ApoE及TRIP4基因多态性与阿尔茨海默病的相关性研究

发布时间：2017-12-26 22:37

本文关键词：ApoE及TRIP4基因多态性与阿尔茨海默病的相关性研究　出处：《安徽医科大学》2016年硕士论文　论文类型：学位论文

【摘要】：背景:阿尔茨海默病(AD)是一种神经退行性疾病,目前中国患者600万,到21世纪中叶,AD患者将接近2000万。美国患者530万人,21世纪中叶预计将增长到1000万以上。AD的遗传分为早发性AD(EOAD)和晚发性AD(LOAD)。EOAD通常遵循常染色体显性遗传模式,单一的基因突变可以导致疾病。其相关的遗传基因有早老素1基因突变(PSEN1)、早老素2(PSEN2)和淀粉样前体蛋白(APP)。LOAD遗传学是更复杂的,涉及多个基因且家族聚集不大。载脂蛋白E(Apo E)尤其是Apo Eε4,是目前公认的LOAD致病最大的风险基因。全基因组关联研究(GWAS)发现AD风险基因超过20多个。甲状腺功能的改变和认知缺陷已经被很多实验证实,甲状腺机能减退或亢进和亚临床甲状腺功能异常在较小程度上恶化认知功能。国际阿尔茨海默病基因组项目(IAGP)大量的Mate分析发现了11个与AD相关的基因为位点,这些发现可能是引领以后研究的方向。后续针对西班牙人的全基因组相关性研究(GWAS)中,证明TRIP4为AD的风险基因,发现TRIP4(rs74615166)为AD新的全基因组位点。在中国老年人群中,尚缺乏足够的证据来证明甲状腺功能异常和认知功能障碍及AD之间的潜在关系,关于该基因的研究也尚未开始。目的探索载脂蛋白E基因(Apo E)及甲状腺激素受体相互作用因子4基因(TRIP4)(rs4776494)的多态性与阿尔茨海默病的相关性。方法运用病例对照研究设计,收集安徽及周边地区77例确诊的阿尔茨海默病患者和80例正常健康对照。通过聚合酶链反应(PCR)及测序的方法,比较病例组和对照组Apo E及TRIP4(rs4776494)的等位基因及基因型频率的差异。并对每例研究对象进行简明智力状况量表(MMSE)、临床痴呆评定量表(CDR)、痴呆伴精神行为异常(BPSD)等量表检测。结果Apo Eε4等位基因在病例组和对照组中的分布差异有统计学意义(P0.01)。AD组Apo Eε4基因型携带者MMSE得分明显低于Apo Eε4基因型非携带者(p0.01),TRIP4基因(rs4776494)的TT、CT和CC基因型在病例组和对照组中的频率分布差异均有统计学意义(P0.01)。病例组中TRIP4 T基因携带者BPSD出现率明显高于非携带者(p0.05)。结论Apo Eε4及TRIP4(rs4776494)T型等位基因是AD的风险基因。Apo Eε4基因多态性与认知功能改变有关联。TRIP4基因可能在一定程度上促进了患者精神症状的发生。
[Abstract]:Background: Alzheimer's disease (AD) is a neurodegenerative disease. At present, 6 million of Chinese patients, by the middle of the twenty-first Century, will be close to 20 million in AD. In the middle of twenty-first Century, 5 million 300 thousand people in the United States are expected to grow to more than 10 million. The heredity of AD is divided into early onset AD (EOAD) and late onset AD (LOAD). EOAD usually follows an autosomal dominant genetic model, and a single gene mutation can lead to disease. The related genetic genes are PSEN1, PSEN2 and APP, which are PSEN1, PSEN2, and amyloid precursor protein (APP). LOAD genetics is more complex, involving multiple genes and small family aggregation. Apolipoprotein E (Apo E), especially Apo E epsilon 4, is currently recognized as the largest risk gene for LOAD. The whole genome association study (GWAS) found that more than more than 20 AD risk genes were found. Thyroid function changes and cognitive deficits have been confirmed by many experiments. Thyroid dysfunction or hyperthyroidism and subclinical thyroid dysfunction aggravate cognitive function to a lesser extent. The Mate analysis of the international Alzheimer's disease genome project (IAGP) has identified 11 AD related gene loci, which may lead the future research direction. Following the Spanish genome wide correlation study (GWAS), we proved that TRIP4 is a risk gene for AD, and found that TRIP4 (rs74615166) is a new whole genome locus of AD. In Chinese elderly population, there is still lack of sufficient evidence to prove the potential relationship between thyroid dysfunction and cognitive dysfunction and AD, and the research on this gene has not yet started. Objective to explore the association between apolipoprotein E gene (Apo E) and thyroid hormone receptor interacting factor 4 (TRIP4) (rs4776494) polymorphism and Alzheimer's disease. Methods a case-control study was used to collect 77 patients with Alzheimer's disease and 80 normal healthy controls in Anhui and its surrounding areas. The differences in allele and genotype frequencies of Apo E and TRIP4 (rs4776494) in case group and control group were compared by polymerase chain reaction (PCR) and sequencing. A simple mental state scale (MMSE), a clinical dementia rating scale (CDR), and a dementia with psycho behavioral abnormalities (BPSD) were tested for each study. Results the distribution of Apo E epsilon 4 allele in the case group and the control group was statistically significant (P0.01). In group AD, the MMSE score of Apo E genotype 4 genotype was significantly lower than that of Apo E genotype 4 genotype P0.01 (P0.01). The frequency distribution of TRIP4, rs4776494 and TT genotype in case group and control group was statistically significant. The incidence of BPSD in the TRIP4 T gene carrier in the case group was significantly higher than that of the non carrier (P0.05). Conclusion Apo E epsilon 4 and TRIP4 (rs4776494) T alleles are the risk genes of AD. Apo E epsilon 4 gene polymorphism is associated with cognitive function changes. The TRIP4 gene may, to a certain extent, promote the occurrence of mental symptoms in patients.
【学位授予单位】：安徽医科大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R749.16

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