Cholesteryl Ester Transfer Protein Gene Research Articles

Association of CETP Gene Polymorphisms and Haplotypes with Acute Heart Rate Response to Exercise.

Polymorphisms in the cholesteryl ester transfer protein (CETP) gene are known to be strongly associated with increased cardiovascular risk, primarily through their effects on the lipid profile and consequently on atherosclerotic risk. The acute heart rate response (AHRR) to physical activity is closely related to individual cardiovascular health. This study aimed to investigate the effect of CETP gene polymorphisms on AHRR. Our analysis examines the association of five single nucleotide polymorphisms (SNPs; rs1532624, rs5882, rs708272, rs7499892, and rs9989419) and their haplotypes (H) in the CETP gene with AHRR in 607 people from the Hungarian population. Individual AHRR in the present study was assessed using the YMCA 3-min step test and was estimated as the difference between resting and post-exercise heart rate, i.e., delta heart rate (ΔHR). To exclude the direct confounding effect of the CETP gene on the lipid profile, adjustments for TG and HDL-C levels, next to conventional risk factors, were applied in the statistical analyses. Among the examined five SNPs, two showed a significant association with lower ΔHR (rs1532624-Cdominant: B = -8.41, p < 0.001; rs708272-Gdominant: B = -8.33, p < 0.001) and reduced the risk of adverse AHRR (rs1532624-Cdominant: OR = 0.44, p = 0.004; rs708272-Gdominant: OR = 0.43, p = 0.003). Among the ten haplotypes, two showed significant association with lower ΔHR (H3-CAGCA: B = -6.81, p = 0.003; H9-CGGCG: B = -14.64, p = 0.015) and lower risk of adverse AHRR (H3-CAGCA: OR = 0.58, p = 0.040; H9-CGGCG: OR = 0.05, p = 0.009) compared to the reference haplotype (H1-AGACG). Our study is the first to report a significant association between CETP gene polymorphisms and AHRR. It also confirms that the association of the CETP gene with cardiovascular risk is mediated by changes in heart rate in response to physical activity, in addition to its effect on lipid profile.

Association of the polymorphisms of the cholesteryl ester transfer protein gene with coronary artery disease: a meta-analysis.

This meta-analysis aimed to assess the association of the polymorphisms of cholesterol ester transfer protein (CETP) rs708272 (G>A), rs5882 (G>A), rs1800775 (C>A), rs4783961 (G>A), rs247616 (C>T), rs5883 (C>T), rs1800776 (C>A), and rs1532624 (C>A) with coronary artery disease (CAD) and the related underlying mechanisms. A comprehensive search was performed using five databases such as PubMed, EMBASE, Web of Science, Cochrane Library and Scopus to obtain the appropriate articles. The quality of the included studies was assessed by the Newcastle-Ottawa Scale. The statistical analysis of the data was performed using STATA 17.0 software. The association between CETP gene polymorphisms and risk of CAD was estimated using the pooled odds ratio (OR) and 95% confidence interval (95% CI). The association of CETP gene polymorphisms with lipids and with CETP levels was assessed using the pooled standardized mean difference and corresponding 95% CI. P < 0.05 was considered statistically significant. A total of 70 case-control studies with 30,619 cases and 31,836 controls from 46 articles were included. The results showed the CETP rs708272 polymorphism was significantly associated with a reduced risk of CAD under the allele model (OR = 0.846, P < 0.001), the dominant model (OR = 0.838, P < 0.001) and the recessive model (OR = 0.758, P < 0.001). AA genotype and GA genotype corresponded to higher high-density lipoprotein cholesterol (HDL-C) concentrations in the blood compared with GG genotype across the studied groups (all P < 0.05). The CETP rs5882 and rs1800775 polymorphisms were not significantly associated with CAD under the allele model (P = 0.802, P = 0.392), the dominant model (P = 0.556, P = 0.183) and the recessive model (P = 0.429, P = 0.551). Similarly, the other mentioned gene polymorphisms were not significantly associated with CAD under the three genetic models. The CETP rs708272 polymorphism shows a significant association with CAD, and the carriers of the allele A are associated with a lower risk of CAD and higher HDL-C concentrations in the blood compared to the non-carriers. The CETP rs5882, rs1800775, rs4783961, rs247616, rs5883, rs1800776, and rs1532624 are not significantly associated with CAD. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023432865, identifier: CRD42023432865.

