Table_1_Derlin-1, as a Potential Early Predictive Biomarker for Nonresponse to Infliximab Treatment in Rheumatoid Arthritis, Is Related to Autophagy.docx

BackgroundThe goal of this study was to identify potential predictive biomarkers for the therapeutic effect of infliximab (IFX) in Rheumatoid arthritis (RA) and explore the potential molecular mechanism of nonresponse to IFX treatment to achieve individualized treatment of RA.
MethodsDifferential gene expression between IFX responders and nonresponders in the GSE58795 and GSE78068 datasets was identified. Coexpression analysis was used to identify the modules associated with nonresponse to IFX therapy for RA, and enrichment analysis was conducted on module genes. Least absolute shrink and selection operator (LASSO) regression was used to develop a gene signature for predicting the therapeutic effect of IFX in RA, and the area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive value of the signature. Correlation analysis and single-sample gene set enrichment analysis (ssGSEA) were used to explore the potential role of the hub genes. Experimental validation was conducted in synovial tissue and RA fibroblast-like synoviocytes (RA-FLSs).
ResultsA total of 46 common genes were obtained among the two datasets. The yellow-green module was identified as the key module associated with nonresponse to IFX therapy for RA. We identified a 25-gene signature in GSE78068, and the AUC for the signature was 0.831 in the internal validation set and 0.924 in the GSE58795 dataset(external validation set). Derlin-1 (DERL1) was identified as the hub gene and demonstrated to be involved in the immune response and autophagy regulation. DERL1 expression was increased in RA synovial tissue compared with OA synovial tissue, and DERL1-siRNA partially inhibited autophagosome formation in RA-FLSs.
ConclusionThe 25-gene signature may have potential predictive value for the therapeutic effect of IFX in RA at the beginning of IFX treatment, and autophagy may be involved in nonresponse to IFX treatment. In particular, DERL1 may be associated with the regulation of autophagy.

研究背景
本研究旨在识别类风湿关节炎（Rheumatoid arthritis, RA）患者接受英夫利昔单抗（infliximab, IFX）治疗的潜在预测生物标志物，并探索英夫利昔单抗治疗应答不佳的潜在分子机制，以实现类风湿关节炎的个体化治疗。

研究方法
本研究在GSE58795与GSE78068数据集内，识别英夫利昔单抗应答者与无应答者之间的差异基因表达情况。通过共表达分析筛选与类风湿关节炎患者英夫利昔单抗治疗应答不佳相关的基因共表达模块，并对模块内基因开展富集分析。采用最小绝对收缩和选择算子（Least absolute shrink and selection operator, LASSO）回归构建用于预测类风湿关节炎患者英夫利昔单抗治疗疗效的基因特征，并通过受试者工作特征曲线下面积（area under the receiver operating characteristic curve, AUC）评估该基因特征的预测价值。利用相关性分析与单样本基因集富集分析（single-sample gene set enrichment analysis, ssGSEA）探究核心基因的潜在作用。此外，在滑膜组织与类风湿关节炎成纤维样滑膜细胞（RA-FLSs）中开展实验验证。

研究结果
本研究在两个数据集中共筛选得到46个共有基因。鉴定出黄绿色模块为与类风湿关节炎患者英夫利昔单抗治疗应答不佳相关的关键基因共表达模块。在GSE78068数据集中构建得到含25个基因的特征模型，该模型在内部验证集中的曲线下面积为0.831，在作为外部验证集的GSE58795数据集中的曲线下面积为0.924。鉴定出Derlin-1（DERL1）为核心基因，其参与免疫应答与自噬调控过程。与骨关节炎滑膜组织相比，Derlin-1在类风湿关节炎滑膜组织中的表达水平升高；且Derlin-1小干扰RNA（DERL1-siRNA）可部分抑制类风湿关节炎成纤维样滑膜细胞中的自噬体形成。

研究结论
本研究所构建的25基因特征模型在类风湿关节炎患者英夫利昔单抗治疗初始阶段，对其治疗疗效具有潜在预测价值；自噬过程可能参与英夫利昔单抗治疗应答不佳的发生机制，其中Derlin-1（DERL1）或与自噬调控密切相关。