骨关节炎相关基因与骨质疏松的关联分析

发布时间：2018-03-13 00:13

本文选题：骨质疏松　切入点：骨密度　出处：《湖南师范大学》2016年硕士论文　论文类型：学位论文

【摘要】：研究目的:骨质疏松症(osteoporosis,OP)和骨关节炎(osteoarthritis,OA)多发生于中老年人群,在部分老年人中,这两种病同时出现。因此,骨关节炎和骨质疏松症之间的关系复杂且相互影响。目前,通过全基因组关联分析(GWAS)已经发现了骨质疏松和骨关节炎的候选致病基因,也有研究已经鉴定了一些两个疾病的共享风险因子,但为了进一步理解两者间的相关性,还需要发现更多的多效基因。本研究旨在探究骨关节炎相关基因是否与骨密度关联,从而鉴定同时影响骨关节炎和骨质疏松的多效基因。研究方法及结果:我们在通过公共数据库PheGenI和Pubmed选择了102个已鉴定的与骨关节炎相关的SNPs(多重检验之后P0.05),然后在7个样本中检测这些SNPs是否与骨密度相关,经过多重检验校正之后,共发现2个骨关节炎相关的SNP(LRP5rs3736228和SP7 rs2016266)与骨质疏松性状相关联,P值分别为:5.99E-05和2.53E-04,eQTL分析发现rs3736228具有eQTL效应,并且对其eQTL基因MTL5和CPT1A具有顺式调节的作用。使用公共数据库GEO中表达谱数据进行差异表达分析,发现GSE13850这一数据集中MTL5和CPT1A在高低骨密度组单核细胞里存在差异表达,t检验P值分别为:1.56E-02和4.83E-02。对rs3736228进行功能预测发现该位点位于错义突变区域,并且位点所编码的氨基酸经错义突变后,由丙氨酸(A)变成了缬氨酸(V),由此推测,rs3736228位点可能通过改变其编码的氨基酸的种类,从而改变蛋白质的结构,来影响甚至是诱发骨质疏松症,对蛋白质进行结构预测也发现错义突变后的蛋白质二级结构发生了变化,更加证明了这一推论。另外,rs3736228还可以通过调节其eQTL基因CPT1A和MTL5的表达进而影响骨质疏松。因此,LRP5和SP7基因是同时影响骨关节炎和骨质疏松的多效基因。基于在线公共数据库数据的信息挖掘,利用整合分析的方法去探究疾病相关SNPs和疾病间的分子功能机制,为进一步研究疾病的致病原因提供了更多证据。
[Abstract]:Objective: osteoporosis (OPO) and osteoarthritis (Osteoarthritis) (OAA) occur mostly in the middle-aged and elderly population, and they occur simultaneously in some elderly people. Therefore, the relationship between Osteoarthritis and Osteoporosis is complex and interacted. At present, the relationship between Osteoarthritis and Osteoporosis is very complicated. GWASA has identified candidate genes for osteoporosis and osteoarthritis, and some studies have identified shared risk factors for both diseases, but in order to further understand the correlation between the two diseases, More multipotent genes need to be found. The aim of this study was to investigate whether osteoarthritis related genes were associated with bone mineral density. Methods and results: we selected 102 identified SNPs associated with osteoarthritis via the public database PheGenI and Pubmed (after multiple tests, P0.05, however. They were then tested in seven samples to see if the SNPs was related to bone mineral density. Two Osteoarthritis related SNP(LRP5rs3736228 and SP7 Rs2016266) were found to be associated with osteoporosis traits (P = 5. 99E-05 and 2. 53E-04EQTL, respectively). Rs3736228 had eQTL effect. The eQTL gene MTL5 and CPT1A have the function of cis regulation. The differential expression analysis was carried out by using the expression profile data in the common database GEO. The differential expression of MTL5 and CPT1A in the GSE13850 data set was found in monocytes of high and low BMD group (P = 1.56E-02 and 4.83E-02, respectively). The functional prediction of rs3736228 revealed that the site was located in the missense mutation region. After missense mutation, the amino acid encoded at the locus changed from alanine to valine, which suggested that rs3736228 might change the structure of protein by changing the amino acid type of the amino acid. In order to influence and even induce osteoporosis, the protein secondary structure after missense mutation was found to have changed by predicting the structure of protein. In addition, rs3736228 can affect osteoporosis by regulating the expression of CPT1A and MTL5 of its eQTL gene. Therefore, LRP5 and SP7 genes are multifunctional genes that affect both osteoarthritis and osteoporosis. Information mining for public database data, The method of integrative analysis is used to explore the molecular functional mechanism between disease-related SNPs and disease, which provides more evidence for the further study of the pathogenicity of disease.
【学位授予单位】：湖南师范大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R580;R684.3

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