Genomic analysis unlocks the potential of denosumab as a targeted therapy for Crohn's disease.

Crohn's disease (CD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract with limited curative therapies. Genomic drug repurposing offers a rapid strategy to identify existing drugs that could be redirected to treat CD. We retrieved 1,333 CD-associated single-nucleotide polymorphisms from the GWAS Catalog and expanded these to 15,590 variants using linkage disequilibrium analysis in HaploReg. Fourteen layers of functional annotation prioritized 45 high-confidence risk genes. Drug-gene interactions were screened against DGIdb, and tissue expression patterns were assessed using GTEx bulk RNA-seq data. Cellular associations were explored via HuBMAP network analysis. Denosumab, an FDA-approved Receptor Activator of NF-κB Ligand (RANKL) inhibitor, exhibited the highest interaction score with TNFSF11 among prioritized genes. TNFSF11 expression peaked selectively in the terminal ileum-the primary site of CD pathology-while other risk genes showed broader. Network analysis linked TNFSF11 to mast cells in the ileal mucosa, suggesting that RANKL blockade could attenuate local inflammatory cascades. Integrating GWAS, functional genomics, and drug-gene interaction data highlights denosumab as a promising candidate for CD repurposing. Targeting TNFSF11 may enable focused anti-inflammatory effects in the ileum while minimizing systemic toxicity, warranting further preclinical and clinical evaluation.