Tag single nucleotide polymorphism rs1532624 located in cholesteryl ester transfer protein gene is associated with atherosclerosis cerebral ischemia

Objective: To investigate the relationship between polymorphisms of rs1532624 and rs289741 loci in cholesteryl ester transfer protein(CETP) genes and atherosclerotic cerebral infarction(ACI). Methods: The CETP gene rs1532624 and rs289741 in 95 patients with ACI and 177 healthy subjects were genotyped by Mass ARRAY mass spectrometry. Each locus genotype and allele frequency distributions were compared. Results: The difference of allele frequency distribution between the rs1532624(χ~2=1.723, P=0.189) and rs289741(χ~2=2.466, P=0.116) were not statistically significant. The frequency distribution of rs1532624 genotype between the cerebral infarction group and healthy control group was statistically significant(χ~2=7.096, P=0.029), while rs289741 genotype frequency distribution between the two groups was not statistically significant(χ~2=2.906, P=0.234). Conclusion: ACI have a positive correlation with rs1532624 polymorphism, and AA genotype may be susceptible factors of ACI.

High level of serum cholesteryl ester transfer protein inactive hepatitis C virus infection

AIM: To determine the significance of cholesteryl ester transfer protein(CETP) in lipoprotein abnormalities in chronic hepatitis C virus(HCV) infection.METHODS: We evaluated the significance of the serum concentration of CETP in 110 Japanese patients with chronic HCV infection. Fifty-five patients had active HCV infection, and HCV eradication had been achieved in 55. The role of CETP in serum lipoprotein abnormalities, specifically, in triglyceride(TG) concentrations in the four major classes of lipoproteins, was investigated using Pearson correlations in conjunction with multiple regression analysis and compared them between those with active HCV infection and those in whom eradication had been achieved. RESULTS: The serum CETP levels of patients with active HCV infection were significantly higher than those of patients in whom HCV eradication was achieved(mean ± SD, 2.84 ± 0.69 μg/m L vs 2.40 ± 1.00 μg/m L, P = 0.008). In multiple regression analysis, HCV infection status(active or eradicated) was an independent factor significantly associated with the serum CETP level. TG concentrations in low-density lipoprotein(mean ± SD, 36.25 ± 15.28 μg/m L vs 28.14 ± 9.94 μg/m L, P = 0.001) and high-density lipoprotein(HDL)(mean ± SD, 25.9 ± 7.34 μg/m L vs 17.17 ± 4.82 μg/m L, P < 0.001) were significantly higher in patientswith active HCV infection than in those in whom HCV eradication was achieved. The CETP level was strongly correlated with HDL-TG in patients with active HCV infection(R = 0.557, P < 0.001), whereas CETP was not correlated with HDL-TG in patients in whom HCV eradication was achieved(R =-0.079, P = 0.56). CONCLUSION: Our results indicate that CETP plays a role in abnormalities of lipoprotein metabolism in patients with chronic HCV infection.

Association between TaqIB polymorphism of cholesteryl ester transfer protein and coronary artery disease in the Chinese population

Objective: To assess whether the TaqIB polymorphism of cholesteryl ester transfer protein (CETP) is associated with coronary artery disease (CAD) in Chinese population, we performed a meta-analysis in this paper. Methods: We searched PubMed, Embase, the Science Citation Index (SCI), the China Biological Medicine database (CBM), the China National Knowledge Infrastructure (CNKI), and the Wanfang database for relevant articles. Data were extracted, and pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Results: The lit- erature search yielded 448 studies, in which 10 case-control studies including 1 694 cases and 1 456 controls matched the selection criteria. The combined B1 and B2 allele frequencies were 0.587 and 0.413, respectively. The pooled OR was 1.10 (95% CI, 0.89-1.34) for comparing the B1B1 or B1B2 carriers with B2B2 carriers, and was 1.27 (95% CI, 1.09-1.49) in the B1B1 carriers versus B2B2 or B1B2 carriers. Conclusions: In the present study, the TaqIB poly- morphism of CETP was found to be associated with CAD in the Chinese population.

