本文選題：NME8　切入點(diǎn)：rs2718058　出處：《青島大學(xué)》2017年碩士論文　論文類型：學(xué)位論文

【摘要】：研究背景及目的隨著世界人口老齡化不斷的加劇,阿爾茨海默病(Alzheimer’s disease,AD)現(xiàn)已成為繼心腦血管病和腫瘤之外,危害老年人生命健康的“第三大殺手”。目前,全球有5000萬人患有該疾病,并到2050年時(shí),AD患病人數(shù)將會(huì)增加3倍。遲發(fā)型阿爾茨海默病(Late-onset Alzheimer's disease,LOAD)是最常見的AD類型,發(fā)病率占AD總數(shù)90%以上,由基因突變與環(huán)境因素共同作用引起,其中基因因素對(duì)LOAD的發(fā)病具有重要的影響。LOAD是一種多基因遺傳病,其遺傳具有復(fù)雜性和異質(zhì)性。到目前為止,Apoe基因是唯一公認(rèn)的與LOAD發(fā)病風(fēng)險(xiǎn)有關(guān)的易感基因,在其發(fā)生與發(fā)展中起著重要作用。研究顯示,LOAD遺傳性非常高,可以達(dá)到58%-79%,然而,Apoeε4等位基因占LOAD基因易感性的比重卻不足50%。研究表明,約50%的LOAD患者并沒有攜帶Apoeε4等位基因,據(jù)此并不能完全解釋LOAD的遺傳性。由此可見,Apoeε4仍不能構(gòu)成LOAD的充分必要條件。鑒于此,這也提示了我們,可能存在除Apoe基因外的候選基因決定了LOAD的遺傳易感性。最近一項(xiàng)Meta分析在高加索人群中發(fā)現(xiàn)位于7號(hào)染色體上的編碼NME/NM23家族成員8基因(NME8)(rs2718058)與LOAD的發(fā)病風(fēng)險(xiǎn)具有強(qiáng)烈的關(guān)聯(lián)性。人類的NME8基因位于7p14.1區(qū),NME8基因多態(tài)性在神經(jīng)系統(tǒng)中扮演著很重要的作用,它參與細(xì)胞骨架的形成、軸突運(yùn)輸與抗氧化反應(yīng)。由于遺傳異質(zhì)性,基因突變與基因的頻率在不同的種族之間可能不盡相同,并且加之地域、飲食文化的不同,基因?qū)OAD發(fā)病風(fēng)險(xiǎn)影響也會(huì)存在差異。目前NME8基因多態(tài)性(rs2718058)與中國北方漢族人群LOAD的關(guān)聯(lián)性還未進(jìn)行驗(yàn)證。因此,本研究旨在闡明NME8基因多態(tài)性與中國北方漢族人群遲發(fā)型阿爾茨海默病發(fā)病風(fēng)險(xiǎn)之間的相關(guān)性。方法本研究采用病例-對(duì)照的研究方法,共收集LOAD病例組992例(其中剔除存在異常數(shù)據(jù)個(gè)體8名)和對(duì)照組1358例(其中剔除存在異常數(shù)據(jù)個(gè)體4名),兩組根據(jù)年齡、性別相匹配,且均為中國北方漢族人群。應(yīng)用高通量SNPscan技術(shù),對(duì)NME8基因的功能性位點(diǎn)rs2718058進(jìn)行基因分型,應(yīng)用聚合酶鏈反應(yīng)-連接酶測定反應(yīng)(PCR-LDR)技術(shù)對(duì)基因Apoe進(jìn)行分型后,分別應(yīng)用卡方檢驗(yàn)和Logistic回歸分析探究rs2718058位點(diǎn)與LOAD之間的相關(guān)性�？紤]到種族差異及樣本量等影響因素,我們整理了目前國際發(fā)表的關(guān)于rs2718058的所有病例-對(duì)照研究,包括高加索人群、西班牙人群、中國南方漢族人群與中國北方漢族人群,對(duì)其進(jìn)行Meta分析(病例組共納入29060名研究個(gè)體,對(duì)照組共納入53653名研究個(gè)體)進(jìn)一步闡釋rs2718058多態(tài)性與中國北方漢族人群LOAD發(fā)病風(fēng)險(xiǎn)之間的相關(guān)性。結(jié)果我們一共研究了2338名中國北方漢族人群,包括984名LOAD患者和1354名健康對(duì)照者。LOAD組與對(duì)照組之間的年齡和性別分布無明顯差異(p0.05)。LOAD病例組的MMSE評(píng)分明顯低于對(duì)照組患者。Apoeε4等位基因的頻率分布在兩組之間具有明顯的差異性(P0.001,OR=2.422,95%CI=1.970~2.977).經(jīng)計(jì)算后,LOAD病例組的G最小等位基因頻率略高于對(duì)照組(22.9%versus 21.3%)。經(jīng)多元線性Logistic回歸分析去除混雜因素(年齡、性別、MMSE評(píng)分、載脂蛋白Eε4)影響后,未發(fā)現(xiàn)rs2718058位點(diǎn)與LOAD存在密切的相關(guān)性。進(jìn)一步將樣本按載脂蛋白(apoprotein E,Apoe)ε4分層后,在Apoeε4攜帶者與非攜帶者人群中,仍然未發(fā)現(xiàn)rs2718058位點(diǎn)與LOAD存在密切的相關(guān)性。最后,我們在對(duì)82513人群的總樣本(包括高加索人群、中國北方和南方漢族人群)meta分析中,發(fā)現(xiàn)rs2718058與遲發(fā)型阿爾茨海默病存在關(guān)聯(lián)(OR=1.08,95%CI=1.05~1.11)。然而,在中國北方漢族人群亞組的meta分析中,我們發(fā)現(xiàn)rs2718058與遲發(fā)型阿爾茨海默病不存在明顯的關(guān)聯(lián)(OR=1.05,95%CI=0.93~1.17)。結(jié)論我們發(fā)現(xiàn),在中國北方漢族人群中,NME8基因多態(tài)性與遲發(fā)型阿爾茨海默病發(fā)病風(fēng)險(xiǎn)之間不存在明顯的相關(guān)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.

【學(xué)位授予單位】：青島大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R749.16

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