12p13.3易感区域TAPBPL基因与银屑病的相关性研究

Psoriasis is a common, chronic, immune abnormal hyperplastic dermatosis that the genetic factors may play an important role in the pathogenesis of disease. In our previously study, we performed the research of identification susceptibility genes of psoriasis by Next Generation sequencing technology and identified the genetic variation rs758739 and rs2243750 were significantly associated with psoriasis in 12p13.3 region. Utilize bio-information analysis, rs758739 and rs2243750 were significantly associated with TAPBPL in eQTL database. We also identified that the expression TAPBPL gene between the lesion and contrast was significant differences (P = 4.04×10-13). TAPBPL gene was connected with major histocompatibility class I molecules, involving in antigen presenting and implicated that this gene was the susceptibility gene of psoriasis. Based on the findings of preliminary studies, we aim to perform Sanger sequencing and genotyping to identify the causal variants of TAPBPL gene. In addition, we will carry out a series of gene functional study (such as RT-PCR, western-blot, Luciferase reporter gene experiment, MTT and flow cytometry) for identified causal variants of TAPBPL gene to uncover the roles of causal variants within TAPBPL gene in disease pathogenesis. It will provide theoretical basis for further study in psoriasis pathogenesis and effective treatment and diagnosis.

银屑病是一种常见慢性免疫异常增殖性皮肤病，遗传因素在其发病中起重要作用。利用新一代测序技术在汉族人中鉴定出12p13.3区域rs758739和rs2243750与银屑病显著相关。利用eQTL数据库提示rs758739和rs2243750分别与TAPBPL基因显著相关; 该基因在皮损与对照之间的表达具有显著差异(P=4.04×10-13)，结合TAPBPL基因与MHC-I类分子相连接参与抗原提呈的功能，提示该基因为12p13.3区域银屑病新的易感基因。本研究拟基于前期研究为基础，对该基因进行测序并结合Sequenom分型平台验证，鉴定与银屑病直接相关的致病性变异;利用RT-RCR、western-blot、MTT比色法、萤光素酶报告基因实验、流式细胞仪技术及凝胶迁移实验等方法对致病变异开展功能学研究。初步揭示TAPBPL基因在银屑病发病中的作用，为深入研究其发病机制及临床诊疗提供理论依据。

银屑病是一种常见的慢性免疫异常增殖性皮肤病，以红斑、鳞屑为特征。遗传因素在银屑病的发病中起到重要作用，符合多基因遗传模式。基于课题组银屑病遗传学研究新一代测序数据分析发现TAPBPL基因可能为12p13.3区域内银屑病新的易感基因。为进一步探讨TAPBPL基因在银屑病发病中的作用，本研究开展该基因功能及相关机制研究。在银屑病皮损、非皮损以及正常皮肤中的免疫组化研究，发现TAPBPL基因在正常皮肤中不表达，在皮损和非皮损组织中高表达。在构建细胞模型内检测干扰和过表达细胞系凋亡和增殖，发现干扰TAPBPL促进HaCaT细胞增殖，过表达TAPBPL抑制HaCaT细胞增殖。针对TAPBPL干扰和过表达均引起HaCaT细胞凋亡增加。干扰TAPBPL后，对细胞周期蛋白CyclinB1和CyclinE1的表达水平进行验证发现CyclinB1低表达，CyclinE1在9064组低表达，9605组未见明显差异。过表达组中CyclinB1和E1表达量均显著降低。通过对TAPBPL基因功能研究发现，该基因可通过调节细胞周期蛋白的表达，影响角质形成细胞的增殖和凋亡，从而参与银屑病的发病过程。