【作者】 郑厚峰；

【导师】 张学军； 杨森；

【作者基本信息】 安徽医科大学 ， 皮肤性病学， 2010， 博士

【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。更多还原

【Abstract】 Background Psoriasis is a common inflammatory cutaneous disorder characterized by red scaly patches. The prevalevence of psoriasis is about 0.123% in Chinese Han population. So far there have heen about 4 million psoriasis patients in China. Clinically, psoriasis vulgaris is the most common, accounting for the total number of patients over 90%. The exact pathogenesis of psoriasis remains unclear. It is agreed generally that the psoriasis is a complex disease which arises from genetic and environmental factors. The predisposing genes can be grouped into two parts: HLA-associated and lacking HLA associations genes. As genome wide association (GWA) studies have produced a large amount of data, further study on gene-gene interaction and multi-marker association would be important for elucidating the biological and biochemical pathways that underline disease.Objective We evaluated the associations of single nucleotide polymorphisms (SNP) in MHC region with psoriasis, and determined the epistasis and combined effects of MHC locus and IL12B, LCE on risk for psoriasis.Method We genotyped SNP rs1265181 (MHC) in 5067 cases and 6404 controls, combining with the prior GWAS data (1139 cases and 1132 controls), we explored the genetic interaction among MHC locus, LCE and IL12B by using logistic regression analysis. We evaluated the combined effects of MHC locus and two non-MHC loci in the combined sample of 6206 cases and 7536 controls. According the combined effects, we finally compared the clinical difference between the carriers of the risk alleles and non-carriers psoriasis patients.Result①Extremely high significance of association was detected between rs1265181 and psoriasis (P combined <10E-300, OR =16.52, 95%CI: 15.28-18.44).②For rs4085613_A, the most significant association evidence was observed under recessive model, the homozygous and heterozygous odds ratio (ORhom / ORhet) estimates of this SNP supported this recessive model. Additive model is the best fit for the association of rs3213094_A, the ORhom / ORhet estimates further suggested the additive effects of this SNP. Similarly, the dominant association model was fit for rs1265181_G, where GG and CG show similar risk effects.③We observed significant interactions between MHC and LCE (p=0.0379) and between MHC and IL12B (p=0.0287) in the discovery sample. Interaction between MHC and LCE was significant in the replication sample (p=0.0091) while interaction between MHC and IL12B just show marginal significance (p=0.066). Analysis of combined sample showed pronounced evidence for both MHC by LCE (p=0.0016) and MHC by IL12B (0.0036) interaction after adjusting for potential study sample effect.④We further analyzed the combined effect of MHC, LCE and IL12B on the risk for psoriasis. the risk increased some 26-fold in individuals with risk alleles in both MHC and LCE as compared with those without risk alleles, and individual carrying risk alleles of MHC and IL12B has around 36-fold higher risk of psoriasis than those with protective alleles. The risk effects decreased in individuals with risk allele in one gene and protective allele in another, as compared with those with risk alleles in both genes.⑤We compared the clinical features between the carriers of the risk alleles and non-carriers psoriasis patients, and observed obvious clinical difference between the two group.Conclusion This study had confirmed a significant association between MHC region and psoriasis. More important, we provided evidence for interactions between MHC and LCE and between MHC and IL12B in determining the risk of psoriasis in Chinese population and estimated the combined effects of these genes. Besides, we suggested that MHC might be the main effect gene on the risk for psoriasis. We also found that carriers of the risk alleles have obvious clinical difference with non-carriers.更多还原