P0181Functional Impact of Non-Coding SNPs in Ulcerative Colitis Revealed using Patient-Specific Network Modelling

Abstract Background The pursuit of effective therapeutic interventions for inflammatory bowel disease (IBