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

BACKGROUND: The cholesteryl ester transfer protein (CETP) is involved in the reverse cholesterol transport and is therefore a candidate gene for atherosclerosis. DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.     

Cholesteryl ester transfer protein in human brain

Summary The evidence that apolipoproteins are found in the cerebrospinal fluid and low-density lipoprotein receptor is found in the brain suggests that the brain may have an active lipid transport system. In plasma, cholesteryl ester transfer protein mediates the exchange and net transfer of cholesteryl ester and triglycerides among lipoproteins. Cholesteryl ester transfer activity was measured in the cerebrospinal fluid and plasma of ten neurologically normal subjects. Cholesteryl ester transfer activity was readily detectable in cerebrospinal fluid (7.4±13% cholesteryl ester was transferred per 20 μl), and this activity was completely abolished with specific antibody against the plasma cholesteryl ester transfer protein. The concentration of cholesteryl ester transfer activity in the cerebrospinal fluid was about 12% of that found in plasma, whereas the concentration of albumin in cerebrospinal fluid was only about 0.6% of that in plasma, suggesting direct synthesis of cholesteryl ester transfer protein within the brain. Cholesteryl ester transfer activity was found in conditioned medium from human neuroblastoma and neuroglioma cells and sheep choroid plexus. The data suggest that cholesteryl ester transfer protein is synthesized and secreted in the brain. This protein could play an important role in the transport and redistribution of lipids within the central nervous system. Deceased January 1991     

Cholesteryl ester transfer protein in human brain.

The evidence that apolipoproteins are found in the cerebrospinal fluid and low-density lipoprotein receptor is found in the brain suggests that the brain may have an active lipid transport system. In plasma, cholesteryl ester transfer protein mediates the exchange and net transfer of cholesteryl ester and triglycerides among lipoproteins. Cholesteryl ester transfer activity was measured in the cerebrospinal fluid and plasma of ten neurologically normal subjects. Cholesteryl ester transfer activity was readily detectable in cerebrospinal fluid (7.4 +/- 13% cholesteryl ester was transferred per 20 microliters), and this activity was completely abolished with specific antibody against the plasma cholesteryl ester transfer protein. The concentration of cholesteryl ester transfer activity in the cerebrospinal fluid was about 12% of that found in plasma, whereas the concentration of albumin in cerebrospinal fluid was only about 0.6% of that in plasma, suggesting direct synthesis of cholesteryl ester transfer protein within the brain. Cholesteryl ester transfer activity was found in conditioned medium from human neuroblastoma and neuroglioma cells and sheep choroid plexus. The data suggest that cholesteryl ester transfer protein is synthesized and secreted in the brain. This protein could play an important role in the transport and redistribution of lipids within the central nervous system.     

Cholesteryl ester transfer protein concentration is associated with progression of atherosclerosis and response to pravastatin in men with coronary artery disease (REGRESS)

BACKGROUND: The TaqIB polymorphism in the cholesteryl ester transfer protein (CETP) gene is associated with HDL-C, progression of coronary artery disease (CAD) and response to pravastatin treatment in men with angiographically proven CAD (REGRESS). We hypothesized that differences in CETP concentration could explain these associations and now investigated whether CETP concentration is an independent determinant of these parameters. MATERIALS AND METHODS: Plasma CETP concentrations at baseline and after 2 years' treatment with pravastatin or placebo were measured (n=674), and correlations with lipid and angiographic parameters (mean segment- and obstruction-diameter; MSD and MOD), and TaqIB genotype were studied. RESULTS: After segregation into three groups (baseline CETP<1.58, 1.58-2.21, >2.21 mg L(-1)), subjects with the highest CETP had significantly higher baseline total cholesterol, LDL-C and triglycerides (P<0.01), while HDL-C, MSD and MOD were not different among these groups. After 2 years of placebo, the MSD decreased threefold (P<0.001) and the MOD decreased 2.4-fold (P=0.042) more in the highest compared with the lowest CETP quartile. Pravastatin treatment reduced total cholesterol LDL-C and triglycerides significantly more in the highest CETP quartile. Moreover, only in the highest CETP quartile, pravastatin significantly reduced the MSD- (P=0.003) and MOD-decrease (P=0.014) compared with placebo, and, notably, this was independent of baseline lipids and differential lipid changes in these quartiles. Strikingly, baseline associations and treatment responses according to baseline CETP were independent of TaqIB genotype. CONCLUSIONS: High CETP concentration is associated with faster progression of coronary atherosclerosis in men with proven CAD. Second, pravastatin yielded the highest improvement of lipid and angiographic parameters in patients with high baseline CETP independent of baseline lipids, lipid changes and TaqIB genotype, indicating that the plasma CETP level itself is an important determinant of the response to statins.     

