Genetic variation in cholesterol ester transfer protein, serum CETP activity, and coronary artery disease risk in Asian Indian diabetic cohort.
ABSTRACT: The role of cholesteryl ester transfer protein (CETP) in the metabolism of high-density lipoprotein cholesterol (HDL-C) is well studied but still controversial. More recently, genome-wide association studies and meta-analyses reported the association of a promoter variant (rs3764261) with HDL-C in Caucasians and other ethnic groups. In this study, we have examined the role of genetic variation in the promoter region of CETP with HDL-C, CETP activity, coronary artery disease (CAD), CAD risk factors, and the interaction of genetic factors with environment in a unique diabetic cohort of Asian Indian Sikhs.We genotyped four variants; three tagging single nucleotide polymorphisms from promoter (rs3764261, rs12447924, rs4783961) and one intronic variant (rs708272 Taq1B) on 2431 individuals from the Sikh Diabetes study. Two variants (rs3764261 and rs708272) exhibited a strong association with HDL-C in both normoglycemic controls (?=0.12; P=9.35×10 for rs3764261; ?=0.10, P=0.002 for rs708272) and diabetic cases (?=0.07, P=0.016 for rs3764261; ?=0.08, P=0.005 for rs708272) with increased levels among minor homozygous 'AA' carriers. In addition, the same 'A' allele carriers in rs3764261 showed a significant decrease in systolic blood pressure (?=-0.08, P=0.002) in normoglycemic controls. Haplotype analysis of rs3764261, rs12447924, rs4783961, and rs708272 further revealed a significant association of 'ATAA' haplotype with an increased HDL-C (?=2.71, P=6.38×10) and 'CTAG' haplotype with decreased HDL-C levels (?=-1.78, P=2.5×10). Although there was no direct association of CETP activity and CETP polymorphisms, low CETP activity was associated with an increased risk to CAD (age, BMI, and sex-adjusted odds ratio=2.2; 95% confidence interval: 1.4-3.4; P=0.001) in this study. Our data revealed a strong interaction of rs3764261 and rs708272 for affecting the association between CETP activity and HDL-C levels (P=2.2×10 and P=4.4×10, respectively).Our results, in conjunction with earlier reports confirm low CETP activity to be associated with higher CAD risk. Although there was no direct association of CETP activity with CETP polymorphisms, our findings revealed a significant interaction between CETP variants and CETP activity for affecting HDL-C levels. These results urge a deeper evaluation of the individual genetic variation in the CETP before implementing pharmaceutical intervention of blocking CETP for preventing CAD events.
Project description:<h4>Objective</h4>Patients treated with statins for dyslipidemia may still have a residual risk of atherosclerotic cardiovascular disease (ASCVD). To determine whether genetic variants in the cholesteryl ester transport protein (CETP), rs3764261 (C>A), rs708272 (G>A), and rs12149545 (G>A) affect ASCVD risk, we studied the association of these variants with dyslipidemia in statin-treated patients.<h4>Patients and methods</h4>We included 299 adult Thai patients treated with a statin (95 men and 204 women). Genotyping was performed by conducting a TaqMan real-time polymerase chain reaction-based analysis. We used logistic regression models adjusted for potential confounders of age, body mass index, blood pressure, insulin resistance, and statin dosage to analyze the association between <i>CETP</i> variants and atherogenic lipoprotein patterns.<h4>Results</h4><i>CETP</i> polymorphisms of rs3764261 and rs708272, but not rs12149545, were significantly associated with high-density lipoprotein cholesterol (HDL-C), apoA-I, triglycerides, very low-density lipoprotein (VLDL)-C, and large LDL (LDL1-C) levels as well as mean LDL particle size (all <i>p</i> < 0.020). However, no significant difference was observed in total cholesterol, LDL-C, or apoB levels by <i>CETP</i> variants. Regardless of sex, the combination of rs3764261 (CC genotype) and rs708272 (GG or GA genotypes) showed a stronger association with atherogenic dyslipidemia, including features of decreased HDL-C, elevated triglycerides, and LDL subclass pattern B (odds ratio [OR]?=?2.99, 95% confidence interval [CI]: 1.78-5.02) compared with the single variant rs3764261 (OR?=?2.11, 95% CI: 1.27-3.50) or rs708272 (OR?=?2.12, 95% CI: 1.29-3.49).<h4>Conclusion</h4>The polymorphisms of <i>CETP</i> rs3764261 (CC genotype) and rs708272 (GG and GA genotypes) may have a higher susceptibility to atherogenic dyslipidemia. Testing for <i>CETP</i> rs3764261 and rs708272 may serve as a surrogate marker for lipid management in statin-treated patients, which may help individualize treatment for reducing the residual risk of ASCVD.
