【作者】 齐伟静；

【导师】 张国华；

【作者基本信息】 河北医科大学 ， 神经病学， 2010， 硕士

【摘要】 目的:血管性痴呆(Vascular dementia, VaD)是指在缺血性、出血性及急慢性缺血缺氧性脑血管病引起的脑组织损害基础上产生的以高级神经认知功能障碍为主的一组临床综合征,是痴呆的常见原因,发病率仅次于阿尔茨海默病(AD)。一般认为血管性痴呆的危险因素与中风相同,常见的有高血压、糖尿病、高胆固醇血症、吸烟、心肌梗塞等。近年来对于VaD的遗传学研究越来越受到国内外学者的重视。载脂蛋白E(ApoE)是1973年由Shore等首先发现的一种富含精氨酸的碱性蛋白,人类ApoE基因定位于19号染色体,含有299个氨基酸。ApoE基因具有明显的遗传多态性。ε2、ε3和ε4三种等位基因分别编码产生三种主要的异构体E2、E3和E4,由此产生六种蛋白表型:三种纯合子ε2/2、ε3/3和ε4/4,三种杂合子ε2/3、ε2/4和ε3/4。ApoE是血浆脂蛋白重要组分之一,主要在肝脏和大脑中合成,在体内脂质代谢和神经系统发育及损伤修复过程中均起着重要作用。近年研究表明,载脂蛋白E基因多态性与Alzheimer病密切相关,ApoEε4可增加Alzheimer病发病风险。但载脂蛋白E基因多态性与血管性痴呆的关系,国内外相关研究结果尚存在争议,现以Meta分析的形式探讨我国人群载脂蛋白E基因多态性与血管性痴呆的相关性,以期对血管性痴呆的遗传学病因有进一步认识。方法:用以下中英文关键词:载脂蛋白E、载脂蛋白E基因多态性、ApoE、ApoE基因多态性、血管性痴呆、痴呆、ApolipoproteinE gene、ApolipoproteinE gene polymorphism、ApoE gene、ApoE gene polymorphism、vascular dementia、dementia、VaD和VD,联合检索中国学术期刊全文数据库(CNKI)和中国万方数据库获得全部相关的中文文献,并检索Pubmed、西文生物医学期刊文献数据库(EMCC)以发现在国外非中文期刊上发表的以中国人群为研究对象的文献,检索年限为1998年至2009年,严格按照纳入标准及排除标准筛选文献,对纳入研究的文献进行质量评价、数据提取及统计分析。使用Q检验评估研究之间的异质性,若各项研究之间存在显著异质性(P<0.05),则采用随即效应模型(REM)进行合并;若无显著异质性(P>0.05),则采用固定效应模型(FEM)进行数据合并,并对所得结果进行敏感性分析。漏斗图(Funnel plot)及失安全系数(fail-safe number, Nfs)用来评估发表偏倚。用于衡量ApoE基因多态性与血管性痴呆相关性的指标是各项研究的合并OR值及其95%可信区间,以上统计分析均应用RevMan 4.2软件进行。结果:经文献检索检出1998年至2009年发表的ApoE基因多态性与血管性痴呆的相关性研究文献共78篇(中文文献73篇,英文文献5篇),经纳入标准及排除标准严格筛选后剩余14篇(中文文献11篇,英文文献3篇),经Hardy-Weinberg遗传平衡检验,剔除6篇对照组不符合Hardy-Weinberg遗传平衡定律的文献,剩余8篇符合条件的文献纳入分析,其中中文文献7篇,英文文献1篇,所有文献均为病例-对照研究,总样本数1104例,其中血管性痴呆组416例,正常对照组688例。Q检验结果显示各研究中的基因型频率和等位基因频率不存在显著异质性(P>0.05),均采用固定效应模型进行数据合并。Meta分析结果表明,血管性痴呆组(VaD组)较之正常对照组(NC组)ApoE基因ε4和ε3/4合并OR值及其95%CI分别为2.00[1.50,2.65]、2.12[1.52,2.97],其合并OR值均具有统计学差异(P<0.01);血管性痴呆组(VaD组)较之对照组(NC组)ApoE基因ε3和ε3/3合并OR值及其95%CI分别为0.65[0.52,0.82]、0.59[0.45,0.77],其合并OR值均具有统计学差异(P<0.01);两组间ε2和ε2/2、ε2/3、ε2/4及ε4/4的合并OR值均无统计学差异。进行敏感性分析后所得结果与原结果相似,表明本次Meta分析所得结果稳定、可靠。两组间有统计学差异的等位基因(ε4、ε3)及基因型(ε3/4、ε3/3)的漏斗图均基本对称,失安全系数相对于纳入研究个数(8篇)均较大,表明发表偏倚较小,结果可靠。结论:中国人群血管性痴呆与载脂蛋白E基因多态性关系密切,等位基因ε4可能是血管性痴呆的危险因子,等位基因ε3可能是血管性痴呆的保护因子。更多还原

