Ester Transfer Protein Gene Polymorphisms Research Articles

One Common Polymorphism of Cholesteryl Ester Transfer Protein Gene in Iranian Subjects With and Without Primary Hypertriglyceridemia

Primary hypertriglyceridemia is considered to be a major risk factor for pancreatitis, atherosclerosis and coronary heart disease. Cholesteryl ester transfer protein gene polymorphisms known to be associated with changes in lipid levels. This study was performed by using polymerase chain reaction and restriction fragment length polymorphisms. Genotype distribution and allelic frequencies of polymorphism were determined and compared in primary hypertriglyceridemic and normotriglyceridemic subjects. The results showed that plasma cholesteryl ester transfer protein activity was significantly higher in primary hypertriglyceridemia than in controls (p = 0.001). In this study all individuals with B2B2 genotype had lower plasma cholesteryl ester transfer protein activity, higher high-density lipoprotein than B1B1 and B1B2 genotypes, whereas triglyceride was significantly decreased in this genotype. The genotype and allelic frequencies for this polymorphism differed significantly between primary hypertriglyceridemic patients and controls (p = 0.014 and p = 0.027, respectively). In both groups, CETP Taq 1B polymorphism (presence of B2 allele) correlated significantly with HDL-C (r = 0.207 and 0.300 in control and patient groups, respectively) and CETP activity (r = -0.193 for controls and r = -0.132 for patients). Taq 1B polymorphism of cholesteryl ester transfer protein gene was associated with changes in lipids profile and plasma cholesteryl ester transfer protein activity in the selected population.

The combination of ApoCIII, hepatic lipase and hormono sensitive lipase gene polymorphisms suggests an association with susceptibility to gestational hypertension

Dyslipidemia and insulin resistance contribute to the endothelial cell dysfunction in hypertensive disorders of pregnancy (HDP) and increase the long-term risk of cardiovascular disease (CVD). The genes linking susceptibility to gestational hypertension (GH) and/or preeclampsia (PE) to the long-term risk of CVD are still unknown. We evaluated the potential association between 14 polymorphisms from six genes involved in lipid metabolism and insulin action and the risk of HDP: namely the lipoprotein lipase (LPL), hepatic lipase (LIPC), hormone sensitive lipase (LIPE), cholesteryl ester transfer protein (CETP), ApoCIII and ApoE gene polymorphisms. Overall, 169 women with HDP [proteinuria (PE) and gestational hypertension without proteinuria (GH)] and 169 controls matched for age and year of delivery were genotyped. Homozygosity of the -514T allele of the -514C > T polymorphism (LIPC gene) decreased the risk of GH (OR = 0.17, CI(95): 0.02-0.76), while there were more -60G carriers of the -60C > G LIPE gene polymorphism (OR = 3.51, CI(95):1.02-12.10) among GH cases, but not in PE cases. The common ApoCIII two-locus -482CC/3238CC genotype was lower in women with GH compared with controls (OR = 0.53, CI(95): 0.3-0.9). The combined frequency of at-risk genotypes was higher in cases of GH compared with controls [one at-risk genotype: OR = 3.38 (95% CI: 0.48-41.8); two or more at-risk genotypes: OR = 7.14 (95% CI: 1.21-92.3, P = 0.01)], suggesting a gene-dose effect. We conclude that the combined effect of LIPC, LIPE and ApoCIII gene polymorphisms may increase the likelihood of GH, but seemingly not of PE.