Pharmacophore-based design,synthesis,and biological evaluation of novel 3-((3,4-dichlorophenyl)(4-substituted benzyl)amino)propanamides as cholesteryl ester transfer protein(CETP)inhibitors

Cholesteryl ester transfer protein(CETP) is a plasma glycoprotein that plays an important role in decreasing high-density lipoprotein cholesterol(HDL-C) levels and increasing low-density lipoprotein cholesterol(LDL-C) levels.Inhibition of CETP may be a new therapy for treating atherosclerosis.Herein,we report the development of a ligand-based pharmacophore model and pharmacophore-based virtual screening of the ZINC/big-n-greasy database,leading to the identification of compound H-10 as a potential CETP inhibitor in vitro.Based on H-10,a series of 3-((3,4-dichlorophenyl)(4-substituted benzyl)amino) propanamides were designed,synthesized,and evaluated against CETP.Compound 41was found to have the best activity,resulting in 85.0%inhibition of CETP at 10 μmol/L.

Taq1B polymorphism and plasma activity of cholesteryl ester transfer protein and restenosis after coronary stent placement

Background Cholesteryl ester transfer protein(CETP),an important regulatory factor in reverse cholesterol transport,has been investigated in relation to plasma HDL cholesterol,which is associated with restenosis after percutaneous transluminal coronary angioplasty(PTCA)and stent implantation.We examined the effect of plasma CETP activity and the Taq1B polymorphism on restenosis in Chinese Han population.Methods and Results Our study included 228 patients with symptomatic coronary artery disease(CAD).The genotype of the subjects for Taq1B polymorphism of CETP was analyzed by using polymerase chain reaction-restriction fragment length polymorphism(PCR-RFLP).In-stent restenosis(ISR)was observed in 93 patients(40.8 %).Baseline clinical,angiographic,and procedural characteristics data were not significantly different in patients with and without restenosis,except previous history of myocardial infarction(MI),left ventricular ejection fraction(LVEF),statin medication,and stent type.Taq1B polymorphism and plasma activity of CETP were not associated with the incidence of ISR(P = 0.68,P = 0.30,respectively).Linear regression analysis revealed that the risk of ISR was statistically significant correlation with stent type,LVEF,statin medication,and lesion length(P < 0.05).Conclusions Useful markers for risk of ISR were stent type,LVEF,statin medication and lesion length but not the Taq1B polymorphism and plasma activity of CETP.[S Chin J Cardiol 2011;12(3):187-196]

High density lipoprotein and cardiovascular diseases

Several epidemiological studies have clearly shown that low plasma levels of high density lipoprotein cholesterol (HDL-C) represent a cardiovascular disease (CVD) risk factor. However, it is unclear if there is a causal association between HDL-C concentration and CVD. A recent study published in the Lancet, which performed two Mendelian randomization analyses, showed that increased HDL-C levels were not associated with a decreased risk of myocardial infarction. These findings, together with the termination of the niacin-based AIM-HIGH trial and the discontinuation of cholesteryl ester transfer protein inhibitor dalcetrapib, challenge the concept that raising of plasma HDL-C will uniformly translate into reductions in CVD risk. HDL particles exhibit several anti-atherosclerotic properties, such as anti-inflammatory and anti-oxidative activities and cellular cholesterol efflux activity. Furthermore, HDL particles are very heterogeneous in terms of size, structure, composition and metabolism. HDL functionality may be associated more strongly with CVD risk than the traditional HDL-C levels. More research is needed to assess the association of the structure of HDL particle with its functionality and metabolism.

