【摘要】：目的近幾年來(lái),大量的研究表明在阿爾茨海默病(Alzheimer disease,AD)的發(fā)病機(jī)理中,遺傳因素占據(jù)不可或缺的地位,基因突變學(xué)說(shuō)成為了人們研究的焦點(diǎn)。近期一項(xiàng)大型的包含兩個(gè)階段的關(guān)于AD全基因組關(guān)聯(lián)性分析研究(genome-wide association study,GWAS)發(fā)現(xiàn)了除APP、PS1、PS2和APOE基因以外的11個(gè)新的基因與AD的發(fā)病風(fēng)險(xiǎn)具有相關(guān)性,ZCWPW1基因是其中一個(gè)風(fēng)險(xiǎn)基因。我們對(duì)ZCWPW1基因的相關(guān)文獻(xiàn)進(jìn)行了收集和整理,發(fā)現(xiàn)其與AD的相關(guān)性?xún)H在高加索人群、西班牙人群中得到證實(shí),但在中國(guó)漢族人群中是否也存在該種關(guān)聯(lián)性不得而知。我們的研究旨在闡明ZCWPW1基因的多態(tài)性與遲發(fā)型阿爾茨海默病(Late-onset Alzheimer’s Disease,LOAD)在中國(guó)北方漢族人群中的相關(guān)性,并對(duì)其參與AD發(fā)病機(jī)制的途徑進(jìn)行分析,以為尋找新的AD治療策略奠定理論基礎(chǔ)。方法本研究采用病例-對(duì)照研究方法,遵循嚴(yán)格的納入和排除標(biāo)準(zhǔn),共收集了992例LOAD患者(病例組)和1358例健康人群(對(duì)照組)的大樣本(兩組研究對(duì)象的年齡、性別相匹配,種族為中國(guó)北方漢族人群)作為研究對(duì)象。通過(guò)一項(xiàng)關(guān)于LOAD的GWAS研究,選取了ZCWPW1基因的一個(gè)功能性位點(diǎn)rs1476679,應(yīng)用聚合酶鏈反應(yīng)-連接酶檢測(cè)反應(yīng)(PCR-LDR)技術(shù)對(duì)其進(jìn)行了基因分型,應(yīng)用改良的多路連接酶檢測(cè)反應(yīng)技術(shù)(i MLDR)對(duì)APOE進(jìn)行了基因分型,用卡方檢驗(yàn)和Logistic回歸等統(tǒng)計(jì)方法分析其與LOAD的相關(guān)性。此外,我們還對(duì)82525例不同人種的人群個(gè)體進(jìn)行了薈萃(Meta)分析,以進(jìn)一步探討ZCWPW1基因與LOAD的發(fā)病率在不同人群中的相關(guān)性。結(jié)果通過(guò)對(duì)樣本進(jìn)行詳細(xì)的數(shù)據(jù)分析,提示ZCWPW1基因rs1476679多態(tài)性位點(diǎn)與LOAD具有密切相關(guān)性(基因型P=0.017,等位基因P=0.044)。在顯性模型中,經(jīng)Logistic回歸分析去除混雜因素(年齡、性別、APOEε4)影響后,可得出rs1476679的最小等位基因(C等位基因)是降低LOAD發(fā)病風(fēng)險(xiǎn)的一個(gè)保護(hù)性因素(OR=0.779,95%CI=0.659-0.921,Pc=0.009)。進(jìn)一步將樣本進(jìn)行APOEε4分層后,在APOEε4非攜帶者人群中,ZCWPW1基因rs1476679位點(diǎn)可分別在顯性模型(OR=0.733,95%CI=0.607 0.884,Pc=0.006)及疊加模型(OR=0.820,95%CI=0.708 0.950,Pc=0.048)中降低LOAD的發(fā)病風(fēng)險(xiǎn),說(shuō)明ZCWPW1基因可作為一個(gè)獨(dú)立性因素降低LOAD的發(fā)病率。此外,本研究進(jìn)一步對(duì)近期ZCWPW1相關(guān)研究的原始數(shù)據(jù)進(jìn)行整合,設(shè)計(jì)了一個(gè)包含82525個(gè)體的Meta分析,進(jìn)一步確認(rèn)了ZCWPW1基因功能性位點(diǎn)rs1476679可降低LOAD的患病率(OR=0.91,95%CI=0.89-0.94),這個(gè)結(jié)論與我們的研究結(jié)果相一致。結(jié)論我們的研究發(fā)現(xiàn),在中國(guó)漢族人群中,ZCWPW1基因多態(tài)性與LOAD的發(fā)病風(fēng)險(xiǎn)密切相關(guān),其可作為一獨(dú)立的保護(hù)性因素降低LOAD的發(fā)病率。在此基礎(chǔ)上,對(duì)于ZCWPW1基因及其區(qū)域內(nèi)相關(guān)基因和位點(diǎn)的結(jié)構(gòu)及生物學(xué)特性進(jìn)行更深入的研究,以探討ZCWPW1以何種途徑或通路參與LOAD的發(fā)病機(jī)制,并以此為基礎(chǔ)為L(zhǎng)OAD的治療策略提供一種新的思路。
[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.
【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(lèi)號(hào)】：R749.16

【參考文獻(xiàn)】

相關(guān)期刊論文 前10條

1 ZHANG Tian-Zhu;YANG Shi-Hai;YAO Jin-Fu;DU Juan;YAN Tian-hua;;Sangxingtang inhibits the inflammation of LPS-induced acute lung injury in mice by down-regulating the MAPK/NF-κB pathway[J];Chinese Journal of Natural Medicines;2015年12期

2 MA WeiXu;MA Ning;CHEN XiaoHui;ZHANG YiYue;ZHANG WenQing;;An overview of chronic myeloid leukemia and its animal models[J];Science China(Life Sciences);2015年12期

3 Xi Zha;Xiaohong Xu;;Dissecting the hypothalamic pathways that underlie innate behaviors[J];Neuroscience Bulletin;2015年06期

4 Cristina Angeloni;Marco Malaguti;Silvana Hrelia;;Antiglycative activity of sulforaphane: a new avenue to counteract neurodegeneration?[J];Neural Regeneration Research;2015年11期

5 秦俊法;;微量元素與阿爾茨海默病(6)[J];廣東微量元素科學(xué);2015年10期

6 雷小峰;;阿爾茨海默病發(fā)病機(jī)制研究進(jìn)展[J];中外醫(yī)療;2014年23期

7 唐偉;張營(yíng)麗;王威;;阿爾茨海默病發(fā)病機(jī)制的研究進(jìn)展[J];醫(yī)學(xué)與哲學(xué)(B);2014年01期

8 曲艷;劉萍;李曉紅;;阿爾茨海默病生物學(xué)標(biāo)志物研究進(jìn)展[J];醫(yī)學(xué)與哲學(xué)(B);2013年10期

9 高麗霞;盧麗萍;湯亞男;成俊英;;阿爾茨海默病研究進(jìn)展[J];中國(guó)現(xiàn)代醫(yī)生;2012年26期

10 陳建平;;阿爾茨海默病患者腦神經(jīng)遞質(zhì)的無(wú)創(chuàng)性研究[J];廣州醫(yī)藥;2008年01期

，

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