中国北方汉族人群NME8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：2018-03-04 16:10

本文选题：NME8　切入点：rs2718058　出处：《青岛大学》2017年硕士论文　论文类型：学位论文

【摘要】：研究背景及目的随着世界人口老龄化不断的加剧,阿尔茨海默病(Alzheimer’s disease,AD)现已成为继心脑血管病和肿瘤之外,危害老年人生命健康的“第三大杀手”。目前,全球有5000万人患有该疾病,并到2050年时,AD患病人数将会增加3倍。迟发型阿尔茨海默病(Late-onset Alzheimer's disease,LOAD)是最常见的AD类型,发病率占AD总数90%以上,由基因突变与环境因素共同作用引起,其中基因因素对LOAD的发病具有重要的影响。LOAD是一种多基因遗传病,其遗传具有复杂性和异质性。到目前为止,Apoe基因是唯一公认的与LOAD发病风险有关的易感基因,在其发生与发展中起着重要作用。研究显示,LOAD遗传性非常高,可以达到58%-79%,然而,Apoeε4等位基因占LOAD基因易感性的比重却不足50%。研究表明,约50%的LOAD患者并没有携带Apoeε4等位基因,据此并不能完全解释LOAD的遗传性。由此可见,Apoeε4仍不能构成LOAD的充分必要条件。鉴于此,这也提示了我们,可能存在除Apoe基因外的候选基因决定了LOAD的遗传易感性。最近一项Meta分析在高加索人群中发现位于7号染色体上的编码NME/NM23家族成员8基因(NME8)(rs2718058)与LOAD的发病风险具有强烈的关联性。人类的NME8基因位于7p14.1区,NME8基因多态性在神经系统中扮演着很重要的作用,它参与细胞骨架的形成、轴突运输与抗氧化反应。由于遗传异质性,基因突变与基因的频率在不同的种族之间可能不尽相同,并且加之地域、饮食文化的不同,基因对LOAD发病风险影响也会存在差异。目前NME8基因多态性(rs2718058)与中国北方汉族人群LOAD的关联性还未进行验证。因此,本研究旨在阐明NME8基因多态性与中国北方汉族人群迟发型阿尔茨海默病发病风险之间的相关性。方法本研究采用病例-对照的研究方法,共收集LOAD病例组992例(其中剔除存在异常数据个体8名)和对照组1358例(其中剔除存在异常数据个体4名),两组根据年龄、性别相匹配,且均为中国北方汉族人群。应用高通量SNPscan技术,对NME8基因的功能性位点rs2718058进行基因分型,应用聚合酶链反应-连接酶测定反应(PCR-LDR)技术对基因Apoe进行分型后,分别应用卡方检验和Logistic回归分析探究rs2718058位点与LOAD之间的相关性。考虑到种族差异及样本量等影响因素,我们整理了目前国际发表的关于rs2718058的所有病例-对照研究,包括高加索人群、西班牙人群、中国南方汉族人群与中国北方汉族人群,对其进行Meta分析(病例组共纳入29060名研究个体,对照组共纳入53653名研究个体)进一步阐释rs2718058多态性与中国北方汉族人群LOAD发病风险之间的相关性。结果我们一共研究了2338名中国北方汉族人群,包括984名LOAD患者和1354名健康对照者。LOAD组与对照组之间的年龄和性别分布无明显差异(p0.05)。LOAD病例组的MMSE评分明显低于对照组患者。Apoeε4等位基因的频率分布在两组之间具有明显的差异性(P0.001,OR=2.422,95%CI=1.970~2.977).经计算后,LOAD病例组的G最小等位基因频率略高于对照组(22.9%versus 21.3%)。经多元线性Logistic回归分析去除混杂因素(年龄、性别、MMSE评分、载脂蛋白Eε4)影响后,未发现rs2718058位点与LOAD存在密切的相关性。进一步将样本按载脂蛋白(apoprotein E,Apoe)ε4分层后,在Apoeε4携带者与非携带者人群中,仍然未发现rs2718058位点与LOAD存在密切的相关性。最后,我们在对82513人群的总样本(包括高加索人群、中国北方和南方汉族人群)meta分析中,发现rs2718058与迟发型阿尔茨海默病存在关联(OR=1.08,95%CI=1.05~1.11)。然而,在中国北方汉族人群亚组的meta分析中,我们发现rs2718058与迟发型阿尔茨海默病不存在明显的关联(OR=1.05,95%CI=0.93~1.17)。结论我们发现,在中国北方汉族人群中,NME8基因多态性与迟发型阿尔茨海默病发病风险之间不存在明显的相关性。
[Abstract]:Background and objective: with the aging of world population intensified, Alzheimer's disease (Alzheimer 's disease, AD) has become the outside of cardiovascular disease and cancer, endanger life and health of the elderly in the third "killer". At present, there are 50 million people worldwide suffer from the disease, and by 2050, the number of patients will be AD an increase of 3 times. Late onset Alzheimer's disease (Late-onset Alzheimer's, disease, LOAD) is the most common type of AD, the incidence of AD accounted for more than 90% of the total, and environmental factors caused by gene mutation, which was due to the onset of LOAD gene has an important effect of.LOAD is a polygenic disease, it is genetic the complexity and heterogeneity. So far, the Apoe gene is the only recognized risk associated with LOAD susceptibility gene, plays an important role in its occurrence and development. The research shows that LOAD is hereditary High, can reach 58%-79%, however, the Apoe 4 allele proportion of LOAD susceptibility was less than 50%. research shows that about 50% of LOAD patients did not carry the Apoe 4 allele, genetic based LOAD can not fully explain. Thus, the Apoe 4 still can not constitute a sufficient and necessary condition for LOAD in view of this, it also reminds us that there may be a candidate gene except Apoe gene determines the genetic susceptibility to LOAD. A recent analysis of Meta is located on chromosome 7 and 8 genes encoding NME/NM23 family members found in Caucasian population (NME8) (rs2718058) has a strong association with