Janus激酶1功能性多态位点参与原发性胆汁性胆管炎易感机制研究

原发性胆汁性胆管炎（PBC）是一种具有明显遗传易感性的自身免疫肝病，不同人种的全基因组关联分析和免疫芯片等研究发现多个PBC易感位点。我们的前期工作发现Janus激酶1（JAK1）基因多态性与中国汉族人群PBC显著关联，但其参与PBC易感的机制尚不清楚。我们推测JAK1受其功能SNP的调控可能导致个体间PBC易感性的差异。鉴于此，本研究拟通过生物信息学分析，筛选JAK1潜在的功能性调节性SNP；通过荧光素酶报告基因检测和凝胶迁移实验阐明它们参与调控JAK1基因表达；结合分子、细胞功能学实验进一步明确功能SNP参与调控JAK1下游其他PBC易感基因及对细胞因子应答敏感性；最后从临床遗传学角度揭示它们与PBC疾病临床表型的关系。本研究将阐明JAK1功能SNP参与PBC易感性机制，为PBC致病机制研究和临床治疗提供新的潜在靶点和理论支持。

Primary biliary cholangitis (PBC) is an autoimmune liver disease with strong genetic predisposition. Genetic variants associated with PBC have been revealed in several GWASs and immunochip studies among different ethnical groups. Actually, our previous study showed Janus kinases 1 (JAK1) genetic polymorphisms were significantly associated with PBC in Chinese Han population. Nevertheless, how JAK1 influences PBC susceptibility is not known. Therefore, we hypothesized that the regulation of JAK1 gene by its functional regulatory SNPs might contribute to differences in PBC susceptibility among individuals. In this study, several bioinformatics databases will be employed to analyze and screen potential functional variants of JAK1 gene. And then we will demonstrate the regulatory activities of the potential SNPs on expression of JAK1 gene by luciferase reporter system and EMSA. Moreover, it will be also clarified that the regulatory SNPs affect the downstream genes of JAK1 as well as the response to cytokine stimulation. Finally, the associations between functional SNP with PBC specific clinical sub-phenotypes will be also illustrated in detail. This study will elucidate the mechanism of JAK1 genetic polymorphisms with functionality contributing to PBC susceptibility and provide new potential targets and theoretical support for the pathogenesis and clinical treatment of PBC.