本文選題：阿爾茨海默病 + 單核苷酸多態(tài)性��； 參考：《新疆醫(yī)科大學》2017年碩士論文

【摘要】：目的:阿爾茨海默病(AD)是由多種基因共同作用的漸進性神經(jīng)系統(tǒng)性質(zhì)改變的疾病。我們進行了一項試點研究,試圖探討五個與AD相關(guān)的基因,包括γ-分泌酶復合物b(APH1B),人朊病毒蛋白基因(PRNP),羥甲基戊二酸單酰輔酶A還原酶(HMGCR),沉默信息調(diào)節(jié)因子2同源物1(SIRT1),載脂蛋白E(APOE)的SNPs與新疆地區(qū)漢族阿爾茨海默病的關(guān)聯(lián)性,同時,我們試圖確定Bcl-2相關(guān)X蛋白(BAX)啟動子甲基化和APOE啟動子甲基化是否與新疆漢族AD相關(guān)。方法:選取2014年至2015年在本院干部病房(老年醫(yī)學專業(yè))住院且年齡大于60歲的漢族老人,由年資較高的神經(jīng)內(nèi)科醫(yī)生、老年病科醫(yī)生根據(jù)DSM-IV標準進行診斷,從中選取診斷為AD的患者17例作為病例組(其中男性7例、女性10例),平均年齡75.65±5.86歲;從同期住院的患者中,選取年齡、性別、族別、文化水平等與病例組相匹配的正常老年人34例為對照組(其中男性17例、女性17例),平均年齡77.59±7.41歲。使用Sanger測序?qū)εcAD相關(guān)基因的六個位點,包括APH1B rs1047552,PRNP rs1799990,HMGCR rs3846662,SIRT1 rs7895833,APOE rs7412和rs429358進行SNP基因分型,比較基因多態(tài)性與新疆漢族阿爾茨海默病關(guān)系。使用實時定量PCR(QMSP)技術(shù)對APOE,BAX兩個基因進行DNA甲基化水平的測定,比較甲基化與新疆漢族阿爾茨海默病關(guān)系。結(jié)果:(1)研究結(jié)果表明由APOE rs7412和rs429358構(gòu)成的APOEε4等位基因與AD相關(guān)(χ2=9.718,P=0.002),而APH1B rs1047552,PRNP rs1799990,HMGCR rs3846662,SIRT1 rs7895833基因多態(tài)性在病例組和對照組間未發(fā)現(xiàn)差異有統(tǒng)計學意義(P0.05)。(2)按是否攜帶APOEε4分層,APH1B rs1047552,PRNP rs1799990,HMGCR rs3846662,SIRT1 rs7895833基因多態(tài)性在兩組間未發(fā)現(xiàn)差異有統(tǒng)計學意義(P0.05)。(3)AD患者中BAX啟動子甲基化的水平低于對照組(t=-2.078,P=0.045),進一步按性別分層,女性AD患者BAX甲基化水平低于對照組(t=-2.230,P=0.046),按是否攜帶APOEε4分層后在病例及對照組間均未發(fā)現(xiàn)差異有統(tǒng)計學意義(P0.05)。(4)APOE啟動子甲基化水平在病例組和對照組間未發(fā)現(xiàn)差異有統(tǒng)計學意義(P0.05),進一步按性別分層,未發(fā)現(xiàn)有統(tǒng)計學差異。按是否攜帶APOEε4分層,攜帶APOEε4基因的AD患者的甲基化水平相對較高(t=2.480,P=0.025)。(5)在病例及對照組中,未發(fā)現(xiàn)年齡與APOE、BAX甲基化水平有相關(guān)性(P0.05)。按性別進一步分組后分析,未發(fā)現(xiàn)APOE,BAX甲基化水平與年齡有相關(guān)性(P0.05)。結(jié)論:(1)在所測六個SNP(APH1B rs1047552,PRNP rs1799990,HMGCR rs3846662,SIRT1 rs7895833,APOE rs7412和rs429358)中,發(fā)現(xiàn)由APOE rs7412和rs429358構(gòu)成的APOEε4等位基因與新疆漢族AD存在關(guān)聯(lián),提示攜帶APOEε4可能是AD的危險因素之一。(2)病例組中BAX基因啟動子甲基化水平低于對照組,在女性中尤為明顯,提示BAX啟動子低甲基化可能是新疆漢族女性AD的風險因素之一。(3)AD患者中攜帶ε4的APOE甲基化水平相對較高,提示APOEε4對AD患者甲基化水平可能有一定影響。
[Abstract]:Objective: Alzheimer's disease (AD) is a progressive neurologic disorder characterized by a variety of genes. We conducted a pilot study to explore five AD related genes, including the gamma secretase complex B (APH1B), the human prion gene (PRNP), the hydroxymethylglutaric acid monoyl coenzyme A reductase (HMGCR), and the silence. Information regulation factor 2 homologue 1 (SIRT1), apolipoprotein E (APOE) SNPs and the association of Alzheimer's disease in Xinjiang Han nationality. Meanwhile, we try to determine whether Bcl-2 related X protein (BAX) promoter methylation and APOE promoter methylation is related to the Xinjiang Han AD. Methods: from 2014 to 2015 in our hospital cadre ward (old medicine) Students aged more than 60 years old were diagnosed with higher age neurosurgeon and geriatric physician based on DSM-IV standards, and 17 cases of patients diagnosed as AD were selected as case groups (7 males and 10 females) with an average age of 75.65 + 5.86 years; age, sex, and nationality were