本文關鍵詞： 白塞氏病 VKH綜合征 ATG5 ATG10 基因多態(tài)性 CD6 CD11c 白塞氏病 VKH綜合征 基因多態(tài)性　出處：《重慶醫(yī)科大學》2016年博士論文　論文類型：學位論文

【摘要】：第一部分自噬家族基因多態(tài)性在白塞氏病和VKH綜合征中的遺傳易感性研究背景:葡萄膜炎是世界范圍內(nèi)導致盲目的主要原因之一。白塞氏病(Behcet’s disease,BD)和VKH綜合征(Vogt-Koyanagi-Harada syndrome)是兩種在我國較常見但性質卻不同的葡萄膜炎類型。白塞氏病是一種自身炎癥性疾病而VKH綜合征是一種自身免疫性疾病。自噬在固有免疫和適應性免疫中都起到了至關重要的作用,此外,自噬家族基因的多態(tài)性與多種腫瘤疾病及自身免疫性疾病相關。目前全世界尚無關于自噬家族基因多態(tài)與白塞氏病和VKH綜合征的相關性的研究報道。目的:探討自噬家族基因多態(tài)性與白塞氏病和VKH綜合征的相關性研究。方法:本研究共納入940例BD患者,1061例VKH綜合征患者,2007例正常對照。采用PCR-RFLP基因分型和Taq Man?SNP基因分型技術對自噬家族的10個基因、16個SNP位點進行分型。BD患者、VKH綜合征患者和正常人的等位基因頻率及基因型數(shù)目采用χ2檢驗統(tǒng)計分析。另外用實時定量PCR檢測陽性位點不同基因型的正常人外周單個核細胞(Peripheral blood mononuclear cells,PBMCs)中ATG(autophagy-related gene)的m RNA表達情況。結果:研究發(fā)現(xiàn)ATG5-rs573775的TT基因型頻率在BD患者中顯著降低(P=1.74×10-7,Pc=8.35×10-6,OR=0.49)。ATG10-rs4703863的AA基因型頻率在VKH綜合征患者中顯著降低(P=1.32×10-7,Pc=6.34×10-6,OR=0.67),AC基因型頻率在VKH綜合征患者中顯著升高(P=2.07×10-6,Pc=9.94×10-5,OR=1.44),A等位基因頻率在VKH綜合征患者中顯著降低(P=1.47×10-6,Pc=7.06×10-5,OR=0.75)。其它14個SNP的等位基因及基因型頻率在BD患者或者VKH綜合征患者中和正常對照組之間無顯著差異。在脂多糖(lipopolysaccharide,LPS)刺激的PBMC中,rs573775位點TT基因型個體中ATG5表達較CC基因型和CT基因型個體均顯著升高。結論:本研究證實了ATG5的遺傳變異與中國漢族人群白塞病的易感性顯著相關,而ATG10與中國漢族人群VKH綜合征的易感性顯著相關。第二部分粘附分子家族基因多態(tài)與白塞氏病和VKH綜合征中遺傳易感性研究背景:細胞粘附分子是一類介導細胞與細胞之間或者細胞與基質間相互接觸或者結合的分子。目前有大量關于粘附分子蛋白的表達在自身免疫性疾病或者炎癥性疾病的研究。雖然已有研究探討了個別粘附分子基因多肽和葡萄膜炎的相關性,但目前沒有整個粘附分子家族基因多肽與白塞氏病或者VKH綜合征遺傳易感性的研究。目的:探討粘附分子家族基因多態(tài)性與白塞氏病和VKH綜合征的相關性研究。方法:本研究中總共納入了1149例BD患者,399例VKH綜合征患者,2107例正常對照。采用Mass ARRAY System,PCR-RFLP和Taq Man?SNP基因分型技術對自噬家族基因的43個位點進行基因多態(tài)性分析。BD患者、VKH綜合征患者和正常對照組間等位基因及基因型頻率的比較采用χ2檢驗統(tǒng)計分析。分別用實時定量PCR和ELISA檢測陽性位點不同基因型的正常人外周單個核細胞中CD6或者CD11c的m RNA表達情況和細胞因子的表達情況。結果:CD6-rs11230563的CC基因型頻率在BD患者中較正常人顯著降低(P=8.501×10-11,Pc=1.097×10-8,OR=0.60),CT基因型頻率在BD患者中顯著升高(P=2.532×10-9,Pc=3.266×10-7,OR=1.63),C等位基因頻率在BD患者中顯著降低(P=1.766×10-10,Pc=7.594×10-9,OR=0.64)。CD11c-rs2929的AG基因型頻率在BD患者中較正常人顯著降低(P=1.618×10-7,Pc=2.087×10-5,OR=0.64),GG基因型頻率在BD患者中顯著升高(P=4.320×10-8,Pc=5.573×10-6,OR=1.56),G等位基因頻率在BD患者中顯著升高(P=3.252×10-7,Pc=1.398×10-5,OR=1.45)。功能研究顯示在LPS刺激的PBMC中,rs2929位點GG基因型個體中CD11c、TNF-α和IL-1beta的表達較AG/AA基因型個體的表達顯著升高。結論:CD6和CD11c的基因多態(tài)性在中國漢族人群中與BD的遺傳易感性相關。
[Abstract]:The first part of the autophagy gene family polymorphism in Behcet's disease and VKH genetic susceptibility syndrome in background: uveitis is a worldwide leading cause of blindness. Behcet's disease (Behcet 's disease, BD) and VKH syndrome (Vogt-Koyanagi-Harada syndrome) is the two in our country is relatively common but have different properties. The type of uveitis. Behcet's disease is a kind of autoinflammatory disease and VKH syndrome is an autoimmune disease. Autophagy in innate and adaptive immunity plays a very important role, in addition, related gene polymorphism and autophagy family of various cancers and autoimmune diseases. At present, the whole world is on autophagy gene family polymorphism and Behcet's disease and VKH syndrome related research reports. Objective: To investigate autophagy gene polymorphisms and Behcet's disease and VKH syndrome The correlation study. Methods: This study included 940 BD patients, 1061 cases of patients with VKH syndrome, 2007 cases of normal controls. The genotype of PCR-RFLP and Taq Man? 10 gene SNP genotyping technology on autophagy family, 16 SNP loci were genotyped for.BD patients, and the allele frequency the number of genotypes in patients with VKH syndrome and normal subjects using chi square test statistics analysis of 2 normal people with positive sites. In addition, real-time quantitative PCR detection of different genotypes of peripheral mononuclear cells (Peripheral blood mononuclear cells, PBMCs) in ATG (autophagy-related