GPR126在青少年特发性脊柱侧凸中基因多态性及PUMC分型关联性研究

发布时间：2018-06-23 23:50

本文选题：青少年特发性脊柱侧凸 + GPR126/ADGRG6　；参考：《北京协和医学院》2017年博士论文

【摘要】：研究背景:青少年特发性脊柱侧凸(Adolescent Idiopathic Scoliosis,AIS)是一种最常见的脊柱畸形,全球范围内发病率约为1%-3%。临床上有多种分类标准,如King分型、Lenke分型和PUMC分型,其中PUMC分型是基于脊柱三维畸形、并具有手术指导意义的分型系统。尽管AIS的研究进行了数十年,确切的病因尚不清楚。研究表明遗传倾向在AIS的发病中起重要作用,近期在日本大规模人群和中国南方人群的全基因组关联性分析研究提示GPR126基因单核苷酸多态性(Single Nucleotide Polymorphism,SNP)与AIS发病相关。Kou等在1819例日本患者及25939例对照中发现rs6570507与AIS的易感性相关联,同时发现gpr126基因沉默斑马鱼模型中出现骨化延迟。Xu等在352例南方中国人群患者及149例对照中重复出了此位点,并发现了另外两个关联位点(rs7774095和rs7755109)。Qin等发现在南方中国人群AIS患者中,另一位点(rs9403380)能够调节GPR126在脊旁肌中的表达。由于在Schwann细胞髓鞘形成起到重要作用,gpr126对于小鼠的存活必不可少,也有研究提示gpr126在软骨中的缺失会导致特发性脊柱侧凸及漏斗胸的小鼠。由此可见,GPR126基因在AIS发病中起重要作用。目前尚无中国北方汉族人群中的GPR126基因关联研究报道。本研究以中国北方汉族人群为研究对象,通过病例-对照人群的关联分析研究,探寻GPR126基因SNP位点对AIS发病的贡献,同时结合基因型-表型关联研究,希望发现不同SNP与PUMC不同亚组的易感性。研究目的:1.建立中国北方汉族人群AIS遗传病因学研究队列。2.完善GPR126基因中与AIS相关联的单核苷酸多态性位点。3.针对关联位点进行功能分析,探寻其潜在致病机理。4.结合PUMC分型进行亚组分析,探索临床应用价值。研究方法:在前期研究基础上继续收集就诊于北京协和医院骨科的AIS患者的临床资料和外周血样标本,扩大研究队列。通过文献检索回顾及公共数据库预测,确定GPR126基因区域候选SNP位点。提取患者及对照组样本全基因组DNA,使用Sequenom MassArray分型平台,对候选基因SNP进行分型,并使用Plink及SPSS软件进行统计学分析。针对关联位点,使用双荧光素酶报告系统研究其对于基因转录功能的潜在影响。结合PUMC分型,对功能位点进行亚组分析研究,确定与基因型相关联的临床亚组表型。研究结果:1.本研究纳入了 480例AIS患者及861例正常对照,选取GPR126基因14处SNP位点。2.位点rs225694、rs7774095和rs2294773的风险等位基因与AIS相关联。3.通过双荧光素酶报告试验发现,位点rs225694和rs7774095对于基因的转录具有潜在的条件作用。4.亚组分析中,rs225694的等位基因A与所有PUMC亚型AIS相关联,rs7774095的等位基因A仅与PUMCI型AIS相关联。研究结论:1.中国北方汉族人群中,位点rs225694、rs7774095和rs2294773的风险等位基因与AIS相关联。而位点rs225694和rs7774095具有潜在的调控基因转录功能。2.Rs225694 与所有 PUMC 亚型 AIS 相关联,rs7774095 与 PUMC I 型 AIS 相关联。3.GPR126易感SNP与PUMC分型系统有关联,可能具有潜在的临床价值。
[Abstract]:Background: adolescent idiopathic scoliosis (Adolescent Idiopathic Scoliosis, AIS) is one of the most common spinal deformities. The global incidence is about 1%-3%. in a variety of classifications, such as King typing, Lenke typing and PUMC typing, in which PUMC typing is based on the three-dimensional deformity of the spine and has the significance of surgical guidance. Although AIS's research has been carried out for decades, the exact cause is still unclear. Studies have shown that genetic tendencies play an important role in the pathogenesis of AIS. A recent study on the whole genome association of large populations in Japan and southern China suggests the GPR126 gene Nucleotide Polymorphism (SNP) and A (SNP) and A. IS associated.Kou was associated with the susceptibility of rs6570507 to AIS in 1819 cases of Japanese and 25939 controls. At the same time, it was found that the occurrence of delayed.Xu in the gpr126 gene silencing zebra fish model was repeated in 352 southern Chinese and 149 controls, and two other associated sites (rs7774095) were found. And rs7755109).Qin and other found in the southern Chinese population of AIS, another locus (rs9403380) can regulate the expression of GPR126 in the para muscle. Because of the important role of the myelin formation in Schwann cells, gpr126 is essential for the survival of the mice, and there are also studies suggesting that the absence of gpr126 in cartilage leads to idiopathic scoliosis and the presence of gpr126 in the cartilage. It can be seen that GPR126 gene plays an important role in the pathogenesis of AIS. At present, there is no report on the association of GPR126 genes in the Han population of northern China. This study takes the Han population of northern China as the research object, and explores the contribution of the GPR126 gene SNP site to the pathogenesis of AIS by analyzing the association analysis of the case control population. In combination with genotype phenotype association studies, we hope to find the susceptibility of different subgroups of different SNP and PUMC. Objective: 1. a cohort of genetic etiology of AIS in the Han population in northern China was established by.2. to perfect the single nucleotide polymorphic loci associated with AIS in the GPR126 gene for functional analysis of the associated loci, and to explore the potential pathogenesis of the GPR126 gene. .4. combined with PUMC typing for subgroup analysis to explore the clinical application value. Research methods: on the basis of previous research, we continue to collect the clinical data and peripheral blood samples of patients with AIS in Peking Union Medical College Hospital Department of orthopedics, and expand the research queue. Through literature retrieval review and public database prediction, the regional candidate SNP of the GPR126 gene is determined. The whole genome DNA was extracted from the patients and the control group, and the Sequenom MassArray typing platform was used to type the candidate gene SNP, and the Plink and SPSS software were used for statistical analysis. The potential effect of the double luciferase reporter system on the function of the gene transfer was studied by the dual luciferase reporter system. The subgroup analysis of the loci was used to determine the clinical subgroup phenotype associated with genotypes. The results of the 1. study included 480 AIS patients and 861 normal controls. The GPR126 gene.2. locus rs225694, rs7774095 and rs2294773 risk alleles associated with AIS phase.3. were detected by the double Luciferase Report test. Now, loci rs225694 and rs7774095 have potential conditions for gene transcription in.4. subgroup analysis. Rs225694 allele A is associated with all PUMC subtype AIS, and rs7774095 allele A is only associated with PUMCI AIS. Conclusions: 1. in the Han population of northern China, the risk allele of loci rs225694, allele and the rs7774095 The gene is associated with AIS, and the locus rs225694 and rs7774095 have a potential regulatory gene transcriptional function.2.Rs225694 associated with all PUMC subtype AIS, rs7774095 is associated with PUMC I AIS, and.3.GPR126 susceptible SNP is associated with the type system, which may have potential clinical value.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R726.8

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