Project description:To explore the association between CETP gene polymorphisms and metabolic syndrome (MS), as well as the relationship between the CETP gene polymorphisms and each component of MS.A total of 571 individuals which were randomly selected from 5692 Uyghur adults were subdivided into two groups, including 280 patients with MS and 291 control subjects, using the group-matching method after matching for gender. We detected CETP polymorphisms (rs5882, rs1800775, rs3764261, rs12149545, rs711752, and rs708272) by using the Snapshot method.(1) Significant differences were found involving the frequency distribution of genotypes and alleles of rs1800775, rs3764261, rs12149545, rs711752, and rs708272 between the control and MS groups (all p < 0.05). (2) rs1800775, rs3764261, rs12149545, rs711752, and rs708272 polymorphisms were significantly related to the risk of MS (all p < 0.05). (3) The rs1800775 polymorphism was associated with high fasting blood glucose levels and low high density lipoprotein cholesterol (HDL-C); rs3764261 and rs12149545 polymorphisms were associated with all components of MS except high blood pressure; rs711752 and rs708272 polymorphisms were associated with low HDL-C (all p < 0.05). (4) Complete linkage disequilibrium (LD) was identified for two pairs of single nucleotide polymorphisms (SNPs) (rs3764261 and rs12149545 (D' = 1.000, r² = 0.931), rs711752 and rs708272 (D' = 1.000, r² = 0.996)). (5) The A-G-G-G-C (p = 0.013, odds ratio [OR] = 0.622, 95% confidence interval [95% CI] = 0.427-0.906) and A-T-A-A-T (p < 0.001, OR = 0.519, 95% CI = 0.386-0.697) haplotypes were more frequent in the control group than in the case group. Conclusions: The rs1800775, rs3764261, rs12149545, rs711752, and rs708272 polymorphisms of CETP were associated with MS and its components among the Uyghur ethnic group. Complete LD was found between two pairs of SNPs (rs3764261 and rs12149545, rs711752, and rs708272). The A-G-G-G-C and A-T-A-A-T haplotypes might be protective factors for MS.
Project description:We have investigated the relationship between the polymorphisms and haplotypes in the CETP gene, and dyslipidemia among the Xinjiang Kazak and Uyghur populations in China. A total of 712 patients with dyslipidemia and 764 control subjects of CETP gene polymorphism at rs12149545, rs3764261, rs1800775, rs711752, rs708272, rs289714, rs5882, and rs1801706 loci were studied by the Snapshot method, linkage disequilibrium analysis and haplotype construction. The results are as follows: (1) the minor allele of eight loci of frequencies in the two groups were different from other results of similar studies in other countries; (2) In the linear regression analysis, the HDL-C levels of rs708272 TT, rs1800775 AA, rs289714 CC and rs711752 AA genotypes were significantly higher than those of other genotypes, however, the rs3764261 GG and rs12149545 GG genotypes were significantly lower than those of other genotypes in the two ethnic groups. The HDL-C levels of the rs12149545 GG genotype were lower than those of other genotypes; (3) in the control group, the rs708272 CT genotype of TG levels were lower than in the CC genotype, the T genotype of LDL-C levels were lower than in the CC genotype, and the HDL-C levels were higher than in the CT genotype; the rs1800775 AC genotype of TG levels were higher than in the AA genotype, the rs711752 AG genotype of TG levels were lower than in the GG genotype, the AA genotype LDL-C levels were lower than in the GG genotype, and the HDL-C levels were higher than in the AG genotype; the rs1800775 AC genotype of TG levels were higher than in the AA genotype. In the dyslipidemia group, the rs708272 TT genotype of TC and LDL-C levels were higher than in the CT genotype and the rs3764261 TT genotype of TC levels were higher than in the GG genotype. The rs711752 AA genotype of TC and LDL-C levels were higher than in the AG genotype, and the rs12149545 AA genotype of TC and LDL-C levels were higher than in the GG genotype; (4) perfect Linkage Disequilibrium was observed for two sets of two SNPs: rs3764261 and rs12149545; rs711752 and rs708272. (5) Using SHEsis software analysis, the five A/T/A/A/T/C/A/G, A/T/A/A/T/T/G/A, G/G/A/G/C/C/G/G, G/G/C/G/C/C/A/G and G/G/C/G/C/T/G/G haplotypes were between dyslipidemia group and control group statistically significantly different (p < 0.05 in each case). The polymorphism of CETP genes rs708272, rs3764261, rs1800775, rs711752, rs12149545 was closely related to the dyslipidemia in the Xinjiang Uyghur and Kazakh ethnic groups; and the rs708272 T, rs3764261 T, rs711752 A, and rs12149545 A alleles could reduce risk of dyslipidemia in the Uyghur and Kazakh populations, however, the rs1800775 C allele showed risk factors.