gene) expression of M RNA. Results: the TT genotype the frequency of ATG5-rs573775 in BD patients was significantly decreased (P=1.74 * 10-7, Pc=8.35 * 10-6, OR=0.49) the frequency of AA genotype.ATG10-rs4703863 in patients with VKH syndrome were significantly decreased (P=1.32 * 10-7, Pc=6.34 * 10-6, OR=0.67), the genotype frequency of AC Significantly increased in patients with VKH syndrome (P=2.07 * 10-6, Pc=9.94 * 10-5, OR=1.44), A allele frequency in patients with VKH syndrome were significantly decreased (P=1.47 * 10-6, Pc=7.06 * 10-5, OR=0.75). Genotype and allele frequencies of 14 SNP in patients with BD or VKH in between syndrome patients and normal control group. No significant difference in lipopolysaccharide (lipopolysaccharide, LPS) stimulated PBMC, ATG5 individuals rs573775 locus of TT gene expression with CC genotype and the CT genotype were significantly increased. Conclusion: This study confirmed the significant correlation of the genetic variation and susceptibility to ATG5 in Han population of Behcet's China disease, and susceptibility to ATG10 and Chinese Han population VKH syndrome was significantly related. The second part adhesion molecule family gene polymorphisms with Behcet's disease and VKH syndrome in genetic susceptibility to background: cell adhesion molecule is a kind of cell mediated and Molecular cell or between cells and matrix interactions or combination. There are lots of studies on adhesion molecule expression in autoimmune or inflammatory diseases. Although the existing research explores the correlation between individual adhesion molecule gene polypeptide and uveitis, but there is no whole adhesion molecule gene family polypeptide with Behcet's disease or VKH syndrome susceptibility. Objective: to investigate the adhesion molecule family gene polymorphism with Behcet's disease and VKH syndrome. Methods: This study included a total of 1149 BD patients, 399 cases of patients with VKH syndrome, 2107 cases of normal control. The Mass ARRAY System, PCR-RFLP Taq and Man 43? The SNP gene typing technique of autophagy gene family gene polymorphism analysis of.BD patients, VKH syndrome patients and normal control group between alleles and Genotype frequency was compared using chi square analysis of 2 test statistics. The expression of cytokines and expression of M RNA or CD6 CD11c in mononuclear cells of normal people with positive loci real-time PCR and ELISA detection of different genotypes of peripheral. Results: CC CD6-rs11230563 genotype frequencies in BD patients compared with normal people decreased (P=8.501 * 10-11, Pc=1.097 * 10-8, OR=0.60), the frequency of CT genotype was significantly higher in patients with BD (P=2.532 * 10-9, Pc=3.266 * 10-7, OR=1.63), C allele frequency was significantly lower in patients with BD (P=1.766 x 10-10, 7.594 x 10-9 Pc=, OR=0.64) AG genotype frequency of.CD11c-rs2929 in patients with BD was significantly lower than normal people (P=1.618 * 10-7, Pc=2.087 * 10-5, OR=0.64), the frequency of GG genotype was significantly higher in patients with BD (P=4.320 * 10-8, Pc=5.573 * 10-6, OR=1.56), G allele frequency was significantly higher in patients with BD (P=3.252 * 10-7, Pc=1.398 * 10-5, OR=1.45). Research on display function in LPS stimulated PBMC, CD11c individuals rs2929 genotype GG, expression of TNF- alpha and IL-1beta than the AG/AA genotype significantly increased. Conclusion: genetic susceptibility and BD in Chinese Han population CD6 gene polymorphism and CD11c related.

【學位授予單位】：重慶醫(yī)科大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R773.9

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