Cholesteryl ester transfer protein inhibitors: challenges and perspectives

Introduction: Cholesteryl ester transfer protein (CETP) inhibitors substantially increase the concentration of high-density lipoprotein cholesterol (HDL-C), which may have a possible beneficial effect for cardiovascular disease risk reduction.

Areas covered: Current data regarding the effects of CETP inhibitors on cardiovascular disease risk and possible mechanisms for their effects and safety are presented in this review.

Expert commentary: The first CETP inhibitor, torcetrapib, was discontinued because of increased off-target adverse effects (increased serum aldosterone and blood pressure levels). The development program of dalcetrapib and evacetrapib, which were not associated with increased blood pressure, was terminated due to futility (insufficient efficacy) concerning cardiovascular outcomes. Although the failure of torcetrapib has been attributed to specific off-target effects, there are some common characteristics between CETP inhibitors pointing to the possibility that certain adverse effects may be class-specific. The newer CETP inhibitors anacetrapib and TA-8995 have promising effects on lipid profile and metabolism (increase of HDL-C and reduction of both low-density lipoprotein cholesterol and lipoprotein (a) levels), but their cardiovascular effects and safety profile have not yet been confirmed in large outcome trials.     

Cholesteryl ester transfer protein gene polymorphisms and severity of coronary stenosis

PURPOSE: Cholesteryl ester transfer protein (CETP) gene is involved in the reverse cholesterol transport in humans. Thus, it is a candidate for studying the susceptibility to coronary heart disease (CHD). The goal of the current investigation was to determine any association between CETP polymorphisms (I405V and TaqIB), and severity of coronary stenosis, since the extent of coronary artery narrowing has been considered as a primary determinant of survival in CHD patients. METHODS: The severity of coronary stenosis was estimated by Gensini (GS) and Duke Jeopardy (JS) scores in 130 men with documented CHD (mean age 61 +/- 10 yr). Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: The allele frequencies for both TaqIB and I405V were found in Hardy-Weinberg equilibrium. Homozygotes for I had lower GS compared with heterozygotes (IV) and homozygotes for V [72(95% CI 51-92) vs. 122(95% CI 88-157) and 136 (95% CI 74-198), P = 0.009, P = 0.010, respectively]. In addition, GS differed between carriers of I and carriers of V allele [86(95% CI 72-101) vs. 128(95% CI 102-154), P = 0.003]. A correlation was found between the GS and I405V polymorphism (r = 0.250, P = 0.005), but not with JS. CONCLUSION: Homozygosity for I405 favours less severe coronary stenosis. Our findings indicate that the I405V polymorphism may have potential importance in screening individuals at high risk for developing CHD, establishing efficient prevention measures, and searching for other risk factors for CHD. However, further prospective investigations in larger populations are required to confirm these findings.     

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.     

胆固醇酯转运蛋白基因rs3764261多态性对中国汉族人群血脂水平的影响

目的 探讨胆固醇酯转运蛋白基因的rs3764261多态性与血脂水平的相关性.方法 应用基质辅助激光解吸电离飞行时间质谱( MALDI-TOF MS)技术进行rs3764261多态性的检测,Hardy-Weinberg平衡进行群体遗传平衡检验,logistic回归分析基因型对血脂异常发病风险的大小.结果 遗传平衡检验(x2=3.958,P＞0.05),符合遗传平衡定律,样本群体具有代表性;男性的总胆固醇(TC)低于女性(P＜0.01),高密度脂蛋白胆固醇(HDL-C)也低于女性(P＜0.01),甘油三酯(TG)和低密度脂蛋白胆固醇(LDL-C)明显高于女性(均P＜0.01);在女性群体中,rs3764261位点GT和TT基因型的低HDL-C血症发病率为GG基因型的0.503倍(P＜0.05).结论 在我国汉族女性人群中rs3764261位点多态性与低高密度脂蛋白血症相关.     