Project description:Metabolic syndrome (MetS) which is caused by obesity and insulin resistance, is well known for its predictive capability for the risk of type 2 diabetes mellitus and cardiovascular disease. The development of MetS is associated with multiple genetic factors, environmental factors and lifestyle. We performed a genome-wide association study to identify single-nucleotide polymorphism (SNP) related to MetS in large Korean population based samples of 1,362 subjects with MetS and 6,061 controls using the Axiom® Korean Biobank Array 1.0. We replicated the data in another sample including 502 subjects with MetS and 1,751 controls. After adjusting for age and sex, rs662799 located in the APOA5 gene were significantly associated with MetS. 15 SNPs in GCKR, C2orf16, APOA5, ZPR1, and BUD13 were associated with high triglyceride (TG). 14 SNPs in APOA5, ALDH1A2, LIPC, HERPUD1, and CETP, and 2 SNPs in MTNR1B were associated with low high density lipoprotein cholesterol (HDL-C) and high fasting blood glucose respectively. Among these SNPs, 6 TG SNPs: rs1260326, rs1260333, rs1919127, rs964184, rs2075295 and rs1558861 and 11 HDL-C SNPs: rs4775041, rs10468017, rs1800588, rs72786786, rs173539, rs247616, rs247617, rs3764261, rs4783961, rs708272, and rs7499892 were first discovered in Koreans. Additional research is needed to confirm these 17 novel SNPs in Korean population.
Project description:Numerous studies have shown a relationship between cholesteryl ester transfer protein (CETP) polymorphism in the synthesis of high-density lipoprotein cholesterol (HDL-C) and the coronary artery disease (CAD) susceptibility, but the results have remained inconsistent. In addition, there was no study exploring the relationship between CETP polymorphisms and atherogenic index of plasma (AIP) levels.We conducted a case-control study to evaluate the relationship between CETP rs708272 polymorphism and CAD risk and lipid levels in Chinese Han population. 556 CAD patients and 414 controls undergoing coronary angiography were consecutively enrolled in the hospital-based study. Polymerase chain reaction-ligase detection reaction (PCR-LDR) method was used to detect the different genotypes at rs708272.No significant association between CETP rs708272 polymorphism and CAD risk was observed in different genetic models. In the whole population, participants with TT genotype had higher HDL-C levels (1.17 ± 0.31 mmol/L vs 1.09 ± 0.29 mmol/L, P = .001) and lower AIP levels (0.08 ± 0.35 vs 0.16 ± 0.31, P = .004) compared to those with CC genotype, after adjusting for age, gender, smoking, essential hypertension (EH), and DM. The T allele carriers had higher HDL-C levels than the T allele non-carriers (1.13 ± 0.29 mmol/L vs 1.09 ± 0.29 mmol/L, P = .023). Furthermore, subgroup analyses based on gender were carried out. In males, the results showed that participants with TT genotype had significant higher HDL-C levels and lower AIP levels compared with CC genotype (P <.05). In addition, males with CT+TT genotypes had higher HDL-C levels and lower AIP levels than those with CC genotypes (HDL-C: CT+TT 1.11 ± 0.31vs CC 1.06 ± 0.30 mmol/L, P = .041; AIP: CT+TT 0.12 ± 0.32vs CC 0.16 ± 0.31, P = .034, respectively). However, there were no significant associations between lipid levels and CETP rs708272 polymorphism in females, after adjusting for confounders.CETP rs708272 polymorphism has a gender-specific effect on lipid and AIP levels but not on the risk of CAD.
Project description: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.
Project description:The heritability of high-density lipoprotein cholesterol (HDL-C) level is estimated at approximately 50%. Recent genome-wide association studies have identified genes involved in regulation of high-density lipoprotein cholesterol (HDL-C) levels. The precise genetic profile determining heritability of HDL-C however are far from complete and there is substantial room for further characterization of genetic profiles influencing blood lipid levels. Here we report an association study comparing the distribution of 139 SNPs from more than 30 genes between groups that represent extreme ends of HDL-C distribution. We genotyped 704 individuals that were selected from Genome Database of Latvian Population. 10 SNPs from CETP gene showed convincing association with low HDL-C levels (rs1800775, rs3764261, rs173539, rs9939224, rs711752, rs708272, rs7203984, rs7205804, rs11076175 and rs9929488) while 34 SNPs from 10 genes were nominally associated (p<0.05) with HDL-C levels. We have also identified haplotypes from CETP with distinct effects on determination of HDL-C levels. Our conclusion: So far the SNPs in CETP gene are identified as the most common genetic factor influencing HDL-C levels in the representative sample from Latvian population.
