摘要目的:本研究旨在通过生物信息学挖掘与RA滑膜中与疾病发生发展相关的差异表达基因，探讨甲氨蝶呤、托珠单抗和利妥昔单抗等DMARDs对RA滑膜差异表达基因（DEGs）的影响。方法:从公共基因芯片数据库（GEO）中获取RA表达谱芯片GSE7307、GSE12021、GSE55457、GSE55235、GSE77298、GSE89408，包括113份RA滑膜组织标本和70份健康对照（HC）滑膜组织标本。同时获得51例RA治疗前后滑膜表达谱芯片GSE45867、GSE24742、GSE97165。纳入甲氨蝶呤治疗样本8例、托珠单抗治疗样本12例、利妥昔单抗治疗样本12例和三联DMARDs联合治疗样本19例。采用R软件筛选DEGs，制作治疗前后及RA和健康对照（HC）DEGs的Venn图并进行基因本体论（GO）功能富集以及京都基因与基因组百科全书（KEGG）通路富集分析。STRING在线分析工具及Cytoscape软件进一步筛选关键基因。结果:与HC相比，RA的滑膜组织中有797个上调DEGs，434个下调DEGs，这些DEGs主要富集在淋巴细胞活化、免疫反应的正向调节等。利用Cytoscape和cytoHubba，在STRING数据库模型的基础上获得的5组差异基因，degree算法筛选出了10个hub基因，分别是LCK、SYK、PTPRC、HLA-DRA、LYN、NCAPG、TOP2A、JUN、CXCR4、CCNB1。甲氨蝶呤治疗显著上调20个DEGs，下调30个DEGs；利妥昔单抗治疗上调100个DEGs，下调55个DEGs；托珠单抗治疗上调91个DEGs，下调317个DEGs。这些差异改变的DEGs分别富集在调节细胞黏附、白细胞-细胞黏附、白细胞转移和胰岛素样生长因子受体信号通路上。值得注意的是，经过治疗，共有306个高表达的DEGs下调，36个低表达的DEGs上调。结论:LCK、胰岛素样生长因子受体信号通路等为RA发生发展以及DMARDs治疗的分子机制和关键枢纽基因，与RA对DMARDs治疗响应密切相关。

abstractsObjective:To identify differentially expressed genes (DEGs) associated with the progression of synovitis in RA by using bioinformatics analysis and explore the effects of DMARDs such as methotrexate, tocilizumab and rituximab on the DEGs in RA synovium.Methods:RA expression profile microarray data GSE7307、GSE12021、GSE55457、GSE55235、GSE77298、GSE89408 were acquired from the public gene chip database (GEO), including 113 synovial tissue samples from RA and 70 healthy controls (HC). At the same time, synovial expression microarrays GSE45867, GSE24742 and GSE97165 after DMARDs treatment were obtained. These data included 8 samples treated with methotrexate, 12 treated with tocilizumab, 12 treated with rituximab and 19 treated with combined tDMARDs. R software was used to screen DEGs and Venn plots using gene ontology function enrichment and Kyoto encyclopedia of genes and genomes pathway enrichment analysis. Hub genes were selected by STRING online analysis tool and Cytoscape software.Results:Compared with HC, 797 DEGs were up-regulated and 434 DEGs were down-regulated in the synovial tissue of RA. These DEGs were mainly enriched in T cell activation, immune response-activating cell surface receptor signaling pathway. Using Cytoscape and cytoHubba to obtain 5 sets of DEGs based on the STRING database model, the degree algorithm screened out 10 hub genes: LCK, SYK, PTPRC, HLA-DRA, LYN, NCAPG, TOP2A, JUN, CXCR4, CCNB1. Methotrexate treatment significantly up-regulated 20 DEGs and down-regulated 30 DEGs. Rituximab treatment up-regulated 100 DEGs and down-regulated 55 DEGs. Tocilizumab treatment up-regulated 91 DEGs and down-regulated 317 DEGs. These altered DEGs were enriched in regulating cell adhesion, leukocyte-cell adhesion, leukocyte transfer, and insulin-like growth factor receptor signaling pathways. It was worth noting that after treatment, a total of 306 high-expressing DEGs were down-regulated, and 36 low-expressing DEGs were up-regulated.Conclusion:LCK, insulin-like growth factor receptor signaling pathway, etc. are the responsible molecular mechanisms and key pivot genes for the occurrence and development of RA, and the treatment of DMARDs, which are closely related to the response of RA to the treatment of DMARDs.