Variants in the CETP gene affect levels of HDL cholesterol by reducing the amount, and not the specific lipid transfer activity, of secreted CETP.

Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters in plasma from high density lipoprotein (HDL) to very low density lipoprotein and low density lipoprotein. Loss-of-function variants in the CETP gene cause elevated levels of HDL cholesterol. In this study, we have determined the functional consequences of 24 missense variants in the CETP gene. The 24 missense variants studied were the ones reported in the Human Gene Mutation Database and in the literature to affect HDL cholesterol levels, as well as two novel variants identified at the Unit for Cardiac and Cardiovascular Genetics, Oslo University Hospital in subjects with hyperalphalipoproteinemia. HEK293 cells were transiently transfected with mutant CETP plasmids. The amounts of CETP protein in lysates and media were determined by Western blot analysis, and the lipid transfer activities of the CETP variants were determined by a fluorescence-based assay. Four of the CETP variants were not secreted. Five of the variants were secreted less than 15% compared to the WT-CETP, while the other 15 variants were secreted in varying amounts. There was a linear relationship between the levels of secreted protein and the lipid transfer activities (r = 0.96, p<0.001). Thus, the secreted variants had similar specific lipid transfer activities. The effect of the 24 missense variants in the CETP gene on the lipid transfer activity was mediated predominantly by their impact on the secretion of the CETP protein. The four variants that prevented CETP secretion cause autosomal dominant hyperalphalipoproteinemia. The five variants that markedly reduced secretion of the respective variants cause mild hyperalphalipoproteinemia. The majority of the remaining 15 variants had minor effects on the secretion of CETP, and are considered neutral genetic variants.

Genome-Wide Association Study of Cardiovascular Resilience Identifies Protective Variation in the CETP Gene.

Background The risk of atherosclerotic cardiovascular disease (ASCVD) increases sharply with age. Some older individuals, however, remain unaffected despite high predicted risk. These individuals may carry cardioprotective genetic variants that contribute to resilience. Our aim was to assess whether asymptomatic older individuals without prevalent ASCVD carry cardioprotective genetic variants that contribute to ASCVD resilience. Methods and Results We performed a genome-wide association study using a 10-year predicted ASCVD risk score as a quantitative trait, calculated only in asymptomatic older individuals aged ≥70 years without prevalent ASCVD. Our discovery genome-wide association study of N=12 031 ASCVD event-free individuals from the ASPREE (Aspirin in Reducing Events in the Elderly) trial identified 2 independent variants, rs9939224 (P<5×10-8) and rs56156922 (P<10-6), in the CETP (cholesteryl ester transfer protein) gene. The CETP gene is a regulator of plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and lipoprotein(a) levels, and it is a therapeutic drug target. The associations were replicated in the UK Biobank (subpopulation of N=13 888 individuals aged ≥69 years without prevalent ASCVD). Carriers of the identified CETP variants (versus noncarriers) had higher plasma high-density lipoprotein cholesterol levels, lower plasma low-density lipoprotein cholesterol levels, and reduced risk of incident ASCVD events during follow-up. Expression quantitative trait loci analysis predicted the identified CETP variants reduce CETP gene expression across various tissues. Previously reported associations between genetic CETP inhibition and increased risk of age-related macular degeneration were not observed among the 3917 ASPREE trial participants with retinal imaging and genetic data available. Conclusions Common genetic variants in the CETP gene region are associated with cardiovascular resilience during aging. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01038583.

Association of dyslipidemia with single nucleotide polymorphisms of the cholesteryl ester transfer protein gene and cardiovascular disease risk factors in a highly admixed population