豚鼠早期动脉粥样硬化模型的建立、机制研究及与大鼠模型的比较

目的建立豚鼠早期动脉粥样硬化模型,探讨模型形成机制,并与大鼠模型进行比较,为豚鼠模型优势提供科学依据。方法应用高脂饲料诱导法,观察豚鼠和大鼠是否可形成早期动脉粥样硬化模型,并应用免疫组化和酶联免疫分析技术探讨模型形成机制。结果豚鼠模型组摄入高脂饲料6周后主动脉内膜-中膜明显增厚、内膜单核细胞、巨噬细胞浸润与聚集增多,同时比例为0.40的动物动脉内膜表层进一步发展形成脂纹脂斑病变。而大鼠模型组未见类似病变。机制研究表明,血清脂蛋白(a)[Lipoprotein(a),LP(a)]、胆固醇酯转运蛋白(Cholesteryl ester transfer protein,CETP)、氧化型低密度脂蛋白(ox-LDL)浓度,肝脏脂酰辅酶A:胆固醇酰基转移酶(Acyl-CoA:cholesterol acyltransferase,ACAT)活性和主动脉增殖细胞核抗原(Proliferating cell nu-clear antigen,PCNA)、分化抗原簇-36(Cluster of differentiation36,CD36)和血管细胞黏附分子(Vascular cell adhesion mole-cule,VCAM-1)表达的变化是动脉病理改变的重要机制。结论豚鼠可能是一种模拟早期动脉粥样硬化的适宜动物模型。

CETP基因TaqⅠB位点多态性与高胆固醇血症的关系

目的探讨胆固醇酯转运蛋白CETP基因TaqⅠB位点多态性与汉族人群高胆固醇血症的关系。方法应用聚合酶链技术-限制性片段长度多态性(PCR-RFLP)技术检测汉族人群464例高胆固醇血症(高胆固醇血症组)、852例边缘高胆固醇血症(边缘高胆固醇血症组)及1 309例正常血脂(正常对照组)人群CETP基因内含子1的TaqⅠB位点多态性。结果按TaqⅠ酶切位点存在与否分为B1B1、B1B2、B2B2 3种基因型和B1、B2 2种等位基因。高胆固醇血症组较边缘高胆固醇血症组、正常对照组LDL-C、CETP升高,HDL-C降低(P<0.05)。CETP基因TaqⅠB多态性基因型及等位基因频率在3组人群中的分布差异有统计学意义,高胆固醇血症组和边缘高胆固醇血症组的B1B1基因型及B1等位基因频率显著高于正常对照组(P<0.05)。CETP基因TaqⅠB多态性B1B1基因型者血清TC、LDL-C和CETP水平明显高于B1B2基因型和B2B2基因型(P<0.05)。多因素logistic回归分析显示CETP基因TaqⅠB B1B1基因型是高胆固醇血症的独立危险因素。结论胆固醇酯转运蛋白基因TaqIB位点存在基因多态性,B1B1基因型及B1等位基因与高胆固醇血症有着密切的关系,可能是汉族人群高胆固醇血症的原因之一。

冠心病患者血浆胆固醇酯转运蛋白水平与高密度脂蛋白亚类组成的关系

目的探讨冠心病患者胆固醇酯转运蛋白(CETP)水平与血浆高密度脂蛋白(HDL)亚类组成的关系。方法收集冠心病患者血浆116例和健康对照组血浆87例,采用双向电泳-免疫印迹检测法分析其HDL亚类浓度,用酶联免疫法测定CETP浓度。按CETP浓度均值加或减去一个标准差作为分割点,将冠心病患者分为3组:低CETP组(CETP≤0.69 mg/L)、中CETP组(0.69<CETP<1.59 mg/L)、高CETP组(CETP≥1.59 mg/L)。结果随着CETP浓度的升高,冠心病患者血浆总胆固醇、甘油三酯、低密度脂蛋白胆固醇水平呈增加趋势,高密度脂蛋白胆固醇、载脂蛋白A1水平和载脂蛋白A1/B100比值呈减少趋势。与低CETP组相比,中CETP组和高CETP组preβ_1-HDL及HDL_(3c)含量增加,而HDL_(2b)含量降低(P<0.05或P<0.001)。直线相关和多元回归分析中发现,血浆CETP水平与preβ_1-HDL浓度呈正相关,与HDL_(2b)浓度呈负相关。结论随着血浆CETP水平的升高HDL颗粒有变小的趋势,CETP可能阻碍了HDL的成熟代谢。

