INPP5D rs35349669与中国北方汉族人群中迟发型阿尔茨海默病的验证性研究

发布时间：2018-07-06 09:47

本文选题：阿尔茨海默病 + INPP5D　；参考：《青岛大学》2017年硕士论文

【摘要】：目的:目前研究表明,磷酸肌醇-5-磷酸酶(INPP5D)基因可以通过调节小胶质细胞的功能参与阿尔茨海默病(AD)发病过程中的炎症和免疫反应,最新一项全基因组关联性研究(GWAS)发现在高加索人群中INPP5D rs35349669基因多态性与迟发型阿尔茨海默病(LOAD)具有显著的相关性。本研究旨在探讨在汉族人群中(INPP5D)rs35349669与LOAD的发病风险是否相关。方法:采用病例对照研究方法,选用LOAD病例组984例和健康对照组1352例为研究对象,研究对象均为中国北方汉族人群且年龄性别完全匹配。应用SNPscanTM多重单核苷酸多态性(SNP)分型技术对INPP5D基因位点rs35349669进行基因分型,对载脂蛋白E(APOE)ε4的基因分型采用改良的多路连接酶检测反应技术(i MLDR)技术,对LOAD病例组及健康对照组之间等位基因及基因型频率分布的差异采用卡方检验进行比较,按照是否携带APOEε4等位基因以及性别来分层分析两者与LOAD发病风险的关联性。对总体样本的关联性分析采用多因素Logistic回归方法。最后结合目前其他研究结果,采用固定效应模型对INPP5D rs35349669基因多态性与LOAD的发病风险进行荟萃分析。结果:我们的研究没有发现INPP5D基因rs35349669多态位点与LOAD的关联性。INPP5D rs35349669的等位基因和基因型频率分布在LOAD组和健康对照组之间无明显差异(等位基因频率分布P=0.094,基因型分布P=0.167)。LOAD组与健康对照组中共存在3种基因型,其中包括TT、CT和CC,这三种基因型所占比例在两组之间比较无明显差异(P0.05);按照是否携带APOEε4等位基因进行分层分析,结果显示在ε4携带者中rs35349669位点基因型和等位基因型频率分布在LOAD组和健康对照组之间并无显著差异(分别是P=0.713,P=0.70),同样的情况也存在于在非ε4携带者中;按照性别进行分层分析后,在LOAD组和健康对照组之间rs35349669位点基因型和等位基因型频率分布无明显差异(P0.05)。在排除了混杂因素(LOAD发病年龄、性别、APOEε4水平)影响后,经过Logistic回归分析发现在三种基因模型中LOAD病例组和对照组并无明显的统计学差异(P0.05)。关于rs35349669与LOAD的关联性研究的荟萃分析显示,rs35349669与LOAD的发生密切相关(OR=1.08,95%CI=1.05-1.11)。亚组分析结果显示,rs35349669基因多态性与汉族人群中AD的发病率并无明显相关性(OR=0.77,95%CI=0.53-1.13),但与高加索人群中LOAD的发病风险紧密相关(OR=1.06,95%CI=1.01-1.10)。结论:我们的研究表明,汉族人群中INPP5D rs35349669基因多态性与LOAD的发病之间无关联性。INPP5D rs35349669基因多态性对AD发病的影响或许存在于特定的种族人群中,还有一个可能的原因就是我们的样本量过小,没能发现该位点与LOAD之间的关联性。除此之外,已有研究证实INPP5D基因可以与LOAD的某些风险基因的产物相结合来参与影响AD的发生发展。鉴于LOAD复杂的遗传背景,未来关于LOAD易感基因的筛查与鉴定需要更大的样本量及更多种族人群的参与。随着未来INPP5D基因在LOAD作用机制方面研究的进展,希望为AD的诊治开辟一条全新的道路。
[Abstract]:Objective: the present study shows that the -5- phosphatase (INPP5D) gene of the inositol phosphate (INPP5D) can participate in the inflammation and immune response in the pathogenesis of Blzheimer's disease (AD) by regulating the function of microglia. The latest whole genome association study (GWAS) has found that the INPP5D rs35349669 gene polymorphism in the Caucasus and the late onset altzi LOAD has a significant correlation. The purpose of this study is to investigate whether the incidence of rs35349669 and LOAD in the Han population (INPP5D) is related to the risk of disease. Methods: a case control study was used, 984 cases of LOAD cases and 1352 healthy controls were selected, and the subjects were all the Han population in northern China and the age and sex were complete. Matching. Using SNPscanTM multiple single nucleotide polymorphisms (SNP) typing technique to genotyping INPP5D gene locus rs35349669 and using the modified multiplex ligase detection reaction technique (I MLDR) technique for the gene typing of apolipoprotein E (APOE) epsilon 4, and the allele and genotype frequency distribution between the LOAD case group and the healthy control group. The difference was compared with the chi square test. According to whether the APOE epsilon 4 alleles were carried and the risk of LOAD was stratified by sex delamination, multiple factor Logistic regression was used to analyze the association of the total samples. Finally, a fixed effect model was applied to the INPP5D rs35349669 gene in combination with other research results. A meta-analysis of the risk of LOAD's morbidity. Results: our study did not find that the allele and genotype frequency distribution of the INPP5D gene rs35349669 polymorphic loci and LOAD were not significantly different between the LOAD group and the healthy control group (the allele frequency distribution P=0.094, the genotype distribution P=0.167).LO. There were 3 genotypes in the AD group and the healthy control group, including TT, CT and CC. The proportion of the three genotypes was not significantly different between the two groups (P0.05). According to whether the APOE epsilon 4 alleles were carried on the stratified analysis, the results showed that the genotype and allele frequencies of the rs35349669 loci and alleles were distributed in the LOAD group in the epsilon 4 carrier. There was no significant difference between the control group and the healthy control group (P=0.713, P=0.70), and the same situation existed in the non epsilon 4 carriers. There was no significant difference in the genotype and allele frequency distribution of the rs35349669 locus between the LOAD group and the healthy control group (P0.05). The confounding factors (LOAD onset) were excluded. After the effect of age, sex, APOE epsilon 4), the Logistic regression analysis showed that there was no significant statistical difference between the LOAD case group and the control group in the three gene models (P0.05). A meta analysis of the association study of rs35349669 and LOAD showed that rs35349669 was closely related to LOAD (OR=1.08,95%CI=1.05-1.11). Subgroup analysis The results showed that there was no significant correlation between the rs35349669 gene polymorphism and the incidence of AD in the Han population (OR=0.77,95%CI=0.53-1.13), but it was closely related to the risk of LOAD in the Caucasus (OR=1.06,95%CI=1.01-1.10). Conclusion: our study shows that the polymorphism of the INPP5D rs35349669 gene in the Han population is not related to the incidence of LOAD. The effect of the.INPP5D rs35349669 gene polymorphism on the incidence of AD may exist in specific ethnic groups, and one possible reason is that our sample size is too small to detect the association between the site and LOAD. In addition, there has been a study that confirmed that the INPP5D gene can be combined with the products of some of the risk genes of LOAD. To participate in the development of AD, in view of the complex genetic background of LOAD, the future screening and identification of LOAD susceptible genes requires greater sample size and participation in more ethnic groups. With the future progress of the INPP5D gene in the mechanism of LOAD, we hope to open a new path for the diagnosis and treatment of AD.
【学位授予单位】：青岛大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R749.16

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