原发性胆汁性肝硬化(PBC)是一种与自身免疫有关的慢性进行性胆汁淤积性肝脏疾病。课题组前期在PBC及对照样本组中对TYK2基因进行关联分析时，发现该基因与中国汉族PBC易感性有关。通过对TYK2基因区域中疾病相关位点进行系统性分析，我们发现这些位点除了影响相应氨基酸编码外，还可能参与TYK2基因的可选择性剪接模式，通过编码不同蛋白变异体而影响其功能的发挥。本项目从TYK2基因不同剪接模式表达水平与SNP的关联、相关剪接因子的鉴定、剪接模式对STATs蛋白磷酸化修饰及相关细胞因子表达水平的影响入手，来研究TYK2基因疾病相关位点的分子机制。本项目的开展可全面的深入了解TYK2基因与PBC疾病的分子作用机理，对深入了解PBC的发病机制可起到积极的推动作用。

Primary biliary cirrhosis (PBC) is a chronic and slowly progressive cholestatic autoimmune disease in the liver. Our group has previously shown that TYK2 gene polymorphism is associated with susceptibility to PBC in Chinese Han population. Systematic analysis of the disease associated loci in TYK2 gene region reveals that those polymorphisms not only modulate amino acid encoding, but they participate in TYK2 alternative splicing process, which leads to generation of different protein variants with different functions. In this study, we investigate the molecular mechanisms involved in the disease associated loci in TYK2 gene region by analyzing the association between expression levels of different splicing pattern and the SNP, characterizing different splicing factors, and studying the effect of different splicing patterns on STATs activation and gene expression of STATs associated cytokines. Our study will enhance our appreciation of the molecular mechanisms of TYK2 in PBC. More importantly, this study will significantly expand our understanding of the pathogenesis of PBC.