Identifying novel inflammatory protein biomarkers and drug targets of inflammatory bowel disease by integrating Mendelian randomization, bioinformatics, and druggability analysis

Inflammatory proteins have the potential to be used as therapeutic targets for inflammatory bowel disease (IBD). We conducted Mendelian randomization (MR) analysis to probe causal associations between 91 circulating inflammatory proteins and IBD in the discovery and replication cohorts. Subsequently, we conducted meta-analysis of results from two cohorts. We further conducted protein-protein interaction (PPI), enrichment analysis, and druggability evaluation to elucidate our results and prioritize potential therapeutic targets. By integrating data from two cohorts, we demonstrated that genetically predicted CD40 (odds ratio [OR] = 0.878, 95% confidence interval [CI] = 0.838-0.919) and C-X-C motif chemokine ligand (CXCL)5 (OR = 0.884, 95%CI = 0.841-0.930) decreased IBD risk. However, genetically predicted CXCL9 (OR = 1.184, 95%CI = 1.084-1.294), Interleukin (IL)-18 (OR = 1.140, 95%CI = 1.076-1.208), CD6 (OR = 1.096, 95%CI = 1.045-1.150), and 4E-binding protein 1 (4E-BP1) (OR = 1.154, 95%CI = 1.070-1.244) increased IBD risk. Moreover, genetically predicted CD40 (OR = 0.855, 95%CI = 0.801-0.912) decreased Crohn's disease (CD) risk. Genetically predicted fibroblast growth factor 21 (FGF21) (OR = 1.259, 95%CI = 1.135-1.397) and 4E-BP1 (OR = 1.202, 95%CI = 1.088-1.327) increased CD risk. We found no inflammatory protein associated with ulcerative colitis. Additionally, CD was significantly associated with elevated levels of three circulating inflammatory proteins, which are suggested to be the consequences of CD. PPI analysis demonstrated interactions between CXCL5, CXCL9, IL-18, CD40, and FGF21. Enrichment analysis indicated these identified proteins significantly enriched in inflammation-related signaling pathways, including interleukin signaling, cytokine signaling, and NF-κB pathway. Three proteins (CD40, IL-18, 4E-BP1) have been targeted for drug development on cancers and immune-related diseases, with potentials of therapeutic targets for IBD. Our results provide new biomarkers and drug targets for CD. Moreover, we further demonstrate critical roles of inflammation and immunity in the occurrence and development of IBD.