自噬家族和粘附分子家族基因多态性与白塞氏病和VKH综合征遗传易感性的研究

发布时间：2018-01-26 16:22

本文关键词： 白塞氏病 VKH综合征 ATG5 ATG10 基因多态性 CD6 CD11c 白塞氏病 VKH综合征基因多态性　出处：《重庆医科大学》2016年博士论文　论文类型：学位论文

【摘要】：第一部分自噬家族基因多态性在白塞氏病和VKH综合征中的遗传易感性研究背景:葡萄膜炎是世界范围内导致盲目的主要原因之一。白塞氏病(Behcet’s disease,BD)和VKH综合征(Vogt-Koyanagi-Harada syndrome)是两种在我国较常见但性质却不同的葡萄膜炎类型。白塞氏病是一种自身炎症性疾病而VKH综合征是一种自身免疫性疾病。自噬在固有免疫和适应性免疫中都起到了至关重要的作用,此外,自噬家族基因的多态性与多种肿瘤疾病及自身免疫性疾病相关。目前全世界尚无关于自噬家族基因多态与白塞氏病和VKH综合征的相关性的研究报道。目的:探讨自噬家族基因多态性与白塞氏病和VKH综合征的相关性研究。方法:本研究共纳入940例BD患者,1061例VKH综合征患者,2007例正常对照。采用PCR-RFLP基因分型和Taq Man?SNP基因分型技术对自噬家族的10个基因、16个SNP位点进行分型。BD患者、VKH综合征患者和正常人的等位基因频率及基因型数目采用χ2检验统计分析。另外用实时定量PCR检测阳性位点不同基因型的正常人外周单个核细胞(Peripheral blood mononuclear cells,PBMCs)中ATG(autophagy-related gene)的m RNA表达情况。结果:研究发现ATG5-rs573775的TT基因型频率在BD患者中显著降低(P=1.74×10-7,Pc=8.35×10-6,OR=0.49)。ATG10-rs4703863的AA基因型频率在VKH综合征患者中显著降低(P=1.32×10-7,Pc=6.34×10-6,OR=0.67),AC基因型频率在VKH综合征患者中显著升高(P=2.07×10-6,Pc=9.94×10-5,OR=1.44),A等位基因频率在VKH综合征患者中显著降低(P=1.47×10-6,Pc=7.06×10-5,OR=0.75)。其它14个SNP的等位基因及基因型频率在BD患者或者VKH综合征患者中和正常对照组之间无显著差异。在脂多糖(lipopolysaccharide,LPS)刺激的PBMC中,rs573775位点TT基因型个体中ATG5表达较CC基因型和CT基因型个体均显著升高。结论:本研究证实了ATG5的遗传变异与中国汉族人群白塞病的易感性显著相关,而ATG10与中国汉族人群VKH综合征的易感性显著相关。第二部分粘附分子家族基因多态与白塞氏病和VKH综合征中遗传易感性研究背景:细胞粘附分子是一类介导细胞与细胞之间或者细胞与基质间相互接触或者结合的分子。目前有大量关于粘附分子蛋白的表达在自身免疫性疾病或者炎症性疾病的研究。虽然已有研究探讨了个别粘附分子基因多肽和葡萄膜炎的相关性,但目前没有整个粘附分子家族基因多肽与白塞氏病或者VKH综合征遗传易感性的研究。目的:探讨粘附分子家族基因多态性与白塞氏病和VKH综合征的相关性研究。方法:本研究中总共纳入了1149例BD患者,399例VKH综合征患者,2107例正常对照。采用Mass ARRAY System,PCR-RFLP和Taq Man?SNP基因分型技术对自噬家族基因的43个位点进行基因多态性分析。BD患者、VKH综合征患者和正常对照组间等位基因及基因型频率的比较采用χ2检验统计分析。分别用实时定量PCR和ELISA检测阳性位点不同基因型的正常人外周单个核细胞中CD6或者CD11c的m RNA表达情况和细胞因子的表达情况。结果:CD6-rs11230563的CC基因型频率在BD患者中较正常人显著降低(P=8.501×10-11,Pc=1.097×10-8,OR=0.60),CT基因型频率在BD患者中显著升高(P=2.532×10-9,Pc=3.266×10-7,OR=1.63),C等位基因频率在BD患者中显著降低(P=1.766×10-10,Pc=7.594×10-9,OR=0.64)。CD11c-rs2929的AG基因型频率在BD患者中较正常人显著降低(P=1.618×10-7,Pc=2.087×10-5,OR=0.64),GG基因型频率在BD患者中显著升高(P=4.320×10-8,Pc=5.573×10-6,OR=1.56),G等位基因频率在BD患者中显著升高(P=3.252×10-7,Pc=1.398×10-5,OR=1.45)。功能研究显示在LPS刺激的PBMC中,rs2929位点GG基因型个体中CD11c、TNF-α和IL-1beta的表达较AG/AA基因型个体的表达显著升高。结论:CD6和CD11c的基因多态性在中国汉族人群中与BD的遗传易感性相关。
[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.

【学位授予单位】：重庆医科大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R773.9

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