Cholesteryl ester transfer protein promotes the formation of cholesterol-rich remnant like lipoprotein particles in human plasma

BACKGROUND: Cholesteryl ester transfer protein (CETP) is suggested to be involved in the cholesterol level in remnant like lipoprotein particles (RLP), but there is no direct evidence that CETP increases cholesterol-rich RLP in plasma. METHODS: Human plasma was incubated with or without HDL containing [(3)H]-labeled cholesteryl ester ([(3)H]CE), recombinant CETP or CETP inhibitors at 37 degrees C in vitro. RESULTS: The RLP-cholesterol (RLP-C) level increased time-dependently and the amount of RLP-C increase (DeltaRLP-C) by the incubation was positively correlated with triglyceride (TG) level in plasma (r=0.597, P=0.0070). [(3)H]CE in HDL was transferred to RLP fraction under 37 degrees C incubation, and the amount of [(3)H]CE transferred to RLP correlated significantly with DeltaRLP-C in plasma (r=0.611, P=0.0156). Human recombinant CETP enhanced the RLP-C increase, while CETP inhibitor JTT-705 and anti-human CETP monoclonal antibody inhibited both the RLP-C increase and [(3)H]CE transfer to RLP. On the other hand, an inhibition of lecithin: cholesterol acyltransferase (LCAT) did not affect the RLP-C increase. In triglyceride-rich lipoproteins (TRL) fraction, JTT-705 inhibited [(3)H]CE transfer to RLP more strongly than that to non-RLP. CONCLUSIONS: CETP promotes the formation of cholesterol-rich RLP through the transfer of CE from HDL to TRL and CETP inhibitors are useful to reduce RLP-C.     

心脑血管疾病患者胆固醇酯转运蛋白及某些基因缺陷

目的 分析心脑血管疾病患者和健康人血清胆固醇酯转运蛋白（CETP）水平、CETPD442G和114A突变频率和基因突变者血脂异常的特点。方法 94例心肌梗死、110例脑卒中和335名健康人,应用ELISA测定GETP浓度;合成^14C胆固醇酯标记的含载脂蛋白AI的双盘状、双层颗粒作基质测定GETP活性;并采用聚合酶链反应－限制性片断长度多态性分析CETP基因突变。结果 心梗组、脑卒中组CETP水平较健康人明显增高。心梗组、脑卒 中组和健康人D442G检出率分别为3.5%、3.6%和5％;114A检出率分别为1.2%、0.9%和1％,其中1名为健康人D442G纯合子。心梗、脑卒中患者两种CETP基因突变频率与健康人无差别。 基因突变者ETP浓度和活性仅为非基因突变者1／3,并伴有血清高密度脂蛋白胆固醇升高,甘油三酯降低。结论 心脑血管疾病患者CETP水平升高;CETP基因突变者有显著的脂蛋白异常。     

Increased levels of high-density lipoprotein cholesterol are ineffective in inhibiting the development of immune responses to oxidized low-density lipoprotein and atherosclerosis in transgenic rabbits expressing human apolipoprotein (apo) A-I with severe hypercholesterolaemia

High levels of high-density lipoprotein (HDL) cholesterol have been reported to protect against the development of atherosclerosis in humans by increasing reverse cholesterol transport and inhibiting the oxidation of low-density lipoprotein (LDL) due to the paraoxonase content of HDL. The purpose of the present study was to assess if there are any relationships between in vivo increases in serum levels of immunological LDL oxidation markers [autoantibodies against oxidized LDL, autoantibodies against malondialdehyde-modified LDL, LDL immune complexes and anti-cardiolipin autoantibodies], paraoxonase activity and the development of atherosclerosis in control rabbits and in transgenic rabbits expressing human apolipoprotein (apo) A-I. A total of 13 apo A-I transgenic rabbits and 18 non-transgenic littermates were fed on a cholesterol-rich diet (0.4%, w/w) for 14 weeks, and were monitored at weeks 0, 2, 6, 10 and 14. Aortic atherosclerotic lesions were measured at the end of this period. Human apo A-I transgenic rabbits with high HDL cholesterol levels were not protected against the development of atherosclerosis when they were fed on a cholesterol-rich diet which induced dramatic hypercholesterolaemia. Immunological markers of LDL oxidation increased and serum paraoxonase activity decreased similarly in control and transgenic rabbits. In conclusion, the present study demonstrates that high HDL cholesterol levels are ineffective in inhibiting increases in immunological markers of LDL oxidation and the development of atherosclerosis in a mammal with severe hypercholesterolaemia.     

