Common variants of Cholesteryl ester transfer protein gene and their association with lipid parameters in healthy volunteers of Tamilian population

BACKGROUND: Cholesteryl ester transfer protein (CETP) is involved in a key pathway of reverse cholesterol transport implicated in atherosclerosis and coronary heart disease. CETP gene is known to have many single nucleotide polymorphisms which have been associated with CETP activity and plasma high density lipoprotein cholesterol (HDL-C) concentrations. No data on the prevalence of these polymorphisms and their phenotypic association is available in South Indian population. METHODS: Three CETP polymorphisms: TaqIB, -629C/A and I405V were studied in 171 healthy volunteers from Tamilnadu, a major population of South India. Subjects were clinically examined and lipid profile was estimated. Genotyping was performed by PCR-RFLP and genotype frequencies estimated. RESULTS: The allele frequencies of TaqIB: B1 allele was 0.51; -629C/A: C allele was 0.36; and that of I405V: I allele was 0.47. Study of association between these three polymorphisms and plasma lipid concentrations revealed no significant differences in lipid parameters between genotypes. A gender based subgroup analysis revealed a significant increase in HDL-C in men with B2B2 genotype and decrease in TG in B1B2 genotype. Analysis of the combined effect of multiple mutant genotypes revealed that as the number of mutant genotypes increased, the concentrations of low density lipoprotein-cholesterol (LDL-C), HDL-C and total cholesterol (TC) increased whereas that of triglyceride (TG) decreased in the group of three mutant genotypes significantly. CONCLUSION: The frequency of B2 and A alleles of TaqIB and -629C/A polymorphisms were highest in Tamilian population when compared to other major ethnic groups while that of V allele of I405V polymorphism is between Caucasians and African Americans. Taq1B polymorphism was associated with HDL-C and TG concentrations only in men. Combination of these three polymorphisms was significantly associated with lipid profile than the individual polymorphisms.     

Gender-related effect of apo E polymorphism on lipoprotein particle sizes in the middle-aged subjects

OBJECTIVES: We determined the frequencies of apolipoprotein E (apo E) alleles and examined the effect of apo E polymorphism on lipoprotein particle sizes in Serbian healthy, middle-aged individuals. DESIGN AND METHODS: We performed apo E phenotype by immunobloting method in 183 men and 143 women (mean years: 56.3+/-10.60 and 54.9+/-10.31, respectively). Plasma lipid and apolipoprotein levels were measured by routine laboratory methods. LDL and HDL particle sizes were determined by nondenaturing polyacrylamide gradient (3-31%) gel electrophoresis. RESULTS: The apo E allele frequencies were epsilon2--4.9%, epsilon3--86.5%, and epsilon4--8.6%. Men with epsilon4 allele had lower HDL-C and Apo AI concentrations than epsilon3 men. The epsilon2 allele men had the smallest LDL particles, highest percent of subjects with LDL phenotype B and highest TG/HDL-C ratio. Women with epsilon2 allele had lowest concentration of apo B. The epsilon4 allele women had smallest HDL particles and highest percent of the subjects with small-sized HDL phenotype. CONCLUSIONS: This study showed gender-related effect of apo E polymorphism on lipoprotein particle size. In men, possession of the epsilon2 allele is associated with small LDL particles, whereas in women, epsilon4 allele is associated with small HDL particles. Differences in gender-related influence of apo E polymorphism on LDL and HDL particle sizes could be clinically useful in strategy for reduction of coronary disease risk in middle-aged men and women.     

Influence of apolipoprotein E polymorphism on serum lipid and lipoprotein changes: a 21-year follow-up study from childhood to adulthood. The Cardiovascular Risk in Young Finns Study.

BACKGROUND: We examined the influence of apolipoprotein E (apoE) polymorphism on longitudinal changes in serum lipids by following the subjects participating in The Cardiovascular Risk in Young Finns Study over a 21-year period. METHODS: Serum lipids were determined in randomly selected Finnish children and adolescents in 1980 and the subjects were re-examined in 1983, 1986 and after 21 years in 2001. ApoE polymorphism was determined in 1736 participants, and serum lipid values and apoE phenotypes were available for 1233 subjects. RESULTS: ApoE phenotype-related differences in serum total and low-density lipoprotein (LDL)-cholesterol were maintained throughout the 21-year follow-up from childhood to adulthood, i.e., the apoE epsilon2 allele was consistently associated with lower and the epsilon4 allele with higher total and LDL-cholesterol (p<0.001 for all). In adulthood, there was also a significant apoE phenotype-related difference in high-density lipoprotein (HDL)-cholesterol (p=0.007), and the epsilon2 allele was associated with higher and the epsilon4 allele with lower apoA-I and HDL-cholesterol. In addition, apoB increased in the phenotype order E3/2相似文献   

Association between the cholesteryl ester transfer protein TaqI-detectable B polymorphism and low high-density lipoprotein cholesterol concentration in Saudis

Plasma concentrations of HDL (high-density lipoprotein) cholesterol are low in the Saudi Arabian population. A B polymorphism at the CETP (cholesteryl ester protein transfer) locus that is detectable with the restriction enzyme Taq I is a genetic determinant of the plasma HDL cholesterol concentration. We assessed the relationship between the Taq I B CETP polymorphism and lipid and apolipoprotein concentrations in a study sample of 335 Saudi residents. The Taq I B1 and B2 allele frequencies were 0.54 and 0.46 respectively, similar to those in other populations. HDL cholesterol levels in B2B2 homozygotes were significantly higher than in B1B1 homozygotes [1.01 (0.3) compared with 0.92 (0.2) mmol/l; mean (S.D.); P=0.03]. There was also a significant difference between the B2B2 and B1B1 homozygotes with regard to apolipoprotein AI concentration [123.6 (16.4) compared with 113.7 (13.9) mg/dl; P=0.04]. This genetic variation was independent of metabolic risk factors known to influence HDL cholesterol levels. The allele frequency of the Taq I B CETP polymorphism and its relatively modest impact on HDL cholesterol concentrations argue against an important role for this allele, or for strongly linked loci, in determining the low levels of HDL cholesterol seen in the Saudi population.     

载脂蛋白E及胆固醇酯转运蛋白基因多态性与冠心病的相关研究

目的探讨载脂蛋白E（ApoE）基因多态性和胆固醇酯转运蛋白（CETP）基因多态性与冠心病发生风险的关系以及二者有无交互作用。方法筛选冠心病患者121例及非冠心病者107例为研究对象,应用聚合酶链反应限制片长多态性分析方法检测ApoE基因多态性和CETP基因多态性。结果冠心病组ApoE4等位基因频率（10.7%）显著高于对照组（4.7%,P〈0.05）;CETP基因型频率在两组间差异无统计学意义（P〉0.05）。ApoE4是冠心病的独立危险因素（OR=2.502,95%CI1.017-6.156,P=0.046）。CETP基因型及其与ApoE的交互作用与冠心病发生风险无显著性关系（P〉0.05）。结论ApoE4基因型与高TC、LDL-C水平有密切关系。冠心病患者ApoE4等位基因频率显著高于对照组。等位基因E4是冠心病的独立危险因素。CETP基因型频率在冠心病组和对照组无显著性差异。CETP基因型及其与ApoE基因型的交互作用对冠心病的发生无显著性影响。     

Pharmacogenetic study of apolipoprotein E, cholesteryl ester transfer protein and hepatic lipase genes and simvastatin therapy in Brazilian subjects

BACKGROUND: In recent years, one of the focuses of genetic investigation in cardiology has been to identify the genetic factors associated with variable response to statin treatment. Polymorphisms in apolipoprotein E (APOE), cholesteryl ester transfer protein (CETP) and hepatic lipase (LIPC), proteins with major roles in lipid metabolism and homeostasis have been shown associated with lipid-lowering drugs response. METHODS: One hundred forty-six hypercholesterolemic patients of European descent were prospectively enrolled and treated with simvastatin 20 mg per day for over 6 months. Ninety-nine subjects completed the 6-month follow-up. Plasma lipids and lipoproteins were measured before and throughout the study. APOE (E*2, E*3 and E*4), LIPC-250A > G and CETP TaqIB genotypes were determined by PCR and restriction mapping. RESULTS: After a 6-month follow-up, no differences among genotypes in the percentage variation in lipid and lipoprotein concentrations for APOE and LIPC SNPs were observed. After adjustment for covariates, CETP B2B2 homozygotes showed a greater HDL-cholesterol increase compared to B1B2 and B1B1 subjects (14.1% vs. 1.7% and 1.3%, P < 0.05, respectively). CONCLUSION: Our study demonstrates that individual plasma HDL-cholesterol response to simvastatin is mediated, in part, by the CETP gene locus, with the B2 homozygotes having more benefit in HDL-C improvement than carriers of B1 allele.     

Association of TaqIB polymorphism in the cholesteryl ester transfer protein gene with serum lipid levels in the Guangxi Hei Yi Zhuang and Han populations

BACKGROUND: Cholesteryl ester transfer protein (CETP) plays an important role in lipoprotein metabolism. The present study was undertaken to compare the difference in the CETP TaqIB gene polymorphism and its association with serum lipid levels between the Guangxi Hei Yi Zhuang and Han populations. METHODS: A total of 758 subjects of Hei Yi Zhuang and 778 participants of Han Chinese were surveyed. Genotyping of the CETP TaqIB was performed using polymerase chain reaction and restriction fragment length polymorphism and then confirmed using direct sequencing. RESULTS: The genotypic and allelic frequencies were significant differences between smokers and nonsmokers, or between hypertensives and normotensives in Hei Yi Zhuang, and between drinkers and nondrinkers in Han. The levels of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein AI in Hei Yi Zhuang but not in Han were higher in B2B2 genotype than in B1B1 genotype (P < 0.01 for each). Higher HDL-C levels in Hei Yi Zhuang were found only in females, nondrinkers, nonsmokers, subjects with a body mass index of 24 kg/m or lesser, or normotensives in B2B2 genotype. Higher HDL-C levels in Han were found only in females in B2B2 genotype and in subjects with a body mass index of 24 kg/m or lesser or normotensives in B1B2 genotype. The levels of HDL-C in B1B1 and B1B2 individuals in both ethnic groups were higher in drinkers than in nondrinkers. CONCLUSIONS: There were significant differences in the interactions between the CETP TaqIB genotypes and several environmental factors in the Hei Yi Zhuang and Han populations. The polymorphism predicted differences in HDL-C and ApoAI in the Hei Yi Zhuang but not in the Han Chinese, even after adjustment for confounding variables. This means that the gene may not be truly involved in regulation of high-density lipoprotein metabolism or that there is an ethnic-specific effect.     