selected from the patients hospitalized at the same time. 34 cases of normal elderly people matched with the case group were compared with the case group (including 17 males and 17 females) with an average age of 77.59 + 7.41 years. Sanger sequencing was used for six loci of AD related genes, including APH1B rs1047552, PRNP rs1799990, HMGCR rs3846662, SIRT1 rs7895833, APOE rs7412 and genetic scores. Type, comparative gene polymorphism and Alzheimer's disease in Xinjiang Han nationality. Using real-time quantitative PCR (QMSP) technique to determine the level of DNA methylation of two genes of APOE and BAX, and compare the relationship between methylation and Alzheimer's disease in Xinjiang Han. Results: (1) the results showed that APOE 4 alleles composed of APOE rs7412 and rs429358 and AD phase (x 2=9.718, P=0.002), while APH1B rs1047552, PRNP rs1799990, HMGCR rs3846662, SIRT1 rs7895833 polymorphisms were not found to be statistically significant between the case group and the control group (P0.05). (2) if the APOE epsilon 4 was stratified or not, the polymorphism of the gene was not found between the two groups. The difference was statistically significant (P0.05). (3) the level of BAX promoter methylation in AD patients was lower than that of the control group (t=-2.078, P=0.045), further stratified by sex, the level of BAX methylation in female AD patients was lower than that of the control group (t=-2.230, P=0.046), and there was no statistical difference between the cases and the control groups after the APOE epsilon 4 layer was carried (P0.) 05) (4) the level of APOE promoter methylation was not found to be statistically significant between the case group and the control group (P0.05). The methylation level of the AD patients carrying the APOE epsilon 4 gene was relatively higher (t=2.480, P=0.025). (5) (5) in the case and the control group, there was no statistical difference between the cases and the control groups. There is a correlation between the present age and the level of APOE, BAX methylation (P0.05). After further grouping by sex, no APOE is found, and the level of BAX methylation is correlated with age (P0.05). (1) in the measured six SNP (APH1B rs1047552, PRNP rs1799990, HMGCR) 8 APOE E 4 allele was associated with the Han AD in Xinjiang, suggesting that carrying APOE E 4 may be one of the risk factors for AD. (2) the methylation level of BAX gene promoter in the case group is lower than that of the control group, especially in women, suggesting that the BAX promoter hypomethylation may be one of the risk factors for AD in the Han women of Han nationality. (3) AD patients carry the risk factors. The APOE methylation level of Er 4 was relatively high, suggesting that APOE E 4 may have a certain effect on the methylation level of AD patients.
【學位授予單位】：新疆醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R749.16

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