基于生物信息学分析鉴定 IgA 肾病诊断和治疗的潜在生物标志物。
Identifying potential biomarkers for the diagnosis and treatment of IgA nephropathy based on bioinformatics analysis.
机构信息
Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
出版信息
BMC Med Genomics. 2023 Mar 28;16(1):63. doi: 10.1186/s12920-023-01494-y.
BACKGROUND
IgA nephropathy (IgAN) has become the leading cause of end-stage renal disease in young adults. Nevertheless, the current diagnosis exclusively relies on invasive renal biopsy, and specific treatment is deficient. Thus, our study aims to identify potential crucial genes, thereby providing novel biomarkers for the diagnosis and therapy of IgAN.
METHODS
Three microarray datasets were downloaded from GEO official website. Differentially expressed genes (DEGs) were identified by limma package. GO and KEGG analysis were conducted. Tissue/organ-specific DEGs were distinguished via BioGPS. GSEA was utilized to elucidate the predominant enrichment pathways. The PPI network of DEGs was established, and hub genes were mined through Cytoscape. The CTD database was employed to determine the association between hub genes and IgAN. Infiltrating immune cells and their relationship to hub genes were evaluated based on CIBERSORT. Furthermore, the diagnostic effectiveness of hub markers was subsequently predicted using the ROC curves. The CMap database was applied to investigate potential therapeutic drugs. The expression level and diagnostic accuracy of TYROBP was validated in the cell model of IgAN and different renal pathologies.
RESULTS
A total of 113 DEGs were screened, which were mostly enriched in peptidase regulator activity, regulation of cytokine production, and collagen-containing extracellular matrix. Among these DEGs, 67 genes manifested pronounced tissue and organ specificity. GSEA analysis revealed that the most significant enriched gene sets were involved in proteasome pathway. Ten hub genes (KNG1, FN1, ALB, PLG, IGF1, EGF, HRG, TYROBP, CSF1R, and ITGB2) were recognized. CTD showed a close connection between ALB, IGF, FN1 and IgAN. Immune infiltration analysis elucidated that IGF1, EGF, HRG, FN1, ITGB2, and TYROBP were closely associated with infiltrating immune cells. ROC curves reflected that all hub genes, especially TYROBP, exhibited a good diagnostic value for IgAN. Verteporfin, moxonidine, and procaine were the most significant three therapeutic drugs. Further exploration proved that TYROBP was not only highly expressed in IgAN, but exhibited high specificity for the diagnosis of IgAN.
CONCLUSIONS
This study may offer novel insights into the mechanisms involved in IgAN occurrence and progression and the selection of diagnostic markers and therapeutic targets for IgAN.
背景
IgA 肾病（IgAN）已成为导致年轻人终末期肾病的主要原因。然而，目前的诊断完全依赖于有创性的肾活检，并且缺乏特定的治疗方法。因此，我们的研究旨在确定潜在的关键基因，从而为 IgAN 的诊断和治疗提供新的生物标志物。
方法
从 GEO 官方网站下载了三个微阵列数据集。使用 limma 包鉴定差异表达基因（DEGs）。进行 GO 和 KEGG 分析。通过 BioGPS 区分组织/器官特异性 DEGs。使用 GSEA 阐明主要富集途径。建立 DEGs 的 PPI 网络，并通过 Cytoscape 挖掘枢纽基因。使用 CTD 数据库确定枢纽基因与 IgAN 的关联。基于 CIBERSORT 评估浸润免疫细胞及其与枢纽基因的关系。此外，使用 ROC 曲线预测枢纽标记的诊断效果。使用 CMap 数据库研究潜在的治疗药物。在 IgAN 和不同肾脏病变的细胞模型中验证 TYROBP 的表达水平和诊断准确性。
结果
筛选出 113 个差异表达基因，主要富集于肽酶调节活性、细胞因子产生调节和含有胶原蛋白的细胞外基质。在这些 DEGs 中，有 67 个基因表现出明显的组织和器官特异性。GSEA 分析显示最显著富集的基因集与蛋白酶体途径有关。确定了 10 个枢纽基因（KNG1、FN1、ALB、PLG、IGF1、EGF、HRG、TYROBP、CSF1R 和 ITGB2）。CTD 显示 ALB、IGF、FN1 与 IgAN 密切相关。免疫浸润分析表明 IGF1、EGF、HRG、FN1、ITGB2 和 TYROBP 与浸润免疫细胞密切相关。ROC 曲线表明所有枢纽基因，尤其是 TYROBP，对 IgAN 具有良好的诊断价值。维替泊芬、莫索尼定和普鲁卡因是最重要的三种治疗药物。进一步研究证明，TYROBP 在 IgAN 中不仅高度表达，而且对 IgAN 的诊断具有高度特异性。
结论
本研究可能为 IgAN 发生和进展的机制以及 IgAN 诊断标志物和治疗靶点的选择提供新的见解。
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