Epithelial regulatory networks link non-coding genetic variation to clinical heterogeneity in ulcerative colitis

Ulcerative colitis (UC) is a genetically heterogeneous disease causing chronic intestinal inflammation. Genome-wide association studies have linked numerous non-coding single nucleotide polymorphisms (SNPs) to UC, yet how these variants relate to intestinal epithelial function and clinical outcomes remains largely unknown. To address this, we aimed to reconstruct patient-specific epithelial signalling and regulatory networks perturbed by non-coding SNPs and to dissect patient heterogeneity in a large UC phase III trial. We analysed genotype data from 452 participants in the etrolizumab phase III HICKORY cohort using the integrated SNP network platform (iSNP) to map the downstream effects of non-coding SNPs and identify transcription factors (TFs) they perturb in each patient. TFs were filtered to retain those with differential regulatory activity in UC epithelial cells, patients were stratified by these TF profiles, and clusters were correlated with etrolizumab outcomes. We identified 14 SNP-propagated TFs with differential epithelial regulatory activity. Unsupervised clustering stratified patients into subgroups differing in disease severity and treatment response: two clusters had the highest severity and lowest remission and response rates, whereas two others had the best outcomes. iSNP-based clustering improved endoscopic healing prediction (p = 0.03), with trends for clinical response and histological endoscopic mucosal improvement. This systems genomics framework links patient-specific non-coding SNPs to epithelial signalling and regulatory networks in UC and captures clinically meaningful heterogeneity associated with treatment outcomes. It supports genetics-informed precision medicine and improved clinical trial design in inflammatory bowel disease and beyond.