冠心病患者血清磷脂转运蛋白及胆固醇脂转运蛋白水平与中医证型相关性研究

目的探讨冠心病患者血清磷脂转运蛋白(phospholipid transfer protein,PLTP)、胆固醇酯转运蛋白(cholesteryl ester transfer protein,CETP)水平与中医病证的相关性,为冠心病证候客观化和开发临床治疗药物探索新的途径。方法选择经冠状动脉造影确诊为冠心病的患者201例,采用国内外公认标准,构建证候四诊合参数据库,进行中医辨证。随机选取健康体检者20名为健康对照组。取静脉血分离血清,分别以酶联免疫法测定血清PLTP、CETP表达;采用乙酰丙酮显色法测定甘油三酯(triglyceride,TG)含量;采用沉淀漂浮酶联法测定总胆固醇(total cholesterol,TC)、低密度脂蛋白胆固醇(low-density lipoprotein cholesterol,LDL-C)、高密度脂蛋白胆固醇(high-density lipoprotein cholesterol,HDL-C)含量。结果各证型冠心病患者血清PLTP、CETP、TC明显高于健康对照组,差异有统计学意义(P<0.05,P<0.01);各证型组血清TG、HDL-C、LDL-C与健康对照组比较,差异有统计学意义(P<0.05,P<0.01)。标实证组各证型血清PLTP与本虚组各证型比较,差异有统计学意义(P<0.05)。标实证组各证型血清TG、HDL-C、LDL-C与本虚组各证型比较,差异有统计学意义(P<0.05、P<0.01)。结论标实证冠心病患者血清PLTP表达明显升高。标实证冠心病患者血清脂质改变较本虚证更为显著。

CETP基因TaqI B多态性与瑞苏伐他汀对糖耐量异常合并冠心病患者疗效的相关性

目的:比较血糖异常合并冠心病组瑞舒伐他汀治疗前后的血脂指标和冠状动脉粥样硬化斑块变化间的关系。方法:血糖异常合并冠心病患者196例及血糖正常160例给予瑞苏伐他汀治疗,分析病例组治疗前后冠脉斑块的血管内超声(intravascular ultrasound,IVUS)结果以及血脂变化情况,用飞行时间质谱检测研究对象血标本的CETP基因TaqI B单核苷酸多态性(SNPs)位点。结果:CETP基因TaqI B B1B1、B1B2、B2B基因型在病例组的分布频率分别为35.7%、48.0%,16.3%;对照组为31.3%、53.1%、15.6%。HDL-C及MLA在瑞苏伐他汀治疗后呈上升趋势,LDL-C、TG、TCH、Lpa、PA、EEMA及PB治疗后呈下降趋势。结论:CETP基因Taql B多态性与瑞苏伐他汀对冠心病患者的血脂调节以及血管斑块退缩作用可能有相关性。

CETP基因启动子区多态与他汀类药物调血脂效果的关联分析

目的探讨胆固醇酯转运蛋白基因启动子区-69G/A、-629C/A、-971G/A和-1337C/T单核苷酸多态性与他汀类药物调血脂效果的关系。方法采用聚合酶链反应-限制性片段长度多态方法检测207例经辛伐他汀调脂治疗的血脂异常患者胆固醇酯转运蛋白基因4个多态性位点的基因型频率分布情况,并比较各项血脂水平的改变量在各多态位点基因型之间的差异。结果 -69G/A多态未检出A等位基因;辛伐他汀治疗后,总胆固醇和低密度脂蛋白胆固醇水平的改变量在-629C/A多态各基因型组间差异均有显著性(P=0.025;P=0.000),-629AA基因型个体的总胆固醇水平下降幅度较CC基因型个体要高出0.495 mmol/L(P=0.020),-629AA和CA基因型个体中的低密度脂蛋白胆固醇水平下降幅度比CC基因型个体分别高出0.577 mmol/L和0.352 mmol/L(P=0.000,P=0.012);高密度脂蛋白胆固醇水平的改变量在-1337C/T多态各基因型组间差异有显著性(F=3.064,P=0.044),高密度脂蛋白胆固醇水平升高的幅度在-1337TT、TC和CC基因型组间有逐渐增大的趋势;各项血脂水平的改变量在-971G/A多态3种基因型组间的差异无统计学意义。结论 -629C/A多态和-1337C/T多态与他汀类药物调血脂效果有关联。