Relation between lipoprotein (a) and in vitro oxidation of apolipoprotein B-containing lipoproteins

OBJECTIVES: To assess the relationship between lipoprotein (a) [Lp (a)] and lipoprotein oxidation in patients with coronary artery disease (CAD). DESIGN AND METHODS: Oxidation of apolipoprotein (apo)B-containing lipoproteins, vitamin E, carotenoids, lipid-lipoprotein levels were determined in 171 CAD and 70 non-CAD subjects. RESULTS: In CAD patients with Lp (a) concentrations >/= 30 mg/dL; total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), malondialdehyde (MDA), and apo B levels were significantly higher and lag-time and age were significantly lower than those of CAD patients with Lp (a) concentrations < 30 mg/dL. In non-CAD subjects with Lp (a) concentrations >/= 30 mg/dL; TC, LDL-C, and vitamin E levels were significantly higher and lag-time was significantly lower than those of non-CAD subjects with Lp (a) concentrations < 30 mg/dL. In CAD patients, Lp (a) correlated negatively with lag-time and positively with MDA levels. Lp (a) correlated negatively with lag-time and vitamin E levels in non-CAD subjects. CONCLUSIONS: We have shown that plasma apo B-containing lipoproteins of both CAD and non-CAD subjects with Lp (a) levels >/= 30 mg/dL are more susceptible to in vitro oxidative modification than those of subjects with Lp (a) levels < 30 mg/dL. The relationship between Lp (a) and enhanced susceptibility of apo B-containing lipoproteins to oxidation, appears to support routine investigation of Lp (a).     

Apolipoprotein E polymorphism--a risk factor for metabolic syndrome.

BACKGROUND: Metabolic syndrome is closely related to several disturbances in lipid and lipoprotein metabolism. The aim of this study was to determine the association between apolipoprotein E (apoE) genotypes and the risk of metabolic syndrome and/or coronary heart disease complications. METHODS: The study included 279 subjects divided into three groups: 1) control subjects, 2) metabolic syndrome patients, and 3) obese patients with coronary heart disease. All subjects were characterized by body mass index, and plasma levels of glucose, triglycerides, cholesterol, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). ApoE genotypes were identified by PCR-restriction fragment length polymorphism using genomic DNA. RESULTS: Statistical analysis of plasma parameters showed that subjects in groups 2 and 3 had higher levels of triglycerides and lower levels of HDL-C compared to group 1. The frequencies of apoE genotypes determined in this Romanian population (65% for E3/3, 19.6% for E4/3, 9.5% for E3/2, 4.1% for E2/2, 0.6% for E4/4, 1.3% for E4/2) were in agreement with those reported for other Caucasian populations. The distribution of apoE alleles indicated a higher frequency of epsilon4 in groups 2 and 3. There was a higher frequency of the apoE4/3 genotype in groups 2 and 3, which was significantly correlated with higher levels of triglycerides and lower levels of HDL-C. CONCLUSIONS: Correlations of apoE genotypes with these markers indicate that the epsilon4 allele is an independent risk factor for metabolic syndrome.     

The genes of atherosclerosis and cardiovascular diseases

The aim of the work was to study polymorphism of atherosclerosis-related genes in patients with different forms of coronary heart disease (CHD) and chronic cerebral ischemia (CCI) in comparison with long-living subjects. Analysis included the distribution of genotypes and alleles of functional polymorphisms of lipid metabolism genes, viz. HindIII--polymorphism of lipoproteinase (LPL) gene; HhaI--polymorphism of apoE gene; TaqIB--polymorphism of cholesterol ether transfer protein (CETP) gene; I/D--polymorphism of angiotensin converting enzyme (ACE) in CHD and CCI patients of different age groups including long livers and those presenting with different clinical variants of CHD and CCI (FC II-III stable angina of effort, acute myocardial infarction, post-infarction cardiosclerosis, acute coronary syndrome) and control subjects. The study revealed potential molecular-genetic markers for primary and secondary prophylaxis of CHD and CCI. It was shown that DD genotypes of ACE gene, H+/+ of LPL gene and E3E4 are associated with an enhanced probability of myocardial infarction (IM) in CHD patients and can be regarded as high risk markers. The DD genotype is associated with an increased risk of recurrent MI, life-threatening post-IM complications and severe cardiac insufficiency as well as peculiar personality and behavioural traits (animosity and type A behaviour)--psychological risk factors of CHD and predictors of delayed application for medical aid. E2 allele of the ApoE gene and H allele of the LPL gene occur much more frequently in CHD patients aged above 90 years (long livers) than in younger subjects; hence, their value as markers of stable ischemic disease. Protective effect in terms of favourable clinical course of CCI and life expectancy is especially pronounced in subjects with a combination of genotypes with E2E3 + H+H-, E2E2 + H+H-, E3E3 + H-H-genes of ApoE and LPL. B2B2 genotype of CETP gene increases the risk of stable CCI and B1B1 genotype of CETP gene enhances predisposition to cardiovascular pathology.     

Higher frequency of abnormal serum angiopoietin-like protein 3 than abnormal cholesteryl ester transfer protein in Japanese hyperalphalipoproteinemic subjects

BACKGROUND: Either a decrease of cholesteryl ester transfer protein (CETP) or an increase of angiopoietin-like protein 3 (ANGPTL3) in plasma has been shown to increase HDL-cholesterol (HDL-C) levels. However, as yet, it is not known which protein is more strongly associated with the modulation of HDL in the Japanese hyperalphalipoproteinemic (HALT) subjects. METHODS: The serum concentration of ANGPTL3 and CETP, together with total cholesterol (TC), triglycerides (TG), adiponectin and ApoE phenotypes were determined in three groups with different HDL-C concentrations: low, <40 mg/dl (n=51); normal, 40-90 mg/dl (n=126) and high, >90 mg/dl (n=89) in the average Japanese population. RESULTS: The normal range (mean+/-2SD) of serum ANGPTL3 (218+/-144 ng/ml) and CETP (1.29+/-0.90 microg/ml) were determined in cases with 40-90 mg/dl HDL-C concentration. The frequency of abnormally high ANGPTL3 cases (>362 ng/ml) were found to be significantly greater (44%) compared with those of low CETP cases (<0.39 microg/ml, 4.5%) in HALT cases (>90 mg/dl). ANGPTL3 showed a high correlation with HDL-C (r=0.67, P<0.0001) and adiponectin (r=0.57, P<0.0001), but not with CETP. CONCLUSION: In average Japanese population, abnormally higher frequency of increased ANGPTL3 prevail in HALT cases as compared with cases with low CETP. These findings suggest that ANGPTL3, the inhibitor of endothelial lipase, may be more strongly associated with increased HDL-C rather than CETP in plasma. Accordingly, ANGPTL3 seems to be a better target for the modulation of HDL-C.     

CETP (cholesteryl ester transfer protein) promoter -1337 C>T polymorphism protects against coronary atherosclerosis in Japanese patients with heterozygous familial hypercholesterolaemia

CETP (cholesteryl ester transfer protein) and HL (hepatic lipase) play a role in the metabolism of plasma lipoproteins, but the effects of CETP and LIPC (gene encoding HL) genotypes on coronary atherosclerosis may be dependent on LDL (low-density lipoprotein)-receptor activity. Recently, the -1337 C>T polymorphism in the CETP gene has been reported in REGRESS (Regression Growth Evaluation Statin Study) to be a major determinant of promoter activity and plasma CETP concentration. In the present study, we have investigated the effects of the CETP promoter -1337 C>T and LIPC promoter -514 C>T polymorphisms on serum lipid profiles and risk of coronary atherosclerosis in 206 patients (154 males) with heterozygous FH (familial hypercholesterolaemia). To evaluate coronary atherosclerosis, we used CSI (coronary stenosis index) calculated from coronary angiograms. The CETP -1337 T allele was less frequent in subjects with a CSI > or =14 (mean value) in the group with coronary artery disease (P=0.04, as determined by chi(2) test). ANOVA revealed that HDL-C (high-density lipoprotein-cholesterol) and triacylglycerol (triglyceride) levels were not significantly higher in the presence of the CETP promoter -1337 T allele. Combined with LIPC promoter polymorphisms, HDL-C levels were highest and CSI were lowest with CETP -1337 CT+TT and LIPC -514 CC genotypes, but a significant interaction was not shown. A multiple logistic regression analysis revealed that, in patients with coronary atherosclerosis, the CETP- 1337 CC genotype was a significant genetic risk factor in FH (odds ratio=2.022; P=0.0256). These results indicate that the CETP promoter -1337C>T polymorphism is associated with the progression of coronary atherosclerosis in Japanese patients with FH, independent of HDL-C and triacylglycerol levels.     

Effects of simvastatin 20 mg/d on serum lipid profiles in Japanese hyperlipidemic patients: A prospective, open-label pilot study

Background:

Hyperlipidemia is a major risk factor for ischemic heart disease. Hydroxymethylglutaryl coenzyme A reductase inhibitors (“statins”) (eg, simvastatin) are considered first-line cholesterol-lowering therapy because they are effective and well tolerated, even at high doses. Based on a literature search, no studies have been published concerning the effects of simvastatin 20 mg/d in Japanese patients who had not previously received lipid-lowering treatment.