TaqI B1/B2 and -629A/C cholesteryl ester transfer protein (CETP) gene polymorphisms and their association with CETP activity and high-density lipoprotein cholesterol levels in a Tehranian population. Part of the Tehran Lipid and Glucose Study (TLGS)

We examined the cholesteryl ester transfer protein (CETP) gene TaqI intron 1 B1/B2 polymorphism and the -629A/C CETP promoter polymorphism in respect to high-density lipoprotein cholesterol (HDL-C) in a healthy Iranian population taken from the Tehran Lipid and Glucose Study (TLGS). The relationship between CETP activity and HDL-C level was also determined along with body mass index, blood pressure and tobacco smoking status. PCR-RFLP used to amplify a segment of the CETP intron 1 TaqI (B2/B1) polymorphism from 1021 individuals and we selected 345 individuals from the lowest, middle and highest HDL-C deciles and investigated the -629A/C polymorphism. We also evaluated the CETP activity of 103 of these individuals, each with at least one homozygous allele. The presence of the TaqI B2 and -629A/C A alleles were significantly associated with increased HDL-C levels (B2B2 = 1.19 ± 0.31 mmolL-1 vs. B1B1 = 1.01 ± 0.2 mmol L-1 for p < 0.001; AA = 1.15 ± 0.41 mmol L-1 vs. CC = 0.95 ± 0.28 mmol L-1 for p < 0.001) and decreased the CETP activity (B1B1 = 67.8 ± 8.9 pmol L-1 vs. B2B2 = 62.6 ± 9.6 pmol L-1 for p < 0.01; CC = 68.6 ± 8.4 pmol L-1 vs. AA = 62.7 ± 9.7 pmol L-1 for p < 0.002). The frequencies were 0.382 for the TaqI B2 allele and 0.462 for the -629A/C A allele, with linkage disequilibrium analysis giving D = 0.0965 and D' = 0.4695. We demonstrated that the TaqI B1 and B2 alleles and the -629A/C A and C alleles were in linkage disequilibrium in our population and that there was a significant association between the B2 and A alleles and high HDL-C levels and low CETP activity. Linkage disequilibrium between the TaqI A and B2 alleles also detected.

Cholesteryl ester transfer protein gene polymorphisms are associated with coronary artery disease in Corsican population (France)

The aim of the present study was to investigate the association between coronary artery disease (CAD) and Cholesterol Ester Transfer Protein (CETP) (gaaa)n polymorphisms of the CETP gene in Central Corsica island (France). The study group was composed by 300 unrelated Corsican patients with angiographically documented CAD and 300 unrelated healthy blood donors. Significant differences were observed in the distribution of CETP (gaaa)n alleles between the groups under study ( p = 0.03; χ 2: 16.8, df: 8). The occurrence of a long allele (408 bp) was higher in cases (12%) than in control group (2%), showing a 6.75-fold increased risk for CAD in Corsica patients ( p = 0.0055; OR = 6.750; 95% CIs = 1.47–31.00). The correlation of this polymorphism with the lipid profile (cholesterol, low density lipoprotein-cholesterol, high density lipoprotein-cholesterol and triglycerides) in the patients group was determined. There was a significant association of the long alleles of CETP (gaaa)n with HDL-C levels. In the patient and in the control groups the LL genotypes had lower HDL-C compared with the SS and SL genotypes ( p < 0.0001). In summary our results suggest that the genetic variation at the CETP gene may play an important role in determining CAD in Corsican population.

Genetic and environmental factors affecting the response to statin therapy in patients with molecularly defined familial hypercholesterolaemia

