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Identification and Verification of Hub Biomarkers and Immune-Related Pathways Participating in the Trabecular Meshwork after using Corticosteroid

Abstract

Background: The corticosteroids is associated with increased Intraocular Pressure (IOP), especially in the way of topical application. However, the cause and potential molecular events are not clearly explained. It was reported that immune cells may impact on matrix metalloproteinase pathway and IOP. The purpose of this study was to identify the key biomarkers and immune-related pathways involved in the Trabecular Meshwork (TM) after corticosteroids use.

Methods: The gene expression omnibus database was used to retrieve the expression profile for GSE124114 and GSE37474. Based on differential expression analysis (DEGs), hub markers for the possible molecular pathways in the TM following the use of corticosteroids were mined. The hub gene modules linked to higher IOP were found using Weighted Gene Co-Expression Network Analysis (WGCNA), and the immune cells presence of the TM was assessed using CIBERSORT.R (version 3.6.1) was used to carry out enrichment analysis on DEGs. The STRING database created the Protein-Protein Interaction (PPI) network of DEGs. The combined GSE6298 and GSE65240 datasets was used to confirm the expression of hub genes, and receiver operating characteristic curve analysis was also carried out.

Results:A total of 30 DEGs were recognized. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses demonstrated that these DEGs focused primarily on positive regulation of cytokine production and phenylalanine metabolism relevant signaling pathways. Two hub modules were enriched on rheumatoid arthritis pathway and the AGE-RAGE signaling pathway in diabetic complications. The 2 most firmly related hub genes (TSC22D3 and FKBP5) among 24 overlapped hub genes were identified from the PPI network. The immune infiltration results revealed the most significant relationship was macrophages M0. TSC22D3 was strongly related with macrophages M0 (R=0.75, p=0.018). ROC curve analysis demonstrated FKBP5 gene was important in TM treated with steroid hormone. FKBP5 gene was verified through the consolidated GSE6298, GSE65240 database.

Conclusion: Two key genes (TSC22D3, FKBP5) are involved in the comprehension of the molecular mechanisms in corticosteroids-induce ocular hypertension. TSC22D3 was strongly related to macrophages, which was associated with the pathogenesis of TM. FKBP5 could be a potential novel diagnostic marker in blood samples from patients with higher IOP.

Liwen Wang, Di Wu, Yuanqiang Sun, Di Song, Xuefeng Pan

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