Objective:

The aim of this study was to assess the clinical tolerability and effectiveness of simvastatin 20 mg/d in achieving the target lipid concentrations recommended in the 2002 Japan Atherosclerosis Society (JAS) guidelines in Japanese patients with hyperlipidemia.

Methods:

This prospective, open-label pilot study was conducted at Kashiwa Hospital, Jikei University School of Medicine, Kashiwa, Japan. Male and postmenopausal female patients aged ≥18 to 70 years with hyperlipidemia (total cholesterol [TC], ≥220 mg/dL; triglycerides [TG], 150-400 mg/dL) who had not received lipid-lowering medications for at least 6 months before the study were enrolled. Patients received simvastatin 20 mg PO QD for 4 weeks. Effectiveness was assessed using serum concentrations of TC, low-density lipoprotein cholesterol (LDL-C), TG, and lipid peroxide, measured at 0 (baseline) and 4 weeks. Target serum TC and LDL-C concentrations as outlined by the JAS were as follows: category A, TC <240 mg/dL and LDL-C <160 mg/dL; category B1 and B2, TC <220 mg/dL and LDL-C <140 mg/dL; and category C, TC <200 mg/dL and LDL-C <120 mg/dL. A subanalysis of the correlation between baseline high-density lipoprotein cholesterol (HDL-C) and target achievement rates was conducted by baseline HDL-C concentration (<50 or ≥50 mg/dL). Tolerability was assessed using spontaneous reporting of adverse events and laboratory analysis, including liver function tests.

Results:

Twenty-two patients participated in the study (16 women, 6 men; mean [SD] age, 56.0 [8.0] years; mean [SD] body mass index, 23.6 [3.4] kg/m²). Mean serum TC, LDL-C, TG, and lipid peroxide concentrations significantly decreased from baseline (changes, −28.6%, −40.4%, −24.0%, and −14.5%, respectively; P < 0.001, <0.001, <0.001, and <0.01, respectively). The mean HDL-C concentration significantly increased from baseline (change, 7.2%; P < 0.001); the mean increase was significantly greater in patients with baseline HDL-C <50 mg/dL compared with those with baseline HDL-C ≥50 mg/dL (changes, 11.3% vs 4.4%; P < 0.05). Target TC and LDL-C concentrations were achieved in 90.9% of patients. No serious adverse events were observed, and liver enzyme and creatine kinase concentrations did not increase to above-normal values.

Conclusions:

The results of this study suggest that simvastatin 20 mg/d might be useful in the clinical treatment of hyperlipidemia in Japanese patients. The study drug was well tolerated.     

家族聚集性与非家族聚集性脑梗死患者载脂蛋白E基因多态性研究

背景载脂蛋白E(apolipoprotein E,ApoE)基因多态性与脑梗死的关系,多数学者认为ApoE ε4等位基因是脑梗死的遗传易患因素之一,而有部分学者却认为与脑梗死无关.目的探讨ApoE基因多态性与家族聚集性和非家族聚集性脑梗死的关系.设计病例对照研究.地点和对象实验地点为江苏南通医学院附属医院神经内科.对象均来源于南通医学院神经内科就诊确诊的脑梗死患者66例,其中家族中无脑卒中史的脑梗死患者40例,家族中有明确脑梗死先证者的家族聚集性脑梗死患者26例.对照组选择江苏地区无血缘关系的健康汉族人群90例.干预应用PCR扩增ApoE基因第4外显子包含编码第11位和第158位氨基酸残基的基因序列,cfoI限制性内切酶切后电泳,银染色分析ApoE基因型,同时检测3组人群的血脂、脂蛋白(a)及部分载脂蛋白.主要观察指标基因型频率、等位基因频率、血清各脂质含量.结果脑梗死组ε3/4基因型频率(30%)较对照组(9%)明显增加,而ε3/3基因型频率(50%)明显低于对照组(76%),差异有显著统计学意义(x2=35.85,P＜0.01);脑梗死组ε4等位基因频率(21%)高于对照组(6%),而ε3等位基因频率(71%)低于对照组(87%),差异有显著统计学意义(x2=35.85,P＜0.01).两脑梗死组之间,家族聚集性脑梗死组ε3/4基因型频率和ε4等位基因频率较非家族聚集性脑梗死有上升的趋势,而ε3/3和ε3频率有下降趋势,但均无统计学差异.血脂检测发现两病例组有相同的脂质代谢异常,非家族聚集性脑梗死组和家族聚集性脑梗死组血清总胆固醇,低密度脂蛋白胆固醇,载脂蛋白B,脂蛋白(a)均高于对照组(P＜0.01);家族聚集性脑梗死组高密度脂蛋白胆固醇水平明显低于对照组和非家族聚集性脑梗死组(P＜0.01和P＜0.05),而后两组间差异无显著性意义.结论ApoE3/4基因型与脑梗死的发生有关,ε4等位基因是脑梗死的遗传易感因子之一,ε3等位基因对脑梗死的发生有保护作用;ApoE基因多态性和HDL-C水平双重作用于家族聚集性脑梗死的发生.     

