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A meta-analytic evaluation of cholesteryl ester transfer protein (CETP) C-629A polymorphism in association with coronary heart disease risk and lipid changes.

ABSTRACT: Lipid metabolism plays an essential role in the pathogenesis of atherosclerosis, a major cause for coronary heart disease (CHD). Cholesteryl ester transfer protein (CETP) is an important glycoprotein involved in lipid metabolism by transferring cholesteryl esters to apolipoprotein B-containing lipoproteins in exchange for triglycerides. The objective of this meta-analysis was to evaluate the association of CETP C-629A polymorphism with CHD risk and lipid changes. Four public databases were searched, and data from 17 qualified articles were extracted in duplicate and analyzed by STATA software. Overall association of C-629A with CHD risk was nonsignificant in 5441 patients and 7967 controls. Subgroup analyses by ethnicity revealed significance only in Caucasians, with the odds of CHD being 1.18, 1.43 and 1.41 under allelic, genotypic and dominant models, respectively (P < 0.001). Similarly, the -629C allele increased the corresponding risk of myocardial infarction by 1.23-, 1.28- and 1.29-fold (P < 0.02). The association of C-629A with CHD was significantly strengthened in prospective and large studies. Moreover, carriers of the -629C allele had significant higher levels of circulating CETP (weighted mean difference [WMD]: 0.45 ?g/mL; 95% confidence interval [CI]: 0.25 to 0.65; P < 0.001), but lower levels of high-density lipoprotein cholesterol (HDL-C) (WMD: -3.65 mg/dL; 95% CI: -5.59 to -1.70; P < 0.001) relative to the -629AA homozygotes. The probability of publication bias was low. Our meta-analytic findings collectively demonstrate that the -629C allele was significantly associated with an increased risk of CHD in Caucasians, and this association may be mediated by its phenotypic regulation on circulating CETP and HDL-C.

SUBMITTER: Lin S

PROVIDER: S-EPMC5356788 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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A meta-analytic evaluation of cholesteryl ester transfer protein (CETP) C-629A polymorphism in association with coronary heart disease risk and lipid changes.

Lin Shouwei S Dai Ruozhu R Lin Rong R

Oncotarget 20170101 2

Lipid metabolism plays an essential role in the pathogenesis of atherosclerosis, a major cause for coronary heart disease (CHD). Cholesteryl ester transfer protein (CETP) is an important glycoprotein involved in lipid metabolism by transferring cholesteryl esters to apolipoprotein B-containing lipoproteins in exchange for triglycerides. The objective of this meta-analysis was to evaluate the association of CETP C-629A polymorphism with CHD risk and lipid changes. Four public databases were searc ...[more]

PMID: 27791990

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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.

Project description:ContextPolymorphisms in the cholesteryl ester transfer protein (CETP) gene have been associated with exceptional longevity and lower cardiovascular risk, but associations with memory decline and dementia risk are unclear.ObjectiveTo test the hypothesis that a single-nucleotide polymorphism (SNP) at CETP codon 405 (isoleucine to valine V405; SNP rs5882) is associated with a lower rate of memory decline and lower risk of incident dementia, including Alzheimer disease (AD).Design, setting, and participantsProspective cohort study comprising 608 community-dwelling adults without dementia aged 70 years or older from the Einstein Aging Study with CETP genotype available. Fifteen participants with prevalent dementia were excluded, and 70 without follow-up--63 lost to follow-up and 7 new to the study--were excluded from the Cox proportional hazards model, which included 523 participants in the analysis. Standardized neuropsychological and neurological measures were administered annually from 1994-2009. Linear mixed-effects models adjusted for sex, education, race, medical comorbidities, and apolipoprotein (APOE) epsilon4 examined associations of V405 genotype with longitudinal performance on cognitive tests of episodic memory (Free and Cued Selective Reminding Test [FCSRT], possible scores of 0-48), attention (Digit Span), and psychomotor speed (Digit Symbol Substitution). The V405 genotype was the main predictor of incident dementia or AD in similarly adjusted Cox proportional hazards models with age as the time scale.Main outcome measuresMemory decline and incident dementia.ResultsValine allele frequency was 43.5%. A total of 40 cases of incident dementia occurred during follow-up (mean [(SD], 4.3 [3.1] years). Compared with isoleucine homozygotes, valine homozygotes had significantly slower memory decline on the FCSRT (0.43 points per year of age for isoleucine; 95% confidence interval [CI], -0.58 to -0.29 vs 0.21 points per year of age for valine; 95% CI, -0.39 to -0.04; difference in linear age slope, 0.22; 95% CI, 0.02 to 0.41; P = .03) and no significant differences on the Digit Span or Digit Symbol Substitution tests. Valine homozygotes also had lower risk of dementia (hazard ratio, 0.28; 95% CI, 0.10-0.85; P = .02) and AD (hazard ratio, 0.31; 95% CI, 0.10-0.95; P = .04).ConclusionThis preliminary report suggests that CETP V405 valine homozygosity is associated with slower memory decline and lower incident dementia and AD risk.

Project description:Although Cholesteryl Ester Transfer Protein (CETP) mediates the transfer of cholesteryl esters and triglycerides between lipoprotein particles and thus plays a crucial role in reverse cholesterol transport, the association of variations in the CETP gene with acute myocardial infarction (MI) remains unclear. In this study we examined whether common genetic variation in the CETP gene is related to early-onset non-fatal MI risk in a population-based case-control study from western Washington State. Genotyping for the CETP -2708 G/A, -971 A/G, -629 A/C, Intron-I TaqI G/A and exon-14 A/G (I405V) SNPs was performed in 578 cases with first acute non-fatal MI and in 666 demographically similar controls, free of clinical cardiovascular disease, identified randomly from the community. In-person interviews and non-fasting blood specimens provided data on coronary heart disease risk factors. In men, there was little evidence for an association between single SNPs and MI risk, but in women the age- and race-adjusted OR was found to be significant in 4 out of the 5 CETP single variants. Haplotype analysis revealed two haplotypes associated with MI risk among men. As compared to men homozygous for the most common haplotype D (-2708 G, -971 G, -629 C, TaqI G and exon-14 A), the fully-adjusted multiplicative model identified haplotype G (-2708 G, -971 A, -629 A, TaqI G and exon-14 G) was associated with a 4.0-6.0-fold increased risk of MI for each additional copy; [95%CI 2.4-14.8] and haplotype B (-2708 G, -971 G, -629 A, TaqI A and exon-14 A) showed a significant decreased risk for early onset MI [OR = 0.18; 95%CI 0.04 - 0.75]. An evolutionary-based haplotype analysis indicated that the two haplotypes associated with the MI risk are most evolutionarily divergent from the other haplotypes. Variation at the CETP gene locus is associated with the risk of early-onset non-fatal MI. This association was found to be independent of HDL-C levels. These data and the sex-specific findings require confirmation in other populations.

Dataset Information

A meta-analytic evaluation of cholesteryl ester transfer protein (CETP) C-629A polymorphism in association with coronary heart disease risk and lipid changes.

Publications

A meta-analytic evaluation of cholesteryl ester transfer protein (CETP) C-629A polymorphism in association with coronary heart disease risk and lipid changes.

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