Identifying potential biomarkers for the diagnosis and treatment of IgA nephropathy based on bioinformatics analysis

BMC Medical Genomics · 11 authors, 1 centre

AI SUMMARY

FIDELITY 80%

POPULATIONPatients with IgA nephropathy (IgAN) providing glomerular tissue samples; 80 IgAN samples and 27 normal controls from three GEO datasets (GSE37460, GSE99339, GSE104948)

INTERVENTIONBioinformatic analysis of gene expression profiles; in vitro validation using aggregated IgA1-stimulated human mesangial cells (HMCs); in vivo validation using renal tissue immunohistochemistry

COMPARISONIgAN glomerular tissue vs. normal glomerular tissue; IgAN vs. other renal pathologies (MCD, DN, FSGS, MN)

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TL;DR

This bioinformatics study identified 113 differentially expressed genes and 10 hub genes (including TYROBP, ALB, ITGB2) in IgA nephropathy (IgAN) by analyzing three microarray datasets. TYROBP showed the highest diagnostic accuracy (AUC 0.910) and was validated as highly expressed in IgAN glomerular tissue and mesangial cells, with ability to distinguish IgAN from other renal pathologies. These findings suggest potential non-invasive diagnostic biomarkers and therapeutic targets for IgAN, though clinical validation is needed.

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**Background:** IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and a leading cause of end-stage renal disease (ESRD) in young adults, with up to 30% of cases progressing to ESRD within 20 years. Current diagnosis relies exclusively on invasive renal biopsy, and treatment options (immunosuppression and supportive care) remain unsatisfactory. The four-hit pathogenesis theory involves abnormal hypogalactosylated IgA1, autoantibody production, immune complex formation, and glomerular deposition leading to inflammation and kidney injury. This study aimed to identify potential crucial genes as novel biomarkers for non-invasive diagnosis and therapeutic targets.

**Methods:** Three microarray datasets (GSE37460, GSE99339, GSE104948) containing 80 IgAN glomerular samples and 27 normal controls were downloaded from GEO. After normalization and batch effect removal, differentially expressed genes (DEGs) were identified using the limma package (|logFC| > 1, p < 0.05). Tissue/organ-specific expression was analyzed via BioGPS. GO and KEGG enrichment analyses were performed using clusterProfiler, and GSEA was conducted on all detected genes. A PPI network was constructed using STRING and visualized in Cytoscape; hub genes were identified using MCODE and MCC (CytoHubba) algorithms. The CTD database assessed gene-disease associations. Immune infiltration was analyzed using CIBERSORT. ROC curves evaluated diagnostic performance. CMap predicted therapeutic small molecules. TYROBP was validated in vitro using aggregated IgA1-stimulated HMCs and in vivo via immunohistochemistry in 15 patients (3 each: MCD, IgAN, DN, FSGS, MN).

**Key Results:** A total of 113 DEGs were identified (49 up-regulated, 64 down-regulated). Among these, 67 genes showed tissue/organ specificity, with the highest proportion in the hematologic/immune system (40.30%) and digestive system (22.39%). GO enrichment showed DEGs were enriched in peptidase regulator activity, regulation of cytokine production, and collagen-containing extracellular matrix. KEGG pathways included complement and coagulation cascades, pertussis, and PPAR signaling. GSEA revealed the proteasome pathway as most significantly enriched (ES = 0.666, NES = 1.782, p < 0.05). Ten hub genes were identified: KNG1 (logFC -1.50), FN1 (logFC 1.12), ALB (logFC -2.44), PLG (logFC -1.43), IGF1 (logFC -1.10), EGF (logFC -1.33), HRG (logFC -1.06), TYROBP (logFC 1.70), CSF1R (logFC 1.01), and ITGB2 (logFC 1.30). CTD analysis showed ALB, IGF1, and FN1 were highly interconnected with IgAN. Immune infiltration analysis revealed increased activated NK cells, monocytes, M0 macrophages, CD8+ T cells, and regulatory T cells in IgAN glomeruli, while naïve B cells, resting CD4 memory T cells, T follicular helper cells, resting dendritic cells, activated mast cells, and neutrophils were decreased. Six hub genes (IGF1, EGF, HRG, FN1, ITGB2, TYROBP) were strongly correlated with immune cell infiltration. ROC analysis showed all hub genes had AUC > 0.75; TYROBP had the highest AUC of 0.910, followed by ALB (0.886) and ITGB2 (0.884). CMap identified verteporfin, moxonidine, and procaine as the top three potential therapeutic compounds. Experimental validation confirmed TYROBP was significantly upregulated in aIgA1-stimulated HMCs and in IgAN renal tissue, while showing low expression in MCD, DN, FSGS, and MN.

**Clinical Implications:** This study identifies TYROBP as a promising diagnostic biomarker for IgAN with high specificity, potentially enabling non-invasive diagnosis and differentiation from other glomerular diseases. The ten hub genes and their immune correlations provide insights into IgAN pathogenesis, particularly regarding immune cell infiltration and the gut-kidney axis. The predicted therapeutic compounds, especially verteporfin (a YAP inhibitor with anti-fibrotic properties), warrant further investigation. However, limitations include modest sample size, need for clinical validation, and potential estimation biases in CIBERSORT analysis. Further clinical and basic research is required before these findings can translate to clinical practice.

PICO

PPOPULATION

Patients with IgA nephropathy (IgAN) providing glomerular tissue samples; 80 IgAN samples and 27 normal controls from three GEO datasets (GSE37460, GSE99339, GSE104948)

IINTERVENTION

Bioinformatic analysis of gene expression profiles; in vitro validation using aggregated IgA1-stimulated human mesangial cells (HMCs); in vivo validation using renal tissue immunohistochemistry

OOUTCOME

Differentially expressed genes (DEGs), hub genes, diagnostic accuracy (AUC), immune cell infiltration patterns, and TYROBP protein expression levels

STUDY TYPE

other

SPECIALTY

nephrology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

80% · B

ORIGINAL PAPER

PMC10044383

Identifying potential biomarkers for the diagnosis and treatment of IgA nephropathy based on bioinformatics analysis

BMC Medical Genomics

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ABSTRACT

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. Supplementary Information The online version contains supplementary material available at 10.1186/s12920-023-01494-y.

CITATION EXPORT

Xiaohui Li, Mengru Zeng, Jialu Liu et al.. Identifying potential biomarkers for the diagnosis and treatment of IgA nephropathy based on bioinformatics analysis. BMC Medical Genomics. (2023). https://doi.org/10.1186/s12920-023-01494-y

AUTHORS

11 · 1 CENTRES

Xiaohui Li, Mengru Zeng, Jialu Liu, Shumin Zhang, Yifei Liu, Yuee Zhao, Cong Wei, Kexin Yang, Ying Huang, Lei Zhang, Li Xiao

grid.216417.70000 0001 0379 7164Department of Nephrology, Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital, Central South University, Changsha, 410011 China