Unveiling the key genes, environmental toxins, and drug exposures in modulating the severity of ulcerative colitis: a comprehensive analysis

Abstract

Background: As yet, the genetic abnormalities involved in the exacerbation of Ulcerative colitis (UC) have not been adequately explored based on bioinformatic methods.

Materials and methods: The gene microarray data and clinical information were downloaded from Gene Expression Omnibus (GEO) repository. The scale-free gene co-expression networks were constructed by R package "WGCNA". Gene enrichment analysis was performed via Metascape database. Differential expression analysis was performed using "Limma" R package. The "randomForest" packages in R was used to construct the random forest model. Unsupervised clustering analysis performed by "ConsensusClusterPlus"R package was utilized to identify different subtypes of UC patients. Heat map was established using the R package "pheatmap". Diagnostic parameter capability was evaluated by ROC curve. The"XSum"packages in R was used to screen out small-molecule drugs for the exacerbation of UC based on cMap database. Molecular docking was performed with Schrodinger molecular docking software.

Results: Via WGCNA, a total 77 high Mayo score-associated genes specific in UC were identified. Subsequently, the 9 gene signatures of the exacerbation of UC was screened out by random forest algorithm and Limma analysis, including BGN,CHST15,CYYR1,GPR137B,GPR4,ITGA5,LILRB1,SLFN11 and ST3GAL2. The ROC curve suggested good predictive performance of the signatures for exacerbation of UC in both the training set and the validation set. We generated a novel genotyping scheme based on the 9 signatures. The percentage of patients achieved remission after 4 weeks intravenous corticosteroids (CS-IV) treatment was higher in cluster C1 than that in cluster C2 (54% vs. 27%, Chi-square test, p=0.02). Energy metabolism-associated signaling pathways were significantly up-regulated in cluster C1, including the oxidative phosphorylation, pentose and glucuronate interconversions and citrate cycle TCA cycle pathways. The cluster C2 had a significant higher level of CD4+ T cells. The"XSum"algorithm revealed that Exisulind has a therapeutic potential for UC. Exisulind showed a good binding affinity for GPR4, ST3GAL2 and LILRB1 protein with the docking glide scores of -7.400 kcal/mol, -7.191 kcal/mol and -6.721 kcal/mol, respectively.We also provided a comprehensive review of the environmental toxins and drug exposures that potentially impact the progression of UC.

Conclusion: Using WGCNA and random forest algorithm, we identified 9 gene signatures of the exacerbation of UC. A novel genotyping scheme was constructed to predict the severity of UC and screen UC patients suitable for CS-IV treatment. Subsequently, we identified a small molecule drug (Exisulind) with potential therapeutic effects for UC. Thus, our study provided new ideas and materials for the personalized clinical treatment plans for patients with UC.

Keywords: bioinformatics; biomarker; genomics; microarray; ulcerative colitis.