不同程度冠脉病变男性患者胆固醇酯转运蛋白水平及其临床意义

目的探讨不同程度冠脉病变男性患者胆固醇酯转运蛋白(CETP)水平及临床意义。方法用ELISA法测定42例男性冠心病(CHD)患者及49例健康男性对照血清CETP浓度。根据冠状动脉造影结果将CHD组分为单支病变组、双支病变组及多支病变组;局限病变组及弥漫病变组;轻度狭窄组及重度狭窄组。结果CHD组CETP水平(1.37±1.07mg/L)明显高于健康对照组(0.99±0.53mg/L)(P<0.05);多支病变组(1.87±1.38mg/L)明显高于双支病变组(1.06±0.62mg/L)及单支病变组(0.93±0.49mg/L)(P<0.05);弥漫病变组(1.56±1.18mg/L)明显高于局限病变组(0.85±0.44mg/L)(P<0.05);重度狭窄组(1.67±1.22mg/L)较轻度狭窄组(0.85±0.36mg/L)明显升高(P<0.01)。结论CETP水平与冠脉病变的严重程度呈一定相关性,提示检测血清CETP水平可能有助于判断冠脉病变程度。     

Cholesteryl ester transfer activity in plasma of patients with familial high-density lipoprotein deficiency

We determined cholesteryl ester transfer activity in whole plasma and in lipoprotein-depleted plasma of normolipidemic subjects and of patients with severe high-density lipoprotein (HDL) deficiency: Tangier disease, lecithin:cholesterol acyltransferase (LCAT) deficiency, and "fish-eye" disease. Transfer rates in plasma were positively correlated (r = 0.950) with rates measured in the absence of the endogenous lipoproteins. This suggests that lipoprotein composition and content may not affect total cholesteryl ester transfer activity in normolipidemic and the HDL-deficient subjects. Cholesteryl ester transfer from solid-phase-bound HDL to plasma lipoproteins was decreased by 39% in fish-eye disease and 33% in LCAT deficiency but increased by 57% in Tangier disease, as compared with normal values. Changes were similar for lipoprotein-depleted plasma from the same individuals. Transfer to plasma HDL was significantly decreased in all HDL-deficient patients, whereas transfer to very-low- and low-density lipoproteins was increased only in Tangier disease. Differences in transfer rates between the patients studied appeared to reflect the LCAT activity and the need to transport cholesteryl ester rather than the HDL cholesterol concentration. Thus, the concentration of HDL in plasma does not directly affect total cholesteryl ester transfer activity in HDL deficiency.     

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.     

环氧化酶抑制剂对兔动脉粥样硬化作用的实验研究

目的观察特异性COX-2抑制剂联合阿司匹林对动脉粥样硬化（As）早期病变及其炎性过程的影响。方法35只健康雄性新西兰白兔随机分为5组,正常对照组、模型对照组（AS组）、阿司匹林干预组[4mg／（kg·d）]、塞来昔布干预组[8mg／（kg·d）]和联合干预组[阿司匹林4mg／（kg·d）＋塞来昔布8mg／（kg·d）],药物与高脂饮食同步应用。10周后,测定血清血脂浓度（TC、TG、LDL）,比浊法测定血小板聚集率,放射免疫法检测TNF-α,ELISA法检测CRP、IL-10,免疫组织化学检测胸主动脉COX-1、COX-2、LOX-1。苏木精伊红染色测定胸主动脉内膜及中膜厚度。结果成功构建经高脂饮食诱导的实验兔AS模型,除正常对照组外,其他4组实验兔血清TC、TG、LDL浓度升高,胸主动脉形成典型脂质条纹,病变处COX-2显著表达。与AS组相比,阿司匹林干预组血小板聚集率显著下降,血清CRP下降;塞来昔布干预组血小板聚集率无变化,姐清TNF-α、CRP水平显著下降（P〈0．05）,胸主动脉COX-2、α-actin表达显著降低,LOX-1的表达亦有下降趋势（P=0．05）;联合干预组血小板聚集率降低,血浆CRP水平下降更为显著（P〈0．05）,IL-10有增高趋势（P=0．055）。除未经高脂饮食诱导的正常对照组之外,其他4组胸主动脉内膜厚度、内膜／中膜厚度比均显著增加。与AS组相比,各药物干预组内膜厚度和内膜／中膜厚度比差异均有统计学意义（P〈0．05）,但下降程度不一,内膜厚度联合组下降程度最大,各组比较均有统计学意义（P〈0．05）。结论针对主动脉炎症反应和血小板活性这两个环节的协同抑制效应将有可能显著抑制AS斑块的早期形成。