本文選題：因果推斷檢驗(yàn)　切入點(diǎn)：表觀遺傳標(biāo)記　出處：《山西醫(yī)科大學(xué)》2017年碩士論文　論文類(lèi)型：學(xué)位論文

【摘要】：目的:上皮性卵巢癌(EOC)是美國(guó)女性因婦科惡性腫瘤導(dǎo)致死亡的主要原因,同時(shí)同時(shí)也是惡性腫瘤引起美國(guó)女性死亡的第五大原因。EOC的早期診斷缺乏成功,及其所帶來(lái)的大量機(jī)體、社會(huì)和經(jīng)濟(jì)負(fù)擔(dān),迫切需要研究者們?nèi)パ芯亢完U明EOC的分子基礎(chǔ)。關(guān)于飲酒與EOC的關(guān)系,相關(guān)研究結(jié)果還未達(dá)成一致,部分研究表明飲用果酒可以減小EOC發(fā)生的風(fēng)險(xiǎn)。關(guān)于飲酒與DNA甲基化的關(guān)系,有研究表明飲酒可引起某些位點(diǎn)DNA甲基化改變,而特異位點(diǎn)DNA甲基化改變是EOC發(fā)生的早期步驟,可能參與EOC的發(fā)病機(jī)制。因此如果EOC相關(guān)聯(lián)的DNA甲基化改變是受飲酒調(diào)節(jié)的話,就為特異DNA甲基化位點(diǎn)及其位置基因作為靶點(diǎn)在EOC預(yù)防和治療中的作用提供依據(jù)。本研究旨在發(fā)現(xiàn)特異位點(diǎn)DNA甲基化改變作為飲酒與EOC間潛在的中介因素。方法:采用高維因果推斷檢驗(yàn)方法和VanderWeele中介模型檢驗(yàn)飲酒、DNA甲基化和EOC三者的統(tǒng)計(jì)因果關(guān)聯(lián)。本研究中采用“去稀疏化”Lasso高維檢驗(yàn)方法替代因果推斷檢驗(yàn)(CIT)過(guò)程的第二步檢驗(yàn),將高維檢驗(yàn)方法和CIT檢驗(yàn)過(guò)程相結(jié)合應(yīng)用在表觀遺傳組學(xué)的高維數(shù)據(jù)分析中。研究對(duì)象由Mayo臨床卵巢癌研究中196例上皮性卵巢癌病例和202例對(duì)照組成。全基因組DNA甲基化數(shù)據(jù)由398例研究對(duì)象外周血白細(xì)胞DNA甲基化水平測(cè)定。結(jié)果:1、CIT檢驗(yàn)過(guò)程第一步分析結(jié)果表明飲酒與EOC有關(guān)聯(lián),OR=0.336,95%CI[0.169,0.651],P=0.001;第二步分析結(jié)果表明控制飲酒變量后,EOC與3,055個(gè)CpG位點(diǎn)有關(guān)聯(lián);第三步分析結(jié)果表明控制EOC后,飲酒與61個(gè)CpG位點(diǎn)有關(guān)聯(lián);第四步分析結(jié)果表明分別控制2個(gè)CpG位點(diǎn)后,飲酒與EOC相互獨(dú)立。綜合四步研究結(jié)果,CIT過(guò)程共檢驗(yàn)出2個(gè)CpG位點(diǎn)(cg11016563,cg09358725)作為中介因子,對(duì)飲酒-EOC發(fā)揮中介效應(yīng)。2、采用VanderWeele中介模型對(duì)CIT檢驗(yàn)結(jié)果進(jìn)行交叉驗(yàn)證后,進(jìn)一步證實(shí)2個(gè)CpG位點(diǎn)是重要的中介因子,飲酒通過(guò)調(diào)節(jié)2個(gè)CpG位點(diǎn)的甲基化水平繼而對(duì)EOC產(chǎn)生影響。3、cg11016563的基因符號(hào)為T(mén)RPC6,TRPC6基因過(guò)表達(dá)與EOC的關(guān)聯(lián)已有研究報(bào)道。本文提示TRPC6基因啟動(dòng)子區(qū)CpG島cg11016563位點(diǎn)低甲基化可能通過(guò)調(diào)節(jié)TRPC6基因表達(dá)而對(duì)EOC產(chǎn)生影響。4、cg09358725的基因符號(hào)為L(zhǎng)MO2,本文提示LMO2基因可能與EOC有關(guān)聯(lián)。結(jié)論:1、首次發(fā)現(xiàn)2個(gè)CpG位點(diǎn)作為中介因子,飲酒通過(guò)調(diào)節(jié)其甲基化水平繼而對(duì)EOC產(chǎn)生影響。提示2個(gè)CpG位點(diǎn)可能作為EOC發(fā)病機(jī)制中新的生物標(biāo)記物。2、TRPC6基因在卵巢癌細(xì)胞中的過(guò)表達(dá)可能受其啟動(dòng)子區(qū)CpG島上cg11016563位點(diǎn)的低甲基化影響。LMO2基因可能與EOC有關(guān)聯(lián)。3、本文提示統(tǒng)計(jì)因果推斷過(guò)程能有效檢驗(yàn)環(huán)境因素、表觀遺傳改變和疾病三者間的統(tǒng)計(jì)因果關(guān)聯(lián)。4、本文提示高維檢驗(yàn)方法與因果推斷檢驗(yàn)過(guò)程相結(jié)合可以改進(jìn)表觀遺傳組等高維數(shù)據(jù)的因果推斷過(guò)程。
[Abstract]:Objective: epithelial ovarian cancer (EOC) is the leading cause of death in women with gynecological malignancies in the United States, and it is also the leading cause of death in women in the United States. The early diagnosis of EOC is not successful. There is an urgent need for researchers to study and elucidate the molecular basis of EOC and the large amount of body, social and economic burdens it brings. There is no agreement on the relationship between alcohol consumption and EOC. Some studies have shown that drinking fruit wine can reduce the risk of EOC. As to the relationship between alcohol consumption and DNA methylation, some studies have shown that drinking alcohol can cause DNA methylation changes at some sites, while DNA methylation at specific sites is the early step of EOC. May be involved in the pathogenesis of EOC. So if the DNA methylation changes associated with EOC are regulated by alcohol consumption, The purpose of this study was