Familial hypercholesterolaemia (FH) is the most common inherited metabolic disease characterized by elevated serum levels of low-density lipoprotein cholesterol (LDL-C) and ischaemic heart disease early in life. Early diagnosis and treatment are essential to prevent premature atherosclerosis in FH patients. The aim of our study was the evaluation of the effects of genetic [class of the LDL receptor (LDLR) gene mutation, apolipoprotein (apo)E, apoA-IV and cholesterol ester transfer protein gene polymorphisms] and environmental factors (age, sex, smoking habit and body mass index) on the lipid-lowering response to statin therapy in patients with molecularly defined FH. Atorvastatin 20 mg/day was prescribed in 49 patients with heterozygous FH. The lipid profile was examined before and after 12 weeks of therapy. Statin therapy resulted in a decrease of 37% and 36% in LDL-C and apoB levels, respectively. The study population was then divided into 2 groups according to the class of the LDLR mutation [patients sharing a class V mutation (the G1775A mutation, n=21) and patients sharing class II mutations (the G1646A and the C858A mutations, n=28)]. In both groups, the percentage decrement in LDL-C and apoB levels were correlated with the initial LDL-C and apoB levels, respectively. The class of the LDLR mutation affected the LDL-C and apoB-lowering response of heterozygous FH patients to statin therapy. In detail, heterozygotes sharing a class V mutation of the LDLR showed a higher percentage decrement in LDL-C and apoB levels after atorvastatin administration compared to patients sharing class II mutations (49+/-9% versus 34+/-9%, P=0.001 for LDL-C and 42+/-16% versus 35+/-20%, P=0.001 for apoB). The influence of the classes of the LDLR gene mutations on the change of LDL-C and apoB levels to atorvastatin was still significant in a multivariate analysis. None of the other genetic and environmental factors studied affected the lipid-lowering response to atorvastatin therapy in patients with heterozygous FH in a multivariate analysis. Our data indicate that the class of the LDLR gene mutation affects the LDL-C and apoB-lowering response of heterozygous FH patients to statin therapy. Specifically, patients with a class V mutation exhibit higher percentage decrease in LDL-C and apoB levels after statin therapy compared to patients sharing class II mutations.

Relationship between gene polymorphisms and prevalence of myocardial infarction among diabetic and non-diabetic subjects

This study was aimed to examine cholesteryl ester transfer protein (CETP), apolipoprotein AI and CIII gene polymorphisms, and to verify whether these genetic determinants are associated with the prevalence of myocardial infarction (MI) or type 2 diabetes. The TaqIB restriction fragment length polymorphism (RFLP) in intron I of the CETP gene, the MspI in the third intron of the APOAI gene, and also SstI in the 3′ untranslated region of the APOCIII gene were determined using standard methods. The prevalence of these polymorphisms was compared between diabetic ( n = 119), and non-diabetic ( n = 100) middle-aged individuals of both sexes. We found a higher prevalence of the B2B2 genotype of the CETP gene among diabetics than that observed in non-diabetics ( P < 0.05), and a lower prevalence of this genotype among patients with previous MI ( P < 0.02). The MspI polymorphisms of the APOAI gene showed that M1++ genotype was found mainly in diabetic patients ( P < 0.04). Conversely, the SstI polymorphism of APOCIII gene was not significantly associated with either MI or diabetes. Therefore, among these genetic polymorphisms, TaqIB of CETP and MspI of apolipoprotein AI appeared to help significantly to identify diabetic individuals. In particular, the former may have an additional role in the primary prevention of coronary disease.

Association of Cholesteryl Ester Transfer Protein Gene Polymorphism with Serum Lipid Concentration and Coronary Artery Disease in Korean Men

Background and Objectives:Cholesteryl ester transfer protein (CETP) plays a key role in the reverse cholesterol transport pathway. The purpose of this study was to investigate the association of CETP gene polymorphism with the plasma lipid levels and coronary artery disease (CAD) in Korean men. Subjects and Methods:Two hundred and sixteen healthy control subjects (46.8±10.6 y) and 95 patients with CAD (58.2±8.8 y) were examined. The genotypes of C-629A, Taq1B and I405V were determined by the SNP-IT assay. Results:The allele frequencies of the C:A in the C-629A, B1:B2 in the Taq1B and I:V in the I405V in the control group were 0.51:0.49, 0.63:0.37 and 0.55:0.45, respectively. The genotype distributions of the C-629 A and Taq1B polymorphisms in the CAD patients did not differ from those in the control group. No variation in the CETP genotype was associated with disease progression in the CAD group. The HDL cholesterol in -629A homozygous and Taq1B B2 homozygous were higher than those of the other genotypes. The Taq1B B2 carrier was an independent determinant for HDL cholesterol in the control group. However, I405V polymorphism was not associated with HDL cholesterol. The V allele in the I405V polymorphism was associated with reduced CAD events after controlling the age, BMI and other risk factors (OR:0.4, p<0.01). Conclusion:The frequencies of Taq1B and C-629A variants between the healthy and CAD groups did not differ. The B2 carrier in the Taq1B polymorphism was associated with a higher HDL cholesterol concentration. The V variation in the I405V polymorphism had a protective effect against the development of CAD in Korean men. (Korean Circulation J 2004;34(6):565-573)

