本文選題：青少年特發(fā)性脊柱側(cè)凸 + GPR126/ADGRG6��； 參考：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文

【摘要】：研究背景:青少年特發(fā)性脊柱側(cè)凸(Adolescent Idiopathic Scoliosis,AIS)是一種最常見的脊柱畸形,全球范圍內(nèi)發(fā)病率約為1%-3%。臨床上有多種分類標(biāo)準(zhǔn),如King分型、Lenke分型和PUMC分型,其中PUMC分型是基于脊柱三維畸形、并具有手術(shù)指導(dǎo)意義的分型系統(tǒng)。盡管AIS的研究進(jìn)行了數(shù)十年,確切的病因尚不清楚。研究表明遺傳傾向在AIS的發(fā)病中起重要作用,近期在日本大規(guī)模人群和中國(guó)南方人群的全基因組關(guān)聯(lián)性分析研究提示GPR126基因單核苷酸多態(tài)性(Single Nucleotide Polymorphism,SNP)與AIS發(fā)病相關(guān)。Kou等在1819例日本患者及25939例對(duì)照中發(fā)現(xiàn)rs6570507與AIS的易感性相關(guān)聯(lián),同時(shí)發(fā)現(xiàn)gpr126基因沉默斑馬魚模型中出現(xiàn)骨化延遲。Xu等在352例南方中國(guó)人群患者及149例對(duì)照中重復(fù)出了此位點(diǎn),并發(fā)現(xiàn)了另外兩個(gè)關(guān)聯(lián)位點(diǎn)(rs7774095和rs7755109)。Qin等發(fā)現(xiàn)在南方中國(guó)人群AIS患者中,另一位點(diǎn)(rs9403380)能夠調(diào)節(jié)GPR126在脊旁肌中的表達(dá)。由于在Schwann細(xì)胞髓鞘形成起到重要作用,gpr126對(duì)于小鼠的存活必不可少,也有研究提示gpr126在軟骨中的缺失會(huì)導(dǎo)致特發(fā)性脊柱側(cè)凸及漏斗胸的小鼠。由此可見,GPR126基因在AIS發(fā)病中起重要作用。目前尚無中國(guó)北方漢族人群中的GPR126基因關(guān)聯(lián)研究報(bào)道。本研究以中國(guó)北方漢族人群為研究對(duì)象,通過病例-對(duì)照人群的關(guān)聯(lián)分析研究,探尋GPR126基因SNP位點(diǎn)對(duì)AIS發(fā)病的貢獻(xiàn),同時(shí)結(jié)合基因型-表型關(guān)聯(lián)研究,希望發(fā)現(xiàn)不同SNP與PUMC不同亞組的易感性。研究目的:1.建立中國(guó)北方漢族人群AIS遺傳病因?qū)W研究隊(duì)列。2.完善GPR126基因中與AIS相關(guān)聯(lián)的單核苷酸多態(tài)性位點(diǎn)。3.針對(duì)關(guān)聯(lián)位點(diǎn)進(jìn)行功能分析,探尋其潛在致病機(jī)理。4.結(jié)合PUMC分型進(jìn)行亞組分析,探索臨床應(yīng)用價(jià)值。研究方法:在前期研究基礎(chǔ)上繼續(xù)收集就診于北京協(xié)和醫(yī)院骨科的AIS患者的臨床資料和外周血樣標(biāo)本,擴(kuò)大研究隊(duì)列。通過文獻(xiàn)檢索回顧及公共數(shù)據(jù)庫(kù)預(yù)測(cè),確定GPR126基因區(qū)域候選SNP位點(diǎn)。提取患者及對(duì)照組樣本全基因組DNA,使用Sequenom MassArray分型平臺(tái),對(duì)候選基因SNP進(jìn)行分型,并使用Plink及SPSS軟件進(jìn)行統(tǒng)計(jì)學(xué)分析。針對(duì)關(guān)聯(lián)位點(diǎn),使用雙熒光素酶報(bào)告系統(tǒng)研究其對(duì)于基因轉(zhuǎn)錄功能的潛在影響。結(jié)合PUMC分型,對(duì)功能位點(diǎn)進(jìn)行亞組分析研究,確定與基因型相關(guān)聯(lián)的臨床亞組表型。研究結(jié)果:1.本研究納入了 480例AIS患者及861例正常對(duì)照,選取GPR126基因14處SNP位點(diǎn)。2.位點(diǎn)rs225694、rs7774095和rs2294773的風(fēng)險(xiǎn)等位基因與AIS相關(guān)聯(lián)。3.通過雙熒光素酶報(bào)告試驗(yàn)發(fā)現(xiàn),位點(diǎn)rs225694和rs7774095對(duì)于基因的轉(zhuǎn)錄具有潛在的條件作用。4.亞組分析中,rs225694的等位基因A與所有PUMC亞型AIS相關(guān)聯(lián),rs7774095的等位基因A僅與PUMCI型AIS相關(guān)聯(lián)。研究結(jié)論:1.中國(guó)北方漢族人群中,位點(diǎn)rs225694、rs7774095和rs2294773的風(fēng)險(xiǎn)等位基因與AIS相關(guān)聯(lián)。而位點(diǎn)rs225694和rs7774095具有潛在的調(diào)控基因轉(zhuǎn)錄功能。2.Rs225694 與所有 PUMC 亞型 AIS 相關(guān)聯(lián),rs7774095 與 PUMC I 型 AIS 相關(guān)聯(lián)。3.GPR126易感SNP與PUMC分型系統(tǒng)有關(guān)聯(lián),可能具有潛在的臨床價(jià)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.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R726.8

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