类风湿关节炎是一个全身性自身免疫性疾病，遗传在其发病中起到非常重要的作用。全基因组关联分析（GWAS）已经发现了100多个和类风湿关节炎发生有关联的遗传位点，但是对于这些基因区段导致疾病产生的分子机理机制仍然知之甚少。我们的前期工作通过生物信息大数据分析发现并确认了类风湿关节炎风险基因ORMDL3，并发现增强子对其潜在的表达调控。本项目拟在此基础上运用分子、细胞、遗传以及免疫等手段探索ORMDL3在类风湿关节炎发病中的作用：1）体外实验研究增强子区段基因型、转录因子对ORMDL3表达调控的分子机制；2）体内实验研究临床样品中增强子基因型对转录因子结合及类风湿关节炎病人ORMDL3表达的影响；3）细胞及小鼠模型，研究ORMDL3对免疫炎症及类风湿关节炎发生的生理机制。本项目的研究对揭示类风湿关节炎发生的机理机制具有重要意义，并可为其将来的诊治提供一个潜在的新靶点。

Rheumatoid arthritis (RA) is an autoimmune disease. Genome-wide association studies (GWASs) have identified more than 100 loci associated with RA, but for most cases, functionally affected genes and their underlying molecular mechanisms contributing to these associations are unknown. By performing an integrative analysis incorporating multiple “omics” data, we identified a RA risk gene ORMDL3 and a potential mechanism regulating its expression. Through molecular, cellular, genetic and immunological approaches, this project aims to investigate 1) whether genetic variants in the enhancer regulate transcription factor binding and ORMDL3 expression in vitro; 2) the regulations of ORMDL3 expression in RA patients in vivo; 3) the functional mechanisms of ORMDL3 on regulation of immune system, as well as the development of RA in a mouse model. This project bears substantial significance to reveal the mechanism of RA development, and may provide a potential target for its future prediction and treatment.