MHC，LCE和IL12B基因交互作用与银屑病的相关性研究

发布时间：2018-11-09 09:09

【摘要】：研究背景银屑病(Psoriasis)是一种常见的以红斑、鳞屑为主要临床表现的慢性复发性炎症性皮肤病。在汉族人中发病率约为0.123%,目前我国银屑病患者约400万。临床上以寻常型银屑病最多见,占患者总数的90%以上。银屑病确切发病机制尚未完全明确,目前认为该病是一种遗传与环境等多种因素共同作用的复杂性疾病。其中可能的遗传易感基因包括人类白细胞抗原(Human leukocyte antigen,HLA)相关基因和非HLA相关基因的共同作用导致发病。全基因组关联分析(Genome wide association studies,GWAS)产生大量数据,进一步研究基因与基因交作用(Gene interaction),特别是MHC与其他基因的交互作用对银屑病发病的影响有重要意义。目的验证MHC区域与银屑病的相关性,分析MHC,LCE与IL12B的基因交互作用对银屑病发病影响,以及估计MHC与LCE,MHC与IL12B的联合作用效应。方法本研究首先对SNP rs1265181(在MHC区域)在5067个银屑病病例和6404个对照进行基因分型,做关联分析,验证MHC与银屑病的相关性。然后把此次验证数据与先前的GWAS数据结合,分别估计MHC,LCE和IL12B变异的最佳关联模型。之后用logistic回归方法分析MHC,LCE和IL12B的基因交互作用,并根据变异的最佳关联模型,估计MHC与LCE,MHC与IL12B的联合作用效应。最后,我们根据联合效应,对所有病例进行分组,比较携带上述基因危险变异的银屑病患者和不携带危险变异的银屑病患者的临床特征差异。结果①MHC_rs1265181在5067个病例和6404个对照中的关联分析结果为P combined 1E-300, OR = 16.52,提示MHC与银屑病的强关联性;②与之前的GWAS研究数据相结合,分析MHC,LCE和IL12B变异的关联模型得知:LCE_rs4085613_A的最佳关联模型是隐形模型( Recessive model ) ,IL12B_rs3213094_A的最佳关联模型是累加模型( Additive model ) ,MHC_rs1265181_G的最佳关联模型是显性模型(Dominant model);③基因交互作用结果如下:我们发现在初筛阶段,MHC和LCE,MHC和IL12B有显著的基因交互作用(分别为p=0.0379和p=0.0287),此交互作用在验证阶段依然显著(MHC和LCE,p=0.0091;MHC和IL12B,p=0.046),在联合样本中,基因交互作用更加显著(MHC和LCE,p=0.0016;MHC和IL12B,p=0.0036)。④我们根据各个变异的关联模型,估计基因联合效应。我们发现同时含有MHC和LCE危险基因型的个体的发病风险比同时含有保护基因型的个体高26倍,同时含有MHC和IL12B危险基因型的个体的发病风险比同时含有保护基因型的个体高36倍。○5根据这两个SNP的联合效应,我们发现携带有危险变异的银屑病患者和不携带有危险变异的银屑病患者的临床特征有显著差异。结论本研究进一步验证了MHC区域与银屑病的相关性,并发现MHC与LCE,MHC与IL12B在有显著的基因交互作用,同时提示MHC是银屑病发病的主效基因。本研究还发现携带MHC,LCE和IL12B危险变异的患者和不携带有危险变异的患者有不同的临床表型。
[Abstract]:Background Psoriasis (Psoriasis) is a common chronic recurrent inflammatory dermatosis with erythema and scales as the main clinical manifestation. The incidence of psoriasis in Han nationality is about 0. 123%. At present, the incidence of psoriasis in China is about 0. 4 million. Psoriasis vulgaris was the most commonly seen clinically, accounting for more than 90% of the patients. The exact pathogenesis of psoriasis has not been completely clarified, and it is considered to be a complex disease which is affected by many factors, such as heredity and environment. The possible genetic susceptibility genes include human leukocyte antigen (Human leukocyte antigen,HLA)-related genes and non-HLA related genes. Genome-wide association analysis (Genome wide association studies,GWAS) produced a large amount of data. It is important to further study the interaction between gene and gene (Gene interaction), especially the interaction between MHC and other genes, on the pathogenesis of psoriasis. Objective to investigate the correlation between MHC region and psoriasis, to analyze the effect of MHC,LCE / IL12B gene interaction on psoriasis, and to estimate the combined effect of MHC and LCE,MHC and IL12B. Methods the genotyping of SNP rs1265181 (in MHC region) in 5 067 psoriasis cases and 6 404 controls was performed to verify the correlation between MHC and psoriasis. Then the best correlation model of MHC,LCE and IL12B mutation was estimated by combining the validation data with previous GWAS data. Then the gene interaction between MHC,LCE and IL12B was analyzed by logistic regression method, and the combined effect of MHC and LCE,MHC and IL12B was estimated according to the best correlation model of variation. Finally, according to the combined effect, we compared the clinical characteristics of patients with psoriasis and psoriasis without risk variation. Results the results of association analysis of 1MHC_rs1265181 in 5067 cases and 6404 controls were P combined 1E-300, OR = 16.52, suggesting strong association between MHC and psoriasis. 2 combining with the previous data of GWAS study, this paper analyzes the correlation model of MHC,LCE and IL12B variation, and finds out that the best correlation model of LCE_rs4085613_A is the invisible model (Recessive model), IL12B_rs3213094_A 's best correlation model is the cumulative model (Additive model),. The best correlation model for MHC_rs1265181_G is the dominant model (Dominant model); 3 the results of gene interaction are as follows: we found that MHC, LCE,MHC and IL12B had significant gene interaction in the initial screening stage (p0. 0379 and p0. 0287, respectively), and the interaction was still significant in the validation stage (MHC and LCE,p=0.0091;). MHC and IL12B,p=0.046), the gene interaction is more significant in the combined samples (MHC and LCE,p=0.0016;MHC and IL12B,p=0.0036). 4 We estimate the gene association effect according to the correlation model of each variation. We found that individuals with both MHC and LCE risk genotypes were 26 times more at risk than those with both protective genotypes. Individuals with both MHC and IL12B risk genotypes were 36 times more at risk than those with protective genotypes. 05 according to the combined effects of the two SNP, We found significant differences in clinical characteristics between psoriatic patients with and without risk mutations. Conclusion this study further verifies the correlation between MHC region and psoriasis, and finds that MHC and LCE,MHC have significant gene interaction with IL12B. It also suggests that MHC is the main gene of psoriasis. The study also found that patients with MHC,LCE and IL12B risk mutations had different clinical phenotypes from those with no risk mutations.
【学位授予单位】：安徽医科大学
【学位级别】：博士
【学位授予年份】：2010
【分类号】：R758.63

【相似文献】