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。

肥胖儿童血浆胆固醇酯转运蛋白与血脂相关性

目的 :探讨单纯性肥胖儿童血浆胆固醇酯转运蛋白 (CETP)与血脂的相关性及其与动脉粥样硬化 (AS)的关系。 方法 :用本室建立的酶联免疫测定法 (EL ISA)检测 49例单纯性肥胖儿童血浆 CETP水平。 结果 :肥胖儿童与健康儿童相比 ,其血浆胆固醇 (TC)、甘油三酯 (TG )、低密度脂蛋白胆固醇 (L DL - C)、载脂蛋白 B(apo B)的浓度均显著升高 (P<0 .0 5 ) ,存在较明显的脂质代谢紊乱 ;高密度脂蛋白胆固醇 (HDL- C)、载脂蛋白 A1(apo A1)水平与健康儿童差异不显著 (P>0 .0 5 ) ;CETP水平显著高于正常儿童 (P<0 .0 5 ) ,且与 L DL- C、apo B、TC/ HDL- C、L DL- C/ HDL- C、apo B/ apo A1显著相关 ,而与 HDL- C、apo A1则不相关。 结论 :肥胖儿童存在脂蛋白代谢紊乱 ,且可能与其 CETP水平增高有密切关系 ;过量脂肪摄入和缺乏体育锻炼也是其 CETP水平增高的重要因素。

抗胆固醇酯转运蛋白单克隆抗体的制备及其应用

目的：自行制备胆固醇酯转运蛋白（ＣＥＴＰ）单克隆抗体（ＭｃＡｂ），建立人血清ＣＥＴＰ的酶联免疫吸附测定法（ＥＬＩＳＡ），调查中国人群ＣＥＴＰ参考值及临床意义。方法：应用杂交瘤技术制备ＣＥＴＰＭｃＡｂ。用棋盘试验确定ＥＬＩＳＡ法的反应条件；进行灵敏度、精密度、回收率、特异性试验。结果：制备出一株特异性好、反应性强的ＣＥＴＰＭｃＡｂ。筛选出ＥＬＩＳＡ法最佳反应条件，样本稀释２０００倍，可检测０．２８～４．５２ｍｇ／Ｌ的血清ＣＥＴＰ水平；平均批内ＣＶ为４．９％，平均批间ＣＶ为１０．２％；平均回收率为９２．５％～９７．２％；特异性高。检测结果同国外实验室ＥＬＩＳＡ法高度相关。１１２８例参考人群血清ＣＥＴＰ浓度为１．８４±１．５５ｍｇ／Ｌ，女性高于男性；随着年龄增高，ＣＥＴＰ浓度降低。冠心病患者ＣＥＴＰ浓度为２．６６±２．０８ｍｇ／Ｌ，较相应对照组显著升高（Ｐ＜０．０１）。结论：该法具有方便、快速、准确、特异等优点，对了解ＣＥＴＰ在动脉粥样硬化发生中的作用有着十分重要的意义。

高脂血症人群血清胆固醇酯转运蛋白的水平

目的分析不同高脂血症人群血清胆固醇酯转运蛋白水平及其对血浆各脂蛋白间脂质转运的调节作用。方法脂蛋白电泳结合酶显色法分别检测血清各脂蛋白中的甘油三酯含量;酶联免疫吸附试验测定血清胆固醇酯转运蛋白和氧化型低密度脂蛋白水平;分析胆固醇酯转运蛋白与脂质水平间的相关性。结果高甘油三酯组、高胆固醇组、混合组和对照组中胆固醇酯转运蛋白水平分别为1.89±1.32、2.37±1.30、2.33±1.73和1.58±1.00 mg/L,与对照组比较,高甘油三酯组变化无显著性(P>0.05),高胆固醇组(P<0.01)和混合组均升高(P<0.05)。高脂血症人群高密度脂蛋白中胆固醇/甘油三酯比值降低;高甘油三酯组和混合组低密度脂蛋白中甘油三酯/胆固醇比值升高,高胆固醇组无差别,其中高甘油三酯组变化程度最大,混合组次之,高胆固醇组最小;且胆固醇酯转运蛋白水平与上述比值相关。高脂血症人群血清氧化型低密度脂蛋白水平升高,与低密度脂蛋白中甘油三酯/胆固醇比值高度呈正相关。结论高脂血症人群胆固醇酯转运蛋白水平升高,促进了脂蛋白间脂质转运,使高密度脂蛋白和低密度脂蛋白脂质组成发生变化,促进了动脉粥样硬化的发生和发展。