A polymorphism of the cholesteryl ester transfer protein gene predicts cardiovascular events in non-smokers in the West of Scotland Coronary Prevention Study.

The association of cholesteryl ester transfer protein (CETP) gene polymorphisms with risk of a cardiovascular event and whether any association was explained by an influence on high-density lipoprotein (HDL) levels or low-density lipoprotein (LDL) size was tested in the West of Scotland Coronary Prevention Study (WOSCOPS). Gene-smoking and gene-treatment interactions were investigated. Cases (n=498) and controls (n=1108) were typed for TaqIB, C(-631)A, C(-629)A, I405V and D442G CETP polymorphisms. Homozygotes for the TaqIB2 allele (B2B2) had a 30% reduced risk of a cardiovascular event (odds ratio [OR] 0.70, CI(95)0.51-0.96, P=0.03) compared to B1B1 homozygotes. Inclusion of HDL or LDL diameter in multivariate analysis only marginally attenuated the relationships. Non-smokers, but not smokers, showed a dose-dependent association of risk with TaqIB genotype. Treatment benefit was not significantly different in B1B1 (OR 0.71, pravastatin vs placebo), B1B2 (OR 0.68) and B2B2 (OR 0.61) individuals. The other CETP polymorphisms studied had no significant association with cardiovascular risk. Haplotype analysis did not add to the information given by the individual polymorphisms. The association between CETP TaqIB genotype and cardiovascular risk is primarily in non-smokers, is not fully explained by effects on HDL levels or LDL size, and the benefit of pravastatin treatment was not influenced by this polymorphism.

Relationship Between TaqIB Cholesteryl Ester Transfer Protein Gene Polymorphism and Macrovascular Complications in Japanese Patients With Type 2 Diabetes

Cholesteryl ester transfer protein (CETP) is a key regulating factor of lipid metabolism, and the polymorphism of its gene may therefore be a candidate for modulating the lipid parameters, altering the susceptibility to atherosclerosis in type 2 diabetic subjects. In a group of 443 unrelated Japanese patients with type 2 diabetes, we studied the B1B2 polymorphism at the CETP locus, which is detectable with the restriction enzyme TaqI. Patients were separated into three groups according to genotype and compared based on their clinical characteristics, lipid parameters, and macrovascular complications. The B2 allele was associated in a dose-dependent fashion with higher HDL cholesterol and apolipoprotein AI levels, together with lower CETP concentrations. Furthermore, the prevalence of macrovascular complications, such as coronary heart disease, arteriosclerosis obliterans, and cerebral vascular disease, was significantly higher in subjects with the B1B1 genotype. Multiple logistic regression analysis also showed that the B1 allele of CETP genotype was associated with the incidence of these three complications independently of other risk factors. Thus, in type 2 diabetic patients, the B1B2 polymorphism of CETP gene is likely to be a strong genetic predictor of macrovascular complications.