【Abstract】 Objective: Vascular dementia (VaD) is defined as loss of cognitive function resulting from ischemic, hemorrhagic or hypoperfusive brain lesions due to cerebrovascular disease. VaD is a common cause of dementia, second in prevalence only to Alzheimer’s disease. Vascular dementia and stoke are thought in general terms to share the same risk factors, commonly including hypertension, diabetes, hypercholesterolemia, smoking, myocardial infarction etc. In recent years, genetic research of VaD has received increasing attentions.Apolipoprotein E (ApoE) was first found by Shore in 1973. It is an alkaline protein which is rich of arginine. ApoE gene is localized on chromosome 19 and consists of 299 amino acids. ApoE gene shows significant genetic polymorphism. The three major isoformes (E2, E3 and E4) are the products of three alleles (ε2,ε3 andε4) and consequently produce six genotypes of different combinations of the three isoformes, including three homozygous genotypes (ε2/2,ε3/3 andε4/4) and three heterozygous genotypes (ε2/3,ε2/4 andε3/4). ApoE is a major component of plasma lipoproteins, which is mainly synthesized in liver and brain. It plays an important role both in the metabolism of plasma lipids and in the growth and repair of the nervous system during development or after injury.ApoE gene polymorphism is significantly associated with Alzheimer’s disease and ApoEε4 can increase the risk of Alzheimer’s disease. However the relationship between ApoE gene polymorphism and vascular dementia is still controversial. So we carried out a meta-analysis of case-control studies of sufficient rigor for the purpose of investigating the relationship between ApoE gene polymorphism and vascular dementia in Chinese population to enrich the understanding of the genetic factors in relation to the pathogenesis of vascular dementia.Methods: CNKI, Wanfang Data, Pubmed and EMCC databases were searched for related literatures published from 1998 to 2009. All studies were inclued or excluded based on the inclusion and exclusion criteria. The qualities of the eligible studies were assessed and the data were extracted for statistical analyse. Between-study heterogeneity was explored by Q test, a pooled effect was calculated with a random-effects model (REM) where between-study heterogeneity existed (P<0.05); otherwise, a fixed-effects model (FEM) was used. Sensitivity analysis was done to the results. Publication bias was assessed with funnel plots and fail-safe numbers (Nfs). Odds ratios (ORs) and its 95% CI of ApoE alleles and genotypes distributions in vascular dementia patients and healthy controls were calculated. All analyses were conducted using software RevMan 4.2.Results: Of the 78 identified studies, 8 studies were selected for statistical analysis based on the criteria and Hardy-Weinberg equilibrium testing. All the studies were case-control studies, seven published in Chinese and one in English. The total samples were 1104, 416 of VaD group and 688 of NC group. Q test showed no significant heterogeneity of ApoE alleles frequencies and genotypes frequencies between every study and all pooled effects were calculated with a fixed-effects model (FEM). Meta-analysis results indicated that the pooled ORs and 95% CIs of alleleε4 and genotypeε3/4 of ApoE gene in VaD group as compaired with NC group were 2.00[1.50, 2.65] and 2.12[1.52, 2.97](P<0.01), and the pooled ORs and 95% CIs of alleleε3 and genotypeε3/3 were 0.65[0.52, 0.82] and 0.59[0.45, 0.77](P<0.01). There were no significant differences of alleleε2 or genotypeε2/2,ε2/3,ε2/4 andε4/4 in VaD group as compaired with those in normal control. Sensitivity analysis results were similar to the original results, which proved that the conclusion of this Meta-analysis was stable and reliable. The funnel plots for ApoEε4,ε3 andε3/4,ε3/3 were all symmetrical and the fail-safe numbers were all larger than the number of the selected studies, which indicated that the publication bias were under control and the result was reliable.Conclusions: The results suggests that ApoE gene polymorphism is significantly associated with vascular dementia in Chinese population.ApoEε4 may be a risk factor andε3 may be a protective factor for VaD.更多还原