Pharmacological modulation of cholesteryl ester transfer protein, a new therapeutic target in atherogenic dyslipidemia

In mediating the transfer of cholesteryl esters (CE) from antiatherogenic high density lipoprotein (HDL) to proatherogenic apolipoprotein (apo)-B-containing lipoprotein particles (including very low density lipoprotein [VLDL], VLDL remnants, intermediate density lipoprotein [IDL], and low density lipoprotein [LDL]), the CE transfer protein (CETP) plays a critical role not only in the reverse cholesterol transport (RCT) pathway but also in the intravascular remodeling and recycling of HDL particles. Dyslipidemic states associated with premature atherosclerotic disease and high cardiovascular risk are characterized by a disequilibrium due to an excess of circulating concentrations of atherogenic lipoproteins relative to those of atheroprotective HDL, thereby favoring arterial cholesterol deposition and enhanced atherogenesis. In such states, CETP activity is elevated and contributes significantly to the cholesterol burden in atherogenic apoB-containing lipoproteins. In reducing the numbers of acceptor particles for HDL-derived CE, both statins (VLDL, VLDL remnants, IDL, and LDL) and fibrates (primarily VLDL and VLDL remnants) act to attenuate potentially proatherogenic CETP activity in dyslipidemic states; simultaneously, CE are preferentially retained in HDL and thereby contribute to elevation in HDL-cholesterol content.Mutations in the CETP gene associated with CETP deficiency are characterized by high HDL-cholesterol levels (>60 mg/dL) and reduced cardiovascular risk. Such findings are consistent with studies of pharmacologically mediated inhibition of CETP in the rabbit, which argue strongly in favor of CETP inhibition as a valid therapeutic approach to delay atherogenesis. Consequently, new organic inhibitors of CETP are under development and present a potent tool for elevation of HDL in dyslipidemias involving low HDL levels and premature coronary artery disease, such as the dyslipidemia of type II diabetes and the metabolic syndrome. The results of clinical trials to evaluate the impact of CETP inhibition on premature atherosclerosis are eagerly awaited.     

Metabolic effects of fluvastatin extended release 80 mg and atorvastatin 20 mg in patients with type 2 diabetes mellitus and low serum high-density lipoprotein cholesterol levels: a 4-month, prospective, open-label, randomized, blinded—end point (probe) trial

Background

Diabetic dyslipidemia is characterized by greater triglyceridation of all lipoproteins and low levels of plasma high-density lipoprotein cholesterol (HDL-C). In this condition, the serum level of low-density lipoprotein cholesterol (LDL-C) is only slightly elevated. The central role of decreased serum HDL-C level in diabetic cardiovascular disease has prompted the establishment of a target of ≥50 mg/dL in patients with diabetes mellitus (DM).

Objective

The aim of the study was to assess the effects of once-daily administration of fluvastatin extended release (XL) 80 mg or atorvastatin 20 mg on serum HDL-C levels in patients with type 2 DM and low levels of serum HDL-C.

Methods

This 4-month, prospective, open-label, randomized, blinded—end point (PROBE) trial was conducted at Endocrinology and Diabetology Service, L. Sacco-Polo University Hospital (Milan, Italy). Patients aged 45 to 71 years with type 2 DM receiving standard oral antidiabetic therapy, with serum HDL-C levels <50 mg/dL, and with moderately high serum levels of LDL-C and triglycerides (TG) were enrolled. After 1 month of lifestyle modification and dietary intervention, patients who were still showing a decreased HDL-C level were randomized, using a 1:1 ratio, to receive fluvastatin XL 80-mg tablets or atorvastatin 20-mg tablets, for 3 months. Lipoprotein metabolism was assessed by measuring serum levels of LDL-C, HDL-C, TG, apolipoprotein (apo) A-I (the lipoprotein that carries HDL), and apo B (the lipoprotein that binds very low-density lipoprotein cholesterol, intermediate-density lipoprotein, and LDL on a molar basis). Patients were assessed every 2 weeks for treatment compliance and subjective adverse events. Serum creatine phosphokinase and liver enzymes were assessed before the run-in period, at the start of the trial, and at 1 and 3 months during the study.