the risk of LOAD. Human NME8 gene is located in 7p14.1 region, NME8 gene polymorphism plays a very important role in the nervous system, it involved in cytoskeleton, axonal transport and antioxidant responses. Because of genetic heterogeneity, gene mutation and gene The frequency may vary between different races, and combined with the region, the diet culture is different, the genes influence the risk of LOAD will be different. The polymorphism of NME8 gene (rs2718058) associated with LOAD in Han population in northern Chinese has not been validated. Because of this, the purpose of this study is to clarify the correlation between NME8 gene polymorphism and Chinese northern Han population between late onset Alzheimer's disease risk. The research method of case-control study, LOAD collected a total of 992 cases (including abnormal data eliminating 8 individuals) and a control group of 1358 cases (including abnormal data eliminating 4 individuals), two groups according to age and gender matched, and are Han China north. Application of high-throughput SNPscan technology, the function of NME8 gene loci rs2718058 were genotyped by polymerase chain reaction ligase detection Reaction (PCR-LDR) technique on Apoe gene typing, respectively using chi square test and Logistic regression analysis to explore the correlation between rs2718058 locus and LOAD. Considering the influence factors of racial differences and sample size, we sort out the all cases about rs2718058 international published case-control study, including Caucasian, Spain the crowd, China and China in Han population of South Han population, the Meta analysis (29060 of individuals were included in the study group and the control group were included in the study of 53653 individuals) further interpretation of correlation between rs2718058 polymorphism and Chinese northern Han population LOAD risk. Results we studied 2338 China northern Han population, including 984 LOAD patients and 1354 healthy controls were age and gender distribution between the.LOAD group and the control group had no significant difference (P0.05).LOAD disease The frequency distribution of the group with MMSE score was significantly lower than that of the control group.Apoe 4 allele has obvious differences between the two groups (P0.001, OR=2.422,95%CI=1.970~2.977). After computing LOAD group G minimum allele frequency slightly higher than the control group (22.9%versus 21.3%). The multivariate linear regression analysis of Logistic removal confounding factors (age, gender, MMSE score, apolipoprotein E epsilon 4) after effects were not found in rs2718058 site and LOAD are closely correlated. Further the sample according to the apolipoprotein (apoprotein E, Apoe) - 4 after stratification in Apoe 4 allele carriers and non carriers in the crowd, still not found rs2718058 there is a close correlation between sites and LOAD. Finally, we in the total sample of 82513 people (including Caucasian population, Chinese northern and Southern Han population) in meta analysis, rs2718058 and late-onset Alzheimer's disease exist Contact (OR=1.08,95%CI=1.05~1.11). However, in the meta subgroup analysis Chinese northern Han population, we found that rs2718058 and late-onset Alzheimer's disease had no obvious correlation (OR=1.05,95%CI=0.93~1.17). Conclusion we found that Chinese in northern Han people, there is no obvious correlation between NME8 gene polymorphism and late onset Alzheimer's disease risk.

【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

【参考文献】