中国北方汉族人群ZCWPW1基因多态性与迟发型阿尔茨海默病的关联性研究

发布时间：2018-09-09 09:58

【摘要】：目的近几年来,大量的研究表明在阿尔茨海默病(Alzheimer disease,AD)的发病机理中,遗传因素占据不可或缺的地位,基因突变学说成为了人们研究的焦点。近期一项大型的包含两个阶段的关于AD全基因组关联性分析研究(genome-wide association study,GWAS)发现了除APP、PS1、PS2和APOE基因以外的11个新的基因与AD的发病风险具有相关性,ZCWPW1基因是其中一个风险基因。我们对ZCWPW1基因的相关文献进行了收集和整理,发现其与AD的相关性仅在高加索人群、西班牙人群中得到证实,但在中国汉族人群中是否也存在该种关联性不得而知。我们的研究旨在阐明ZCWPW1基因的多态性与迟发型阿尔茨海默病(Late-onset Alzheimer’s Disease,LOAD)在中国北方汉族人群中的相关性,并对其参与AD发病机制的途径进行分析,以为寻找新的AD治疗策略奠定理论基础。方法本研究采用病例-对照研究方法,遵循严格的纳入和排除标准,共收集了992例LOAD患者(病例组)和1358例健康人群(对照组)的大样本(两组研究对象的年龄、性别相匹配,种族为中国北方汉族人群)作为研究对象。通过一项关于LOAD的GWAS研究,选取了ZCWPW1基因的一个功能性位点rs1476679,应用聚合酶链反应-连接酶检测反应(PCR-LDR)技术对其进行了基因分型,应用改良的多路连接酶检测反应技术(i MLDR)对APOE进行了基因分型,用卡方检验和Logistic回归等统计方法分析其与LOAD的相关性。此外,我们还对82525例不同人种的人群个体进行了荟萃(Meta)分析,以进一步探讨ZCWPW1基因与LOAD的发病率在不同人群中的相关性。结果通过对样本进行详细的数据分析,提示ZCWPW1基因rs1476679多态性位点与LOAD具有密切相关性(基因型P=0.017,等位基因P=0.044)。在显性模型中,经Logistic回归分析去除混杂因素(年龄、性别、APOEε4)影响后,可得出rs1476679的最小等位基因(C等位基因)是降低LOAD发病风险的一个保护性因素(OR=0.779,95%CI=0.659-0.921,Pc=0.009)。进一步将样本进行APOEε4分层后,在APOEε4非携带者人群中,ZCWPW1基因rs1476679位点可分别在显性模型(OR=0.733,95%CI=0.607 0.884,Pc=0.006)及叠加模型(OR=0.820,95%CI=0.708 0.950,Pc=0.048)中降低LOAD的发病风险,说明ZCWPW1基因可作为一个独立性因素降低LOAD的发病率。此外,本研究进一步对近期ZCWPW1相关研究的原始数据进行整合,设计了一个包含82525个体的Meta分析,进一步确认了ZCWPW1基因功能性位点rs1476679可降低LOAD的患病率(OR=0.91,95%CI=0.89-0.94),这个结论与我们的研究结果相一致。结论我们的研究发现,在中国汉族人群中,ZCWPW1基因多态性与LOAD的发病风险密切相关,其可作为一独立的保护性因素降低LOAD的发病率。在此基础上,对于ZCWPW1基因及其区域内相关基因和位点的结构及生物学特性进行更深入的研究,以探讨ZCWPW1以何种途径或通路参与LOAD的发病机制,并以此为基础为LOAD的治疗策略提供一种新的思路。
[Abstract]:Objective in recent years, a large number of studies have shown that genetic factors play an indispensable role in the pathogenesis of Alzheimer's disease (Alzheimer disease,AD), and the theory of gene mutation has become the focus of research. A large two-stage AD genome-wide association analysis (genome-wide association study,GWAS) study recently found that 11 new genes other than APP,PS1,PS2 and APOE genes are associated with the risk of AD. ZCWPW1 gene is one of the risk genes. We collected and collated the related literatures of ZCWPW1 gene, and found that the correlation between AD and AD was only confirmed in Caucasian population and Spanish population, but it is not known whether there is this kind of association in Chinese Han population. Our aim of our study was to elucidate the association between ZCWPW1 gene polymorphism and delayed Alzheimer's disease (Late-onset Alzheimer's Disease,LOAD) in the Han population of northern China, and to analyze the pathway of its involvement in the pathogenesis of AD. To find a new treatment strategy for AD to lay a theoretical foundation. Methods A total of 992 cases of LOAD patients (case group) and 1358 healthy people (control group) were collected by using a case-control study, followed by strict inclusion and exclusion criteria. Race as the Han population in northern China) as the research object. Through a GWAS study on LOAD, a functional site of the ZCWPW1 gene, rs1476679, was selected for genotyping by polymerase chain reaction-ligase assay (PCR-LDR). The genotyping of APOE was carried out by modified multiplex ligase assay (i MLDR). The correlation between APOE and LOAD was analyzed by chi-square test and Logistic regression. In addition, 82525 individuals of different ethnic groups were analyzed by meta-( Meta) to further explore the correlation between the incidence of ZCWPW1 gene and the incidence of LOAD in different populations. Results through the detailed data analysis of the samples, it was suggested that the rs1476679 polymorphism of ZCWPW1 gene was closely related to LOAD (genotype P0. 017, allele P0. 044). In the dominant model, the minimum allele (C allele) of rs1476679 was found to be a protective factor (OR=0.779,95%CI=0.659-0.921,Pc=0.009) to reduce the risk of LOAD after removing the influence of confounding factors (age, sex) by Logistic regression analysis. After further stratification of APOE 蔚 4, the rs1476679 locus of ZCWPW1 gene decreased the risk of LOAD in the dominant model (OR=0.733,95%CI=0.607 0.884) and the superposition model (OR=0.820,95%CI=0.708 0.950 PcCN 0.048) in the APOE 蔚 4 non-carrier population, respectively. The results suggest that ZCWPW1 gene can be used as an independent factor to reduce the incidence of LOAD. In addition, this study further integrates the original data from recent ZCWPW1 related studies and designs a Meta analysis containing 82525 individuals. It was further confirmed that rs1476679, a functional locus of ZCWPW1 gene, can reduce the prevalence of LOAD (OR=0.91,95%CI=0.89-0.94), which is consistent with our findings. Conclusion our study found that the polymorphism of ZCWPW1 gene is closely related to the risk of LOAD in Chinese Han population, and it can be used as an independent protective factor to reduce the incidence of LOAD. On the basis of this, the structure and biological characteristics of ZCWPW1 gene and its related genes and loci were studied in order to explore the pathway or pathway of ZCWPW1 involved in the pathogenesis of LOAD. On this basis, it provides a new idea for the treatment strategy of LOAD.
【学位授予单位】：青岛大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R749.16

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