Results

One hundred patients were enrolled (50 patients per treatment group; fluvastatin XL group: 33 men, 17 women; mean [SD] age, 58 [12] years; atorvastatin group: 39 men, 11 women; mean [SD] age, 59 [11] years). In the fluvastatin group after 3 months of treatment, mean (SD) LDL-C decreased from 149 (33) to 95 (25) mg/dL (36%; P < 0.01), TG decreased from 437 (287) to 261 (164) mg/dL (40%; P < 0.01), and HDL-C increased from 41 (7) to 46 (10) mg/dL (12%; P < 0.05). In addition, apo A-I increased from 118 (18) to 124 (15) mg/dL (5%; P < 0.05) and apo B decreased from 139 (27) to 97 (19) mg/dL (30%; P < 0.05). In the atorvastatin group, LDL-C decreased from 141 (25) to 84 (23) mg/dL (40%; P < 0.01) and TG decreased from 411 (271) to 221 (87) mg/dL (46%; P < 0.01). Neither HDL-C (41 [7] vs 40 [6] mg/dL; 2%) nor apo A-I (117 [19] vs 114 [19] mg/dL; 3%) changed significantly. However, apo B decreased significantly, from 131 (20) to 92 (17) mg/dL (30%; P < 0.05). Mean changes in HDL-C (+5 [8] vs −1 [2] mg/dL; P < 0.01) and apo A-I (+6 [18] mg/dL vs −3 [21] mg/dL; P < 0.01) were significantly greater in the fluvastatin group than in the atorvastatin group, respectively. However, the decreases in LDL-C (54 [31] vs 57 [32] mg/ dL), TG (177 [219] vs 190 [65] mg/dL), and apo B (42 [26] vs 39 [14] mg/dL) were not significantly different between the fluvastatin and atorvastatin groups, respectively. No severe adverse events were reported.

Conclusions

Fluvastatin XL 80 mg and atorvastatin 20 mg achieved mean serum LDL-C (≤ 100 mg/dL) and apo B target levels (≤ 100 mg/dL) in the majority of this population of patients with type 2 DM, but mean serum HDL-C level was increased significantly only with fluvastatin—16 patients (32%) in the fluvastatin group compared with none in the atorvastatin group achieved HDL-C levels ≥50 mg/dL. The increase in HDL-C in the fluvastatin-treated patients was associated with an increase in apo A-I, suggesting a potential pleiotropic and selective effect in patients with low HDL-C levels.     

Cholesteryl ester transfer protein inhibitor (JTT-705) and the development of atherosclerosis in rabbits with severe hypercholesterolaemia

Cholesteryl ester transfer protein (CETP) is a major determinant of plasma levels of high-density lipoprotein-cholesterol (HDL-C) in humans. The anti-atherogenic effect of lowering CETP levels is dependent not only on HDL-C levels but also on a metabolic background of increased low-density lipoprotein or very-low-density lipoprotein. Here we investigated the effects of JTT-705, a chemical inhibitor of CETP, on the development of atherosclerosis in Japanese white rabbits fed on a high cholesterol diet. After 4 weeks on a diet of 0.25% cholesterol-containing chow, 100 mg/kg (low dose) or 300 mg/kg (high dose) JTT-705 was given, and the animals were monitored at weeks 0, 4, 8 and 12. Aortic atherosclerotic lesions were determined at the end of this period. JTT-705 induced a significant increase in HDL-C in the high-dose group [from 21+/-3 to 50+/-7 mg/dl (mean+/-S.E.M.); P <0.0001] compared with the control group (from 21+/-2 to 27+/-2 mg/dl). The atheromatous area was 60+/-9% in the high-dose group and 58+/-9% in the control group. Moreover, correlation analysis showed that triacylglycerol and non-HDL-C levels had a direct relationship with the development of atherosclerosis, but CETP activity and HDL-C levels did not. Thus the CETP inhibitor JTT-705 alone did not have an anti-atherogenic effect in our rabbit model, of severe hypercholesterolaemia suggesting a relatively minor effect of HDL-elevating therapy as compared with decreases in non-HDL-C (or triacylglycerol) levels in patients with severe hypercholesterolaemia, such as familial hypercholesterolaemia.     

载脂蛋白E基因多态性与青年动脉粥样硬化性脑梗死的关系(英文)

目的分析载脂蛋白E(ApoE)基因在青年动脉粥样硬化性脑梗死(ACI)患者与正常人群中的分布,探讨这些基因多态性在青年脑梗死发病中的意义。方法ACI患者组:36例ACI患者为中国医科大学附属第二医院神经内科住院患者,男30例,女6例。对照组:自愿健康体检沈阳籍汉族100例,男66例,女34例。用PCR技术检测其ApoE基因多态性,分析等位基因分布及其与血脂、脂蛋白含量的关系。结果(1)ACI组ε3/4型频率、ε2/4型频率和ε4等位基因频率均明显高于对照组(χ2=4.14,5.09,4.48,P<0.05)。(2)ε4等位基因引起血清三酰甘油(TG)、总胆固醇(TC)、脂蛋白(a)犤Lp(a)犦升高及高密度脂蛋白(HDL-C)降低的发病风险率(RR)依次为8.23,4.85,4.39,29.9(χ2=16.0,8.76,7.89,16.7,P<0.01～0.001)。结论ApoE基因多态性影响血脂、脂蛋白代谢;ApoE等位基因ε4与青年ACI关系密切,是一种遗传易感性因子。     

Effects on serum lipid profiles of continuous 17beta-estradiol, intermittent norgestimate regimens versus continuous combined 17beta-estradiol/norethisterone acetate hormone replacement therapy

