset Information

Interaction between cholesteryl ester transfer protein and hepatic lipase encoding genes and the risk of type 2 diabetes: results from the Telde study.

Publications

Interaction between cholesteryl ester transfer protein and hepatic lipase encoding genes and the risk of type 2 diabetes: results from the Telde study.

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