Cholesteryl ester transfer protein gene polymorphism and coronary heart disease

Cholesteryl ester transfer protein gene polymorphism and coronary heart disease

HDL Cholesterol and TaqIB Cholesteryl Ester Transfer Protein Gene Polymorphism in Renal Transplant Recipients

Decreased serum levels of high-density lipoprotein cholesterol (HDL-C) are a well-known risk factor for coronary heart disease (CHD) in the general population and have been suggested as one of the best predictor of CHD after renal transplantation. However, very heterogeneous HDL-C levels have been reported in renal transplant recipients. In this patient population, serum HDL-C levels are determined by complex interactions between hormonal, environmental (such as a high amount of abdominal adipose tissue), and genetic factors and drugs (particularly glucocorticoids). We, therefore, evaluated the effects of the cholesteryl ester transfer protein (CETP) gene TaqIB polymorphism as well as of abdominal obesity on HDL-C levels in 78 male renal transplant recipients who were receiving azathioprine and/or ciclosporin A in combination with prednisone as immunosuppression. The patients were classified into genotypic groups according to the presence or absence of the restriction site (B1 allele or B2 allele, respectively). The distribution of CETP genotypes was similar to that previously described in the general population. Overall, HDL-C levels were 19 and 26% higher in B1B2 and B2B2 patients as compared with B1B1 homozygotes (p < 0.05), even after control for other lipid measurements. Patients with abdominal obesity (waist girth ≧93 cm) showed reduced HDL-C levels as compared with lean (waist girth <93 cm) patients (1.20 ± 0.28 vs. 1.42 ± 0.41 mmol/l, respectively, p < 0.01). Moreover, the HDL-C levels were markedly affected by the CETP TaqIB polymorphism in lean patients (+28 and +41% in B1B2 and B2B2 as compared with B1B1 patients, p < 0.05), but no significant difference was observed among obese patients. Significantly lower total cholesterol:HDL-C ratios were obtained in lean B2B2 homozygotes, suggesting that these patients could be less susceptible to atherosclerosis than lean B1B1 homozygotes. In addition, patients with the B1B1 genotype had more documented CHD as compared with patients carrying at least one B2 allele, supporting the protective effect of the B2 allele against CHD. In conclusion, considerable variation in HDL-C levels appears to be explained by the CETP TaqIB gene polymorphism in male renal transplant recipients, but this potential protective gene effect appears strongly reduced by concomitant abdominal obesity.

Cholesteryl ester transfer protein gene polymorphisms are associated with carotid atherosclerosis in men.

The cholesteryl ester transfer protein (CETP) is involved in the reverse cholesterol transport and is therefore a candidate gene for atherosclerosis. The prevalences of the I405V and the R451Q polymorphisms were studied in a population sample of 515 men and women. Genotypes were determined by PCR and carotid atherosclerosis by ultrasonography as the mean intima-media thickness (IMT) of the carotid arteries. The Q451 allele was associated with significantly lower intima media thickness in men (P = 0.001). The Q451 allele was, in our earlier study, associated with high plasma CETP activity in men. The VV405 genotype was associated with lower plasma CETP activity compared with the II405 genotype (P < 0.01 for the difference). In the general linear model general factorial procedure the interaction between alcohol consumption and the I405V genotype on IMT was significant (P = 0.013) in men, and when the interaction term was taken into the model the I405V genotype also significantly affected IMT (P = 0.008). The VV405 genotype seems to be most harmful for men with the highest alcohol consumption. We describe two polymorphisms of the CETP gene associated with intima media thickness in men. A significant interaction was found between alcohol consumption and the I405V genotype on IMT.

Influence of insulin sensitivity and the TaqIB cholesteryl ester transfer protein gene polymorphism on plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities and their response to hyperinsulinemia in non-diabetic men