Cardiovascular diseases (CVD) are major causes of mortality worldwide, leading to premature deaths, loss of quality of life, and extensive socioeconomic impacts. Alterations in normal plasma lipid concentrations comprise important risk factors associated with CVD due to mechanisms involved in the pathophysiology of atherosclerosis. Genetic markers such as single nucleotide polymorphisms (SNPs) are known to be associated with lipid metabolism, including variants in the cholesteryl ester transfer protein (CETP) gene. Thus, the study's objective was to assess the relationship among lipid profile, socioeconomic and demographic characteristics, health status, inflammatory biomarkers, and CETP genetic variants in individuals living in a highly admixed population. The study comprises an analysis of observational cross-sectional data representative at the population level from a highly admixed population, encompassing 901 individuals from three age groups (adolescents, adults, and older adults). Socioeconomic, demographic, health, and lifestyle characteristics were collected using semi-structured questionnaires. In addition, biochemical markers and lipid profiles were obtained from individuals' blood samples. After DNA extraction, genotyping, and quality control according to Affymetrix's guidelines, information on 15 SNPs in the CETP gene was available for 707 individuals. Lipid profile and CVD risk factors were evaluated by principal component analysis (PCA), and associations between lipid traits and those factors were assessed through multiple linear regression and logistic regression. There were low linear correlations between lipid profile and other individuals' characteristics. Two principal components were responsible for 80.8% of the total variance, and there were minor differences in lipid profiles among individuals in different age groups. Non-HDL-c, total cholesterol, and LDL-c had the highest loadings in the first PC, and triacylglycerols, VLDL-c and HDL-c were responsible for a major part of the loading in the second PC;, whilst HDL-c and LDL-c/HDL-c ratio were significant in the third PC. In addition, there were minor differences between groups of individuals with or without dyslipidemia regarding inflammatory biomarkers (IL-1β, IL- 6, IL-10, TNF-α, CRP, and MCP-1). Being overweight, insulin resistance, and lifestyle characteristics (calories from solid fat, added sugar, alcohol and sodium, leisure physical activity, and smoking) were strong predictors of lipid traits, especially HDL-c and dyslipidemia (p<0.05). The CETP SNPs rs7499892 and rs12691052, rs291044, and rs80180245 were significantly associated with HDL-c (p<0.05), and their inclusion in the multiple linear regression model increased its accuracy (adjusted R2 rose from 0.12 to 0.18). This study identified correlations between lipid traits and other CVD risk factors. In addition, similar lipid and inflammatory profiles across age groups in the population suggested that adolescents might already present a significant risk for developing cardiovascular diseases in the population. The risk can be primarily attributed to decreased HDL-c concentrations, which appear to be influenced by genetic factors, as evidenced by associations between SNPs in the CETP gene and HDL-c concentrations, as well as potential gene-diet interactions. Our findings underscore the significant impact of genetic and lifestyle factors on lipid profile within admixed populations in developing countries.

CETP expression ameliorates endothelial function in female mice through estrogen receptor-α and endothelial nitric oxide synthase pathway.

Endothelial dysfunction is an early manifestation of atherosclerosis. The cholesteryl ester transfer protein (CETP) has been considered pro-atherogenic by reducing plasma HDL levels. However, CETP may exhibit cell- or tissue-specific effects. We have previously reported that male mice expressing the human CETP gene show impaired endothelium-mediated vascular relaxation associated with oxidative stress. Although sexual dimorphisms on the metabolic role of CETP has been proposed, possible sex differences in the vascular effects of CETP were not previously studied. Thus, here we investigated the endothelial function of female CETP transgenic mice as compared to non-transgenic controls (NTg). Aortas from CETP females presented preserved endothelium-dependent relaxation to acetylcholine and an endothelium-dependent reduction of phenylephrine-induced contraction. eNOS phosphorylation (Ser1177) and calcium-induced NO levels were enhanced, while reactive oxygen species (ROS) production and NOX2 and SOD2 expression were reduced in the CETP female aortas. Furthermore, CETP females exhibited increased aortic relaxation to 17β-estradiol (E2) and upregulation of heat shock protein 90 (HSP90) and caveolin-1, proteins that stabilize estrogen receptor (ER) in the caveolae. Indeed, CETP females showed an increased E2-induced relaxation in a manner sensitive to ERα and HSP90 inhibitors methylpiperidinopyrazole (MPP) and geldanamycin, respectively. MPP also impaired the relaxation response to acetylcholine in CETP but not in NTg females. Altogether, the study indicates that CETP expression ameliorates anti-contractile endothelial effect and relaxation to E2 in females. This was associated with less ROS production, and increased eNOS-NO and E2-ERα pathways. These results highlight the need for considering sex-specific effects of CETP on cardiovascular risk.

