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GADD45A may be a potential biomarker associated with endoplasmic reticulum stress in focal segmental
Hongyu Wang1, Jun Zou1, Hongbin Li2
1Division of Nephrology, Department of Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
Objective:
This study aimed to identify and validate potential endoplasmic reticulum stress-related biomarkers of focal segmental glomerulosclerosis(FSGS).
Methods:
Five microarray datasets were downloaded from the GEO database. The endoplasmic reticulum stress-related genes were extracted from GeneCards database. GSE104948, GSE129973, and GSE121233 datasets were used to identify DEGs by limma R package. WGCNA was performed to obtain hub gene modules. We intersected the DEGs, genes from hub module of WGCNA, and ERSRGs. GO and KEGG pathway enrichment analyses were performed. LASSO, SVM-RFE, and RF algorithms were used to screen characteristic genes. Further, GSE108109 and GSE104066 were used as validated datasets. Box plots, ROC curves, and AUC were created to identify potential biomarkers. A novel nomogram model was constructed using potential biomarkers. Immunohistochemistry validated the expression of the potential biomarkers, and correlation analysis was used to assess the correlation between the integrated optical density(IOD) value of GADD45A and the levels of 24-hour urinary protein, eGFR, and blood urea nitrogen.
Results:
Intersecting DEGs, the brown module genes, and ERSRGs, we identified 15 hub ERSRGs of FSGS. AGO2, CCND1, GADD45A, TRAM2, and PTPN1 genes were screened by using Lasso, SVM-RFE, and RF. Further, CCND1, GADD45A, and TRAM2 were validated as significant in training and validation datasets. A nomogram based on CCND1, GADD45A, and TRAM2 expression was constructed. The calibration curves, decision analysis curve, and clinical impact curve showed that the nomogram had good consistency and clinical practical benefit. The expression of GADD45A is higher in FSGS than controls in immunohistochemical(IHC) results(P < 0.0001). The integrated optical density value of GADD45A shows a strong correlation with 24-hour urinary protein(r 2 = 0.8459,P < 0.0001), eGFR(r 2 = -0.8233,P < 0.0001), and blood urea nitrogen(r 2 = 0.8695,P < 0.0001).
Conclusions:
GADD45A may be a potential biomarker associated with endoplasmic reticulum stress in FSGS.With its potential applicability spanning both biomarker identification and therapeutic intervention, GADD45A offers a compelling avenue for improving FSGS detection and clinical management in subsequent investigations.