Lecithin:cholesteryl acyl transferase (LCAT), cholesteryl ester transfer protein (CETP), phospholipid transfer protein (PLTP), and lipoprotein lipases are involved in high density lipoprotein (HDL) metabolism. We evaluated the influence of insulin sensitivity and of the TaqIB CETP gene polymorphism (B1B2) on plasma LCAT, CETP, and PLTP activities (measured with exogenous substrates) and their responses to hyperinsulinemia. Thirty-two non-diabetic men without hyperlipidemia were divided in quartiles of high (Q1) to low (Q4) insulin sensitivity. Plasma total cholesterol, very low + low density lipoprotein cholesterol, triglycerides, and apolipoprotein (apo) B were higher in Q4 compared to Q1 (P < 0.05 for all), whereas HDL cholesterol and apoA-I were lowest in Q4 (P < 0.05 for both). Plasma LCAT activity was higher in Q4 than in Q1 (P < 0.05) and PLTP activity was higher in Q4 than in Q2 (P < 0.05). Insulin sensitivity did not influence plasma CETP activity. Postheparin plasma lipoprotein lipase activity was highest and hepatic lipase activity was lowest in Q1. Insulin infusion decreased PLTP activity (P < 0.05), irrespective of the degree of insulin sensitivity. The CETP genotype exerted no consistent effects on baseline plasma lipoproteins and LCAT, CETP, and PLTP activities. The decrease in plasma PLTP activity after insulin was larger in B1B1 than in B2B2 homozygotes (P < 0.05).▪These data suggest that insulin sensitivity influences plasma LCAT, PLTP, lipoprotein lipase, and hepatic lipase activities in men. As PLTP, LCAT, and hepatic lipase may enhance reverse cholesterol transport, it is tempting to speculate that high levels of these factors in association with insulin resistance could be involved in an antiatherogenic mechanism. A possible relationship between the CETP genotype and PLTP lowering by insulin warrants further study.—Riemens, S. C., A. Van Tol, B. K. Stulp, and R. P. F. Dullaart. Influence of insulin sensitivity and the TaqIB cholesteryl ester transfer protein gene polymorphism on plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities and their response to hyperinsulinemia in non-diabetic men. J. Lipid Res. 1999. 40: 1467–1474.

High-density lipoprotein cholesterol is related to the TaqIB cholesteryl ester transfer protein gene polymorphism and smoking, but not to moderate alcohol consumption in insulin-dependent diabetic men

In non-diabetic subjects, the high-density lipoprotein (HDL) cholesterol level is increased by alcohol and decreased by smoking. The biallelic B1B2 polymorphism of the cholesteryl ester transfer protein (CETP) gene is a genetic determinant of HDL cholesterol. We evaluated the effect of moderate alcohol consumption, the CETP gene polymorphism and clinical variables on HDL cholesterol and other lipoprotein parameters in insulin-dependent diabetic (IDDM) men. Thirteen moderate alcohol using IDDM men (median alcohol consumption 17 g/d) and 13 abstainers, individually matched for the CETP gene polymorphism and clinical factors including smoking, were studied. HDL cholesterol, serum apo AI and serum CETP activity levels were very similar in alcohol users compared to abstainers (1.36 +/- 0.28 vs 1.36 +/- 0.36 mmol l-1, 1.71 +/- 0.31 vs 1.75 +/- 0.33 g l-1 and 134 +/- 27 vs 138 +/- 53 nmol l-1h-1, respectively, n.s. for all). No significant differences in apo B-containing lipoproteins were observed. Multiple regression analysis (multiple r = 0.68) showed that HDL cholesterol was positively associated with the presence of the B2 allele (0.23 mmol l-1 higher for each B2 allele present, p = 0.004) and negatively with smoking (0.15 mmol l-1 lower per 10 cigarettes smoked daily, p = 0.011), but not with alcohol consumption (p = 0.66). This study suggests that moderate alcohol consumption has no beneficial effect on the lipoprotein profile in IDDM men. HDL cholesterol is adversely influenced by smoking, whereas considerable variation in its level appears to be explained by the CETP gene polymorphism.

Cholesteryl ester transfer protein gene polymorphism is a determinant of HDL cholesterol and of the lipoprotein response to a lipid-lowering diet in type 1 diabetes

Cholesteryl ester transfer protein gene polymorphism is a determinant of HDL cholesterol and of the lipoprotein response to a lipid-lowering diet in type 1 diabetes