候选基因多态性、甲基化与新疆汉族阿尔茨海默病的关联性研究

发布时间：2018-06-18 23:59

本文选题：阿尔茨海默病 + 单核苷酸多态性　；参考：《新疆医科大学》2017年硕士论文

【摘要】：目的:阿尔茨海默病(AD)是由多种基因共同作用的渐进性神经系统性质改变的疾病。我们进行了一项试点研究,试图探讨五个与AD相关的基因,包括γ-分泌酶复合物b(APH1B),人朊病毒蛋白基因(PRNP),羟甲基戊二酸单酰辅酶A还原酶(HMGCR),沉默信息调节因子2同源物1(SIRT1),载脂蛋白E(APOE)的SNPs与新疆地区汉族阿尔茨海默病的关联性,同时,我们试图确定Bcl-2相关X蛋白(BAX)启动子甲基化和APOE启动子甲基化是否与新疆汉族AD相关。方法:选取2014年至2015年在本院干部病房(老年医学专业)住院且年龄大于60岁的汉族老人,由年资较高的神经内科医生、老年病科医生根据DSM-IV标准进行诊断,从中选取诊断为AD的患者17例作为病例组(其中男性7例、女性10例),平均年龄75.65±5.86岁;从同期住院的患者中,选取年龄、性别、族别、文化水平等与病例组相匹配的正常老年人34例为对照组(其中男性17例、女性17例),平均年龄77.59±7.41岁。使用Sanger测序对与AD相关基因的六个位点,包括APH1B rs1047552,PRNP rs1799990,HMGCR rs3846662,SIRT1 rs7895833,APOE rs7412和rs429358进行SNP基因分型,比较基因多态性与新疆汉族阿尔茨海默病关系。使用实时定量PCR(QMSP)技术对APOE,BAX两个基因进行DNA甲基化水平的测定,比较甲基化与新疆汉族阿尔茨海默病关系。结果:(1)研究结果表明由APOE rs7412和rs429358构成的APOEε4等位基因与AD相关(χ2=9.718,P=0.002),而APH1B rs1047552,PRNP rs1799990,HMGCR rs3846662,SIRT1 rs7895833基因多态性在病例组和对照组间未发现差异有统计学意义(P0.05)。(2)按是否携带APOEε4分层,APH1B rs1047552,PRNP rs1799990,HMGCR rs3846662,SIRT1 rs7895833基因多态性在两组间未发现差异有统计学意义(P0.05)。(3)AD患者中BAX启动子甲基化的水平低于对照组(t=-2.078,P=0.045),进一步按性别分层,女性AD患者BAX甲基化水平低于对照组(t=-2.230,P=0.046),按是否携带APOEε4分层后在病例及对照组间均未发现差异有统计学意义(P0.05)。(4)APOE启动子甲基化水平在病例组和对照组间未发现差异有统计学意义(P0.05),进一步按性别分层,未发现有统计学差异。按是否携带APOEε4分层,携带APOEε4基因的AD患者的甲基化水平相对较高(t=2.480,P=0.025)。(5)在病例及对照组中,未发现年龄与APOE、BAX甲基化水平有相关性(P0.05)。按性别进一步分组后分析,未发现APOE,BAX甲基化水平与年龄有相关性(P0.05)。结论:(1)在所测六个SNP(APH1B rs1047552,PRNP rs1799990,HMGCR rs3846662,SIRT1 rs7895833,APOE rs7412和rs429358)中,发现由APOE rs7412和rs429358构成的APOEε4等位基因与新疆汉族AD存在关联,提示携带APOEε4可能是AD的危险因素之一。(2)病例组中BAX基因启动子甲基化水平低于对照组,在女性中尤为明显,提示BAX启动子低甲基化可能是新疆汉族女性AD的风险因素之一。(3)AD患者中携带ε4的APOE甲基化水平相对较高,提示APOEε4对AD患者甲基化水平可能有一定影响。
[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.
【学位授予单位】：新疆医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R749.16

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