OBJECTIVE: To compare the effects of a daily oral 1-mg dose of continuous 17beta-estradiol (E2) plus intermittent (3 days off, 3 days on) norgestimate (NGM) 90 microg (n = 221), an oral 2-mg dose of continuous E2 plus intermittent NGM 180 microg (n = 219), and an oral 2-mg dose of continuous E2 plus continuous norethisterone acetate (NETA) 1 mg (n = 217) on blood lipids and lipoproteins in postmenopausal women. BACKGROUND: The present study was undertaken because some progestins have adverse effects on lipid profiles, thereby negating the favorable effects of estrogens. METHODS: This was a multicenter, randomized, parallel-group trial that focused primarily on the 2 marketed regimens--E2 1 mg/NGM 90 microg and E2/NETA. Both subjects and investigators were blinded to the intermittent regimens; the continuous combined regimen was administered open-label. After a minimum 12-hour overnight fast, blood samples were collected at baseline and during months 7 and 12 to determine lipid and lipoprotein concentrations using validated methods. RESULTS: E2 1 mg/NGM 90 microg was associated with significant (ie, the 95% CI did not include 0) increases in high-density lipoprotein cholesterol (HDL-C) (6.8% [95% CI = 4.7%, 9.0%] and 4.8% [2.3%, 7.2%] at months 7 and 12, respectively) and high-density lipoprotein 2 cholesterol (HDL2-C) (10.8% [6.2%, 15.3%] and 24.1% [18.9%, 29.4%]) concentrations, and decreases in total cholesterol (-7.7% [-9.0%, -6.3%] and -9.2% [-10.5%, -7.9%]), low-density lipoprotein cholesterol (-14.3% [-16.3%, -12.4%] and -14.9% [-16.7%, -13.2%]), and lipoprotein(a) (-30.6% [-41.4%, -20.0%] at month 12) concentrations. A significant difference (P < 0.001 by analysis of variance) between the E2 1-mg/NGM 90-microg and NETA regimens was seen for HDL-C and HDL2-C concentrations, which were elevated in subjects receiving E2 1 mg/NGM 90 microg but reduced (-9.1% [-11.1%, -7.1%] and -12.3% [-14.3%, -10.3%] for HDL-C at months 7 and 12, respectively; -14.2% [-18.0%, -10.4%] and -2.5% [-7.8%, +2.8%] for HDL2-C at months 7 and 12, respectively) in those receiving E2/NETA. CONCLUSIONS: In the present study, continuous E2 1 mg/NGM 90 microg was associated with beneficial effects on lipids and lipoproteins in healthy postmenopausal women, effects that were greater at least for HDL-C and HDL2-C than those observed with continuous combined E2/NETA. The applicability of the study results to women with preexisting cardiovascular disease or dyslipidemia, or those who are overweight, remains to be investigated.     

Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major determinant of increased levels of high density lipoprotein cholesterol.

Genetic determinants of HDL cholesterol (HDL-C) levels in the general population are poorly understood. We previously described plasma cholesteryl ester transfer protein (CETP) deficiency due to an intron 14 G(+1)-to-A mutation(Int14 A) in several families with very high HDL-C levels in Japan. Subjects with HDL-C > or = 100 mg/dl (n = 130) were screened by PCR single strand conformational polymorphism analysis of the CETP gene. Two other mutations were identified by DNA sequencing or primer-mediated restriction map modification of PCR products: a novel intron 14 splice donor site mutation caused by a T insertion at position +3 from the exon14/intron14 boundary (Int14 T) and a missense mutation (Asp442 to Gly) within exon 15 (D442G). The Int14 T mutation was only found in one family. However, the D442G and Int14 A mutations were highly prevalent in subjects with HDL-C > or = 60 mg/dl, with combined allele frequencies of 9%, 12%, 21% and 43% for HDL-C 60-79, 80-99, 100-119, and > or = 120 mg/dl, respectively. Furthermore, prevalences of the D442G and Int14 A mutations were extremely high in a general sample of Japanese men (n = 236), with heterozygote frequencies of 7% and 2%, respectively. These two mutations accounted for about 10% of the total variance of HDL-C in this population. The phenotype in a genetic compound heterozygote (Int14 T and Int14 A) was similar to that of Int14 A homozygotes (no detectable CETP and markedly increased HDL-C), indicating that the Int14 T produces a null allele. In four D442G homozygotes, mean HDL-C levels (86 +/- 26 mg/dl) were lower than in Int14 A homozygotes (158 +/- 35 mg/dl), reflecting residual CETP activity in plasma. In 47 D442G heterozygotes, mean HDL-C levels were 91 +/- 23 mg/dl, similar to the level in D442G homozygotes, and significantly greater than mean HDL-C levels in Int14 A heterozygotes (69 +/- 15 mg/dl). Thus, the D442G mutation acts differently to the null mutations with weaker effects on HDL in the homozygous state and stronger effects in the heterozygotes, suggesting dominant expression of a partially defective allele. CETP deficiency, reflecting two prevalent mutations (D442G and Int14 A), is the first example of a genetic deficiency state which is sufficiently common to explain a significant fraction of the variation in HDL-C in the general population.