Association of CETP Gene Polymorphisms and Haplotypes with Cardiovascular Risk.

Cholesteryl ester transfer protein (CETP) is known to influence HDL-C levels, potentially altering the profile of HDL subfractions and consequently cardiovascular risk (CVR). This study aimed to investigate the effect of five single-nucleotide polymorphisms (SNPs; rs1532624, rs5882, rs708272, rs7499892, and rs9989419) and their haplotypes (H) in the CETP gene on 10-year CVR estimated by the Systematic Coronary Risk Evaluation (SCORE), the Framingham Risk Score for Coronary Heart Disease (FRSCHD) and Cardiovascular Disease (FRSCVD) algorithms. Adjusted linear and logistic regression analyses were used to investigate the association of SNPs and 10 haplotypes (H1-H10) on 368 samples from the Hungarian general and Roma populations. The T allele of rs7499892 showed a significant association with increased CVR estimated by FRS. H5, H7, and H8 showed a significant association with increased CVR based on at least one of the algorithms. The impact of H5 was due to its effect on TG and HDL-C levels, while H7 showed a significant association with FRSCHD and H8 with FRSCVD mediated by a mechanism affecting neither TG nor HDL-C levels. Our results suggest that polymorphisms in the CETP gene may have a significant effect on CVR and that this is not mediated exclusively by their effect on TG and HDL-C levels but also by presently unknown mechanisms.

SNPs and haplotypes in the CETP gene and their effects on cardiovascular risk estimated by FRS and score in the Hungarian general and Roma populations

Background and Aims : Cholesteryl ester transfer protein (CETP) is known to reduce high-density lipoprotein cholesterol (HDL-C) levels and, as a result, increase cardiovascular risk. Serum levels of CETP are genetically determined, therefore the polymorphisms influencing it are also suspected to influence cardiovascular risk. This study aims to explore the association between 5 single nucleotide polymorphisms (SNPs) and their haplotypes (H) in CETP genes and the 10-year cardiovascular risk estimated by the Framingham Risk Score for hard coronary heart disease (FRSCHD) and for cardiovascular disease in general (FRSCVD), and the Systematic Coronary Risk Evaluation (SCORE) among the Hungarian general (HG) and Roma populations.

Assessment of Cholesteryl Ester Transfer Protein Gene Taq1B Polymorphism and Its Relationship with Lipid Levels of Hypertensive Iraqi Patients

Lipid disorder is one of the main causes of essential hypertension. Cholesteryl ester transfer protein (CETP) gene polymorphism is known to be associated with changes in lipid profile. Therefore, this study designed to detect the CETP Taq1 B polymorphism (rs708272) and evaluate its relationship with lipid profile levels among some hypertensive Iraqi patients. One hundred and seventy blood samples were collected from two groups, the first group included a hundred hypertensive patients and the second group included seventy healthy individuals as control group. For both groups, lipid profile was estimated, genomic DNA was extracted from all samples and Polymerase Chain Reaction - Restriction Fragment Length Polymorphism (PCR-RFLP) technique was used to detect CETP gene Taq1 B polymorphism. Results indicated that levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL-C), and very-low-density lipoprotein (VLDL-C) had increased, while the level of high-density lipoprotein (HDL-C) was decreased in hypertensive patients in comparison to control group. The study also showed that the frequency of B1B1 genotype and (B1) allele was higher in hypertensive patients in compare with control group (p ≤ 0.01). Lipid profile concentrations according to CETP gene Taq1 B genotypes showed non-significant differences. This study concluded that the CETP gene Taq1B polymorphism may associated with associated with lipid disorder and CETP (B1) allele which could be used as a genetic marker for increasing hypertensive susceptibility in Iraqi population.

Los polimorfismos rs4783961 y rs708272 del gen CETP son asociados con la enfermedad arterial coronaria y no con la restenosis tras el implante de un stent coronario

Objective:We evaluated whether cholesteryl ester transfer protein (CETP) gene polymorphisms are associated with the presence of coronary artery disease (CAD) and/or restenosis in patients with coronary stent.Methods:Two polymorphisms of the CETP gene [−971 A/G (rs4783961), and Taq1B A/G (rs708272)] were genotyped by 5’exonuclease TaqMan assays in 219 patients with CAD (66 patients with restenosis and 153 without restenosis) and 607 control individuals.Results:The distribution of polymorphisms was similar in patients with and without restenosis. However, when the whole group of patients (with and without restenosis) was compared to healthy controls, under dominant model, the G allele of the Taq1B A/G polymorphism was associated with increased risk of CAD (odds ratio [OR] = 1.48, pCDom = 0.032). In the same way, under codominant, dominant, and additive models, the A allele of the −971 A/G polymorphisms was associated with an increased risk of developing CAD (OR = 2.03, pCCo-dom = 0.022, OR = 1.83, pCDom = 0.008, and OR = 1.39, pCAdd = 0.011, respectively). In addition, the linkage disequilibrium showed that the “AG” haplotype was associated with increased risk of developing CAD (OR = 1.28, p = 0.03).Conclusion:This study demonstrates that CETP Taq1B A/G and CETP −971 A/G polymorphisms are associated with an increased risk of developing CAD, but no association with restenosis was observed.

The loss-of-function mutation of CETP affects HDLc levels but not ApoA1 in patients with acute myocardial infarction

Background and aimsLoss of the cholesteryl ester transfer protein (CETP) function affects HDLc levels, but its effects on major HDL protein component ApoA1 are not well understood in patients with acute myocardial infarction (AMI). Methods and resultsWe investigated the effects of an East Asian loss-of-function variant (rs2303790; p.D442G) in CETP gene on HDLc and ApoA1 levels and its relationship with AMI. A total of 2327 AMI patients and 2615 age- and sex-matched controls from INTERHEART-China study were included. In controls, both levels of HDLc (1.24 vs. 1.04 mmol/L, P = 0.001) and ApoA1 (1.48 vs. 1.37 mmol/L, P = 0.042) were significantly higher in CETP variant G allele carriers compared to CETP wildtype D allele carriers. In AMI patients, levels of HDLc were significantly higher (1.14 vs. 1.01 mmol/L, P = 0.013) while levels of ApoA1 were not statistically difference (1.31 vs. 1.32 mmol/L, P = 0.468) in CETP variant group compared to CETP wildtype group. Moreover, CETP variant is associated with HDLc increase, but is not associated with AMI risk (P = 0.564), even after adjusting for age, sex, history of hypertension and diabetes, waist to hip ratio, smoking, total cholesterol, LDL cholesterol, triglycerides, physical activity, depression, alcohol, vegetables and fruit consumption. ConclusionsLoss of CETP function is associated with increased HDLc and ApoA1 levels in healthy subjects, and in AMI patients, it is associated with HDLc levels but not ApoA1 levels. The lack of association of CETP variant with AMI may be related to the inability to increase ApoA1 levels and warranted further studies.

Genotyping of 2 Cholesteryl Ester Transfer Protein Gene Variants Among Coronary Artery Disease Patients

Introduction: Coronary artery diseases (CAD) are still among the top causes of death in most populations. The polymorphisms of the cholesteryl ester transfer protein (CETP) gene can influence the risk of CAD through modulating cholesterol metabolism. In this regard, the current study aimed to determine the role of the 2 important CETP gene polymorphisms in CAD patients. Methods: To this end, DNA was extracted from the whole blood of 100 CAD patients and 100 healthy controls and then subjected to polymerase chain reaction-restriction fragment length polymorphism for the genotyping of rs5882 and rs708272 polymorphisms.Results: Based on the results, no meaningful association was found between rs5882 and rs708272 polymorphisms, neither separately nor in combination, and the risk of CAD. However, the risk of CAD significantly increased in male rs5882 polymorphism carriers (P = 0.01). Finally, no significant association was demonstrated between serum high-density lipoprotein levels and the genotypes or alleles of neither rs5882 nor rs708272 polymorphism. Conclusion: Despite the finding regarding the lack of an association between CAD and the studied polymorphisms of the CETP gene, the importance of those variants in CETP protein function and CAD pathogenesis warrants further investigation on larger populations.

The Effect of Haplotypes in the CETP and LIPC Genes on the Triglycerides to HDL-C Ratio and Its Components in the Roma and Hungarian General Populations.