胆固醇酯转运蛋白基因变异与血脂和动脉粥样硬化性心血管病的关系

胆固醇酯转运蛋白(CETP)介导血浆脂蛋白之间胆固醇酯、磷脂和三酰甘油的转运,直接关联各种脂蛋白分子的组成、大小和浓度,与动脉粥样硬化的发生发展密切相关。CETP基因存在着多种变异,影响CETP浓度和活性,引起机体的脂代谢异常。作者就有关CETP基因变异与脂类参数、心血管疾病发生风险性关系的研究进展作一综述。

胆固醇酯转运蛋白及其基因多态性与2型糖尿病大血管病变的关系

探讨胆固醇酯转运蛋白在 2型糖尿病大血管病变发生中所起的作用及胆固醇酯转运蛋白TaqⅠB基因多态性与大血管病变的关系。对 96例正常对照者及 2 2 6例 2型糖尿病患者的血清胆固醇酯转运蛋白水平及胆固醇酯转运蛋白TaqⅠB基因型进行研究。结果发现 :① 2型糖尿病组胆固醇酯转运蛋白水平较正常对照组明显升高 ,大血管病变组升高更显著 ;②糖尿病大血管病变组B1B1基因型频率 (37.3% )显著高于无大血管病变组(16 .4 % ) ,B1B1基因型大血管病变发生率 (6 8.3% )明显高于B1B2 (4 6 .6 % )和B2B2 (2 9.1% )型 ;③多元回归分析显示 ,高胆固醇酯转运蛋白水平和B1等位基因是 2型糖尿病大血管病变的危险因素。提示 :① 2型糖尿病患者血清胆固醇酯转运蛋白水平升高 ,后者是 2型糖尿病大血管病变的危险因素 ;②胆固醇酯转运蛋白TaqⅠB基因多态性与 2型糖尿病大血管病变发生有关 ,B1等位基因是 2型糖尿病大血管病变的易感基因。

胆固醇酯转运蛋白基因15外显子D442G突变的检测

应用聚合酶链反应 限制性片段长度多态性分析 (PCR RFLP)的方法检测 110例脑动脉粥样硬化患者胆固醇酯转运蛋白 (CETP)基因 15外显子D44 2G错义突变。首先用聚合酶链反应特异性扩增包含人CETP基因 15外显子第 15 0 6位碱基的基因序列 ,扩增产物用限制性内切酶MspⅠ酶切 ,聚丙烯酰胺凝胶电泳后分析结果。 110例脑动脉粥样硬化患者中发现 4例杂合突变 ,突变率 3 6 % ,与对照组 4%比较无明显差异。该方法简单、快速、准确 ,适合于一般实验室开展及大规模人群调查。

胆固醇酯转运蛋白D^(442)→G突变对高密度脂蛋白胆固醇水平的影响

目的探讨胆固醇酯转运蛋白D442→G变异对国人血脂水平的影响。方法收集天津地区189例健康人群,检测其血脂水平,并应用聚合酶链反应限制片长多态性分析方法对胆固醇酯转运蛋白D442→G突变进行检测。结果高密度脂蛋白胆固醇水平较高组与对照组D442→G等位基因频率分别为6.03%和1.53%,具有统计学差异(P<0.05)。D442→G基因变异携带组高密度脂蛋胆固醇水平显著高于对照组(P<0.01),其它血脂水平无显著性差异。结论胆固醇酯转运蛋白第15外显子D442→G突变与高密度脂蛋白胆固醇水平升高密切相关。