Project description:BACKGROUND: Coronary atherosclerosis, the most common form of coronary artery disease (CAD), is characterized by accumulation of lipid in the walls of coronary arteries. Recent data from clinical trials have showed that high-density lipoprotein cholesterol (HDL-C) has causal role in the pathogenesis and development of coronary atherosclerosis. Cholesteryl ester transfer protein (CETP) is an important regulator of plasma HDL-C. Several genetic mutations in the CETP gene were found to be associated with HDL-C levels. The aim of the present study is to evaluate the association of HDL-C-related CETP polymorphisms and risk of coronary atherosclerosis. METHODS: We investigated the association of seven single nucleotide polymorphisms (SNP) (rs1800775, rs708272, rs5882, rs1532624, rs1864163, rs7499892, and rs9989419) in the CETP gene with the risk of coronary atherosclerosis and levels of HDL-C in a case-control study in China. Included in the study were 420 patients with coronary atherosclerosis and 424 healthy controls. SNP genotyping was performed by TaqMan allelic discrimination assay and serum lipid levels were measured by standard laboratory methods. RESULTS: Carriers of the AA and GA?+?AA genotypes of rs708272 had significant lower risks of coronary atherosclerosis (OR?=?0.55, 95% CI: 0.36-0.85, p?=?0.003; OR?=?0.67, 95% CI: 0.50-0.90, p?=?0.007, respectively) compared to those with GG genotype. These relations remained significant after adjustment for confounding effects of age, smoking, diabetes and hypertension. The rs1800775 polymorphism was significantly associated with serum levels of HDL-C in healthy controls (p?=?0.04). Besides, rs708272 was in close linkage disequilibrium (LD) with rs1800775 in this study. CONCLUSIONS: Our findings indicated that CETP rs708272 may be associated with the risk of coronary atherosclerosis and rs1800775 may influence serum HDL-C levels in healthy controls in Chinese.
Project description:BACKGROUND:Individuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans. METHODS:We performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing. RESULTS:The meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (?unadjusted=3.179?mg/dl (P value=5.25×10-509), ?adjusted=0.859?mg/dl (P value=9.51×10-25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261. CONCLUSIONS:The causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C.
Project description:BACKGROUND:Coronary artery disease (CAD) is a complex disease resulting from the cumulative and interactive effects of large number of genes along with environmental exposure. Therefore, the present study was envisaged as an effort to study the association of candidate genes ESR1 (rs2234693 and rs9340799), CETP (rs708272), MTHFR (rs1801133 and rs2274976) and MS (rs185087) polymorphisms with the risk of CAD, targeting the populations of Jammu (JandK). METHOD:A total of 400 confirmed CAD patients and 400 healthy controls were enrolled for the present study. Genotyping was done by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP). RESULTS:ESR1 gene (rs9340799) polymorphism was found to be associated with CAD in all the genetic models. The haplotype analysis of ESR1 (rs2234693 and rs9340799) gene revealed that C-G haplotype was conferring approximately 5-fold risk and T-A haplotype was adding 1.4-fold risk towards the disease. 'T' allele of MTHFR rs1801133 SNP was observed to be responsible for development of CAD in our study population (p?<?0.0001). In case of MTHFR (rs1801133 and rs2274976) gene, the haplotype T-G was observed to confer 4.7-fold risk towards CAD whereas haplotype C-G provided nearly a 1.7 fold protection towards development of CAD. For MS gene, rs185087 was also found to be associated with CAD in a co-dominant (p =?0.003 and p =?0.03), dominant (p =?0.001) and allelic models (p?=?0.001). The gene-gene interaction revealed strong epistasis between single nucleotide polymorphisms (SNPs), ESR1 rs9340799 and MTHFR rs2274976. Furthermore, the dendrogram for gene-environment dataset indicated moderately synergistic interaction between CETP rs708272 and physical inactivity. CONCLUSION:In the study under reference, a significant association of ESR1-XbaI (rs9340799), MTHFR C677T (rs1801133) and MS A2756G (rs185087) gene polymorphisms with the susceptibility of CAD in the population of Jammu region (JandK) has been observed.