to find out that the methylation of specific DNA sites and their location genes may act as potential mediators between alcohol consumption and EOC in the prevention and treatment of EOC. High dimensional causality inference test method and VanderWeele intermediary model were used to test the statistical causal relationship between Lasso methylation and EOC. In this study, the "de-sparse" Lasso high-dimensional test method was used to replace the second step test of causality inference test. The high dimensional test method and the CIT test procedure were used in the analysis of high dimensional data of epigenetics. The subjects were 196 cases of epithelial ovarian cancer and 202 cases of control group in Mayo clinical ovarian cancer study. DNA methylation data were measured by peripheral blood leukocyte DNA methylation level in 398 subjects. Results the first step analysis of EOC test showed that there was a correlation between alcohol consumption and EOC, CI [0.169 鹵0.651] P0. 001.The results of the second step analysis showed that after controlling drinking variables, EOC and EOC were higher than that of EOC. 3,055 CpG loci were associated; The results of the third step analysis showed that alcohol consumption was associated with 61 CpG loci after EOC control, and the results of 4th step analysis showed that two CpG loci were controlled respectively. Alcohol consumption and EOC were independent of each other. Two CpG loci (cg11016563cg09358725) were tested by the four-step study results. The alcohol drinking / EOC was used as a mediating effect. The results of CIT test were cross-validated by VanderWeele mediation model. It is further confirmed that two CpG loci are important mediators. Alcohol consumption affects EOC by regulating the methylation level of two CpG loci, and the symbol of the gene. 3cg11016563 is reported to be the association between the overexpression of TRPC6 gene and EOC. This article suggests that the TRPC6 gene promoter region CpG island cg11016563 site is hypomethylated. LMO2 is the gene symbol that may affect EOC by regulating the expression of TRPC6 gene. This paper suggests that the LMO2 gene may be associated with EOC. Conclusion: 1, two CpG loci were first found as mediators. Alcohol consumption affects EOC by regulating its methylation level. It suggests that two CpG loci may act as a new biomarker in the pathogenesis of EOC, and the overexpression of TRPC6 gene in ovarian cancer cells may be affected by the CpG island of its promoter region. The hypomethylation effect of cg11016563 locus. LMO2 gene may be associated with EOC. This paper suggests that the statistical causal inference process can effectively test environmental factors. The statistical causal correlation between epigenetic change and disease. 4. This paper suggests that the combination of high dimensional test method and causality inference test process can improve the causal inference process of high dimensional data such as epigenetic group.
【學(xué)位授予單位】：山西醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R737.31

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相關(guān)期刊論文 前1條

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本文編號(hào)：1591894