Background: The triglycerides (TG) to high-density lipoprotein (HDL)-cholesterol (HDL-C) ratio (TG/HDL-C) is a well-known predictor for cardiovascular diseases (CVDs) with great heritability background. The cholesteryl ester transfer protein (CETP) and hepatic lipase (LIPC) gene affect TG/HDL-C ratio. This study aims to explore the association between haplotypes (H) in CETP (based on 5 single nucleotide polymorphisms (SNPs)) and LIPC (based on 6 SNPs) genes and the TG/HDL-C ratio and its components, among Roma and Hungarian general populations. Methods: The prevalence of haplotypes and their effect on HDL-C, TG and TG/HDL-C ratio were calculated in both populations and compared. Results: Ten haplotypes in CETP and 6 in LIPC gene were identified. Three haplotypes in CETP and 3 in LIPC have significant effect on HDL-C level, whereas two in CETP and 3 in LIPC on TG level. The H6 in CETP (β = 0.52, p = 0.015; odds ratio (OR) = 1.87, p = 0.009) and H5 in LIPC (β = 0.56, p < 0.001; OR = 1.51, p = 0.002) have a significant increasing effect on TG/HDL-C ratio and have shown higher prevalence among the Roma, as compared to Hungarian general population. The H2 in the CETP gene has a decreasing effect on the TG/HDL-C ratio (OR = 0.58, p = 0.019) and is significantly less frequent among the Roma. Conclusions: Accumulation of harmful haplotypes in CETP and LIPC genes might have a role in the elevated TG/HDL-C ratio in the Roma population, which contributes to a higher risk in the development of cardiovascular diseases.

Cholesteryl Ester Transfer Protein Genetic Variants Associated with Risk for Type 2 Diabetes and Diabetic Kidney Disease in Taiwanese Population.

Cholesteryl ester transfer protein (CETP) plays an important role in lipid metabolism. Low levels of high-density lipoprotein cholesterol (HDL-C) increase the risk of type 2 diabetes (T2D). This study investigated CETP gene variants to assess the risk of T2D and specific complications of diabetic kidney disease (DKD) and diabetic retinopathy. Towards this, a total of 3023 Taiwanese individuals (1383 without T2D, 1640 with T2D) were enrolled in this study. T2D mice (+Leprdb/+Leprdb, db/db) were used to determine CETP expression in tissues. The A-alleles of rs3764261, rs4783961, and rs1800775 variants were found to be independently associated with 2.86, 1.71, and 0.91 mg/dL increase in HDL-C per allele, respectively. In addition, the A-allele of rs4783961 was significantly associated with a reduced T2D risk (odds ratio (OR), 0.82; 95% confidence interval (CI), 0.71–0.96)), and the A-allele of rs1800775 was significantly related to a lowered DKD risk (OR, 0.78; 95% CI, 0.64–0.96). CETP expression was significantly decreased in the T2D mice kidney compared to that in the control mice (T2D mice, 0.16 ± 0.01 vs. control mice, 0.21 ± 0.02; p = 0.02). These collective findings indicate that CETP variants in the promoter region may affect HDL-C levels. Taiwanese individuals possessing an allele associated with higher HDL-C levels had a lower risk of T2D and DKD.

A Molecular and Biochemical Study for Cholesteryl Ester Transfer Protein (CETP) Taq1B in Iraqi Patients with Hyperlipidemia

Cholesteryl ester transfer protein gene contains some single nucleotide polymorphisms, which have been associated with serum high-density lipoprotein concentration and other lipoproteins. This study is done for determining of cholesteryl ester transfer protein polymorphism and evaluate its effect on serum lipid profile concentrations in some hyperlipidemic patients compared with healthy subjects in Salah Al-din governorate-Iraq. Blood samples were taken from (90) patients suffering from hyperlipidemia, and (70) samples that were apparently healthy controls. Serum lipid concentrations were measured by enzymatic assays. The polymorphism was genotyped using polymerase chain reaction restriction fragment length polymorphism analysis. The results showed that there was a significant decrease (P&lt;0.05) in the frequency B2 allele, and B1B2, B2B2 genotype, and a significant increase (P&lt;0.05) in the frequency B1 allele, and B1B1 genotype between patients and controls groups. There was a non-significant decrease in the levels of high density lipoproteins, total cholesterol, low density lipoproteins, and very low density lipoproteins levels, and non-significant increase in levels of triglycerides in individuals with the B1B1 genotype than in the B1B2 and B2B2 genotype. However, high density lipoproteins showed a significant decrease (P&lt;0.001) between individuals with the B1B1 genotype and B2B2 genotype. Also, there was a non-significant difference in the levels of high density lipoproteins, total cholesterol, low density lipoproteins, and very low density lipoproteins levels, in individuals with the B1B2 genotype when compared with that of the B2B2 genotype.

The association of genetic variants in the cholesteryl ester transfer protein gene with hemostatic factors and a first venous thrombosis

BackgroundCholesteryl ester transfer protein (CETP) plays an important role in lipoprotein metabolism. Previous studies have suggested that the CETP TaqI B1/B2 allele is associated with the risk of venous thrombosis (VT). AimTo investigate the associations between genetically determined CETP concentrations and 22 hemostatic factors in healthy individuals, and the risk of a first VT event, in a large VT case‐control study. MethodsAnalyses were performed in the Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) case‐control study. CETP unweighted/weighted genetic risk scores (GRSs) were derived from three single‐nucleotide polymorphisms that were identified from a recent genome‐wide association study on serum CETP concentrations. The associations between CETP GRSs and 22 hemostatic factors (procoagulant/anticoagulant and fibrinolytic factors) were assessed by linear regression from an additive model in controls (n = 2813). The associations between CETP GRSs and the risk of a first VT were assessed by logistic regression analyses in 3950 VT cases and 4765 controls. ResultsIn the controls (median age, 49 years; 53% women), both unweighted and weighted GRSs showed that factor VII activity was negatively associated with the genetically determined CETP concentration (weighted GRS β –3.08 IU/dL per μg/mL genetically determined CETP, 95% confidence interval −5.73 to −0.42). No association was observed with the risk of a first VT. ConclusionsGenetically determined CETP concentrations only showed a weak negative association with factor VII activity. However, this did not lead to an association with the risk of a first VT.

Cholesteryl ester transfer protein: the physiological and molecular characteristics in the pathogenesis of atherosclerosis and Alzheimer’s disease

Cholesteryl ester transfer protein (CETP) is involved in reverse cholesterol transport, mediates the exchange of cholesteryl esters for triglycerides between high-density lipoproteinsand low-density lipoproteins/very low-density lipoproteins. Lipid transfer mechanism by CETP is unknown. Two main models have been proposed for the mechanism of action of CETP: shuttle and tunnel mechanisms. The variants of CETP gene affect activity and level of protein, thus they are associated with lipid profile and risk of many diseases. Some clinical studies reported that polymorphisms of CETP, including TaqIB and I405V, are associated with risk of atherosclerosis and/or Alzheimer’s disease. CETP plays important role an in the metabolism of cholesterol, thus is correlated with pathomechanism of coronary artery disease. Inhibition of CETP can be an effective strategy to improve the lipid profile and reduce risk of cardiovascular diseases. Therefore, new therapeutic strategies to reduce activity of CETP or decrease its level are developed. Effectiveness of following pharmacological methods of modulation of CETP activity was studied: anti-CETP vaccines, antisense oligonucleotide and small molecule inhibitors of CETP. This article presents an overview of the literature on the correlation between cardiovascular diseases and CETP protein/CETP gene. Furthermore, it discusses the impact of CETP on pathogenesis of Alzheimer’s disease.

Cholesteryl Ester Transfer Protein Influences High-Density Lipoprotein Levels and Survival in Sepsis.

High-density lipoprotein (HDL) cholesterol (HDL-C) levels decline during sepsis, and lower levels are associated with worse survival. However, the genetic mechanisms underlying changes in HDL-C during sepsis, and whether the relationship with survival is causative, are largely unknown. We hypothesized that variation in genes involved in HDL metabolism would contribute to changes in HDL-C levels and clinical outcomes during sepsis. We performed targeted resequencing of HDL-related genes in 200 patients admitted to an emergency department with sepsis (Early Infection cohort). We examined the association of genetic variants with HDL-C levels, 28-day survival, 90-day survival, organ dysfunction, and need for vasopressor or ventilatory support. Candidate variants were further assessed in the VASST (Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock Trial) cohort (n = 632) and St. Paul's Hospital Intensive Care Unit 2 (SPHICU2) cohort (n = 203). We identified a rare missense variant in CETP (cholesteryl ester transfer protein gene; rs1800777-A) that was associated with significant reductions in HDL-C levels during sepsis. Carriers of the A allele (n = 10) had decreased survival, more organ failure, and greater need for organ support compared with noncarriers. We replicated this finding in the VASST and SPHICU2 cohorts, in which carriers of rs1800777-A (n = 35 and n = 12, respectively) had significantly reduced 28-day survival. Mendelian randomization was consistent with genetically reduced HDL levels being a causal factor for decreased sepsis survival. Our results identify CETP as a critical regulator of HDL levels and clinical outcomes during sepsis. These data point toward a critical role for HDL in sepsis.

Kiwifruit effect on adipose tissue cell size and cholesteryl ester transfer protein gene expression in high-fat diet fed Golden Syrian hamsters.

The effects of kiwifruit on the histology and cell size of adipose tissue in hyperlipidemic models have not yet been reported. Therefore, this study aimed to investigate the effect of kiwifruit on the adipose tissue cell size and activity as well as the gene expression of cholesteryl ester transfer protein (CETP) in high-fat diet (HFD) fed hamsters. Forty-two male Syrian hamsters were divided into six groups. Control normal (CN) hamsters received normal diet, control HFD (CHF) were fed with a HFD plus a normal diet (15% butter fat + 0.05% cholesterol + a normal diet). Two groups were fed with normal diet including kiwifruit (1.86; Nd.1 or 3.73 g/kg; Nd.2) and two groups were fed with HFD including kiwifruit (1.86;HFd.1or 3.73 g/kg; HFd.2), for 8 weeks. Histological examination of adipose tissue showed that the cell size was significantly reduced in the kiwifruit-treated groups (low and high dose) in comparison to their control groups (p<0.05). Kiwifruit supplementation (low and high dose) in normal and HFD groups significantly increased gene expression of CETP in adipose tissue. Kiwifruit had no significant effect on serum concentration of low-density lipoprotein cholesterol, total cholesterol and triglyceride. Although, high-density lipoprotein cholesterol concentration increased in HFD-fed hamsters supplemented with 3.73 g/kg of kiwifruit (p<0.05). Kiwifruit consumption reduces the size of adipocytes and increases the expression of CETP gene in adipose tissue cells. Despite the increases in CETP expression in adipose tissue, its activity in serum was not changed following kiwifruit supplementation.

The interaction of cholesteryl ester transfer protein gene variations and diet on changes in serum lipid profiles.

Gene-diet interactions may have an important role in the disparities between the lipid responses of individuals to diet. This study aimed to investigate whether polymorphisms (rs5882 and rs3764261) in the cholesteryl ester transfer protein (CETP) gene modify the association of diet with changes in serum lipid profiles. A total of 4700 individuals aged ≥18 years were selected from among participants of the Tehran Lipid and Glucose Study. After 3.6 years of follow-up, changes in serum lipid profiles were evaluated. Usual dietary intake was assessed using a validated food frequency questionnaire. DNA samples were genotyped with HumanOmniExpress-24-v1-0 bead chips (containing 649,932 SNP loci). No significant interaction was found between CETP polymorphisms and dietary patterns in changing lipid profiles. Mean changes of total cholesterol (TC) decreased in higher quartiles of fish intake in A allele carriers (Q1:8.02, Q4:5.58, Ptrend = 0.01) compared to the CC genotype (Q1:3.65, Q4:8.93, Ptrend = 0.11) (Pi = 0.02). There are ascending trends of changes in triglyceride (TG) concentrations across quartiles of total fat, monounsaturated and saturated fat consumption in G allele carriers of rs5882 compared to the AA genotype. There was a declining trend for mean changes in TG concentrations across quartiles of carbohydrate intake in G allele carriers of rs5882 compared to the AA genotype (Pi = 0.01). Our data demonstrated that minor allele carriers of rs5882 had a better TG value than AA homozygote individuals when consuming a low fat and high carbohydrate diet. Fish intake modifies the association of rs3764261with TC concentrations.