Identification Of Key Genes And Pathways In The Keratoconus Immune Response By Bioinformatics Analysis

Objective: To explore the relationship between keratoconus(KC)and immune response and further elaborate its possible pathological mechanism through text mining and analysis using computer and related databases.Methods: Through Pubmed2 Ensembl,we conducted text mining of previously published literatures to find out the gene sets related to keratoconus and immune response.Gene Codis was used to conduct GO and KEGG enrichment analysis on the genes obtained from text mining and the protein-protein interaction(PPI)network was constructed through STRING.Cytoscape software MCODE plug-in was used to screen subnetworks,and then Cytohubba plug-in was used to screen Hub genes in PPI networks.Finally,functional enrichment was conducted through DAVID database.Results:Through text mining,150 genes related to keratoconus and immune response were found.GO biological process is mainly enriched in extracellular matrix organization,positive regulation of gene expression,cytokine-mediated signaling pathway,extracellular matrix disassembly,negative regulation of apoptosis process,immune response,leukocyte migration and positive regulation of cell population proliferation,signal transduction and positive regulation of MAPK cascade.KEGG pathways are mainly enriched in the pathways in cancer,cytokine-cytokine receptor interaction,malaria,cell adhesion molecules,rheumatoid arthritis,PI3K-Akt signaling pathway,human T-cell leukemia virus infection 1 infection,allograft rejection,graft-versus-host disease,MAPK signaling pathway,type I diabetes mellitus,TNF signaling pathway,proteoglycans in cancer,autoimmune thyroid disease and cellular senescence,etc.Two main clusters were obtained by MCODE screening,Cluster 1 consisted of IL4,PDGFB,IL6,TNC,MMP1,IGFBP3,TF,TGFB2,IFNG,BMP4,MMP13,HLA-G,MMP3,HLA-B,EGF,HGF,HLA-A,MMP9,TGFB1,VCAM1,ICAM1,IL10,IL2,B2 M,MMP2 and TNF 26 genes.Cluster 2 consisted of BCR,FGF1 and FGF4 3genes.Functional enrichment analysis of cluster genes was performed through DAVID database,including GO enrichment and KEGG enrichment.At the level of biological processes,Cluster 1 genes are mainly enriched in the interferon mediated signaling pathway,immune response,regulation of immune response,response to drug,platelet degranulation,positive regulation of cell proliferation,antigen processing and presentationofexogenouspeptide antigen via MHC-class 1,TAP-independent,cellular response to lipopolysaccharide,positive regulation of vascular smooth muscle cell proliferation and gene expression.Clustering 2 gene enrichment mainly in peptidyl-tyrosine phosphorylation,and regulation of endothelial cell of chemotaxis to fibroblast growth factor,and phosphatidylinositol-mediated signaling,positive regulation of GTPase activity,signal transduction,positive regulation of cell division,phosphatidylinositol phosphorylation,fibroblast growth factor receptor signaling pathway,positive regulation of ERK1 and ERK2 cascade and MAPK cascade,etc.The enrichment analysis results of KEGG signal pathway showed that Cluster 1 significant enrichment of signaling pathways including allograft rejection,graft-versus-host disease,inflammatory bowel disease,HTLV –1 infection,rheumatoid arthritis,autoimmune thyroid diseases,pathways in cancer,antigen processing and presentaion,cytokine-cytokine receptors interaction,herpes simplex infection,asthma,TNFsignaling pathway,TGF-beta signaling pathway,T cell receptor signaling pathway,JAK-STAT signaling pathway,NF-Kappa B signaling pathway,PI3K-Akt signaling pathway,HIF-1 signaling pathway,Fox O signaling pathway,MAPK signaling pathway,etc.The significantly enriched signaling pathways in cluster 2 mainly included melanoma and tumor pathways.Conclusion:In this study,two core gene clusters related to the immune response of keratoconus were screened out through bioinformatics analysis.TGF-Beta,T cell receptor,Jak-Stat,PI3K-Akt,NF-Kappa Band HIF-1 signaling pathways may be closely related to the immune response in the pathogenesis of keratoconus.Genes such as IL6,TNF,ICAM1,IL10,B2 M,HLA-A,VCAM1,IL2,HLA-G and HLA-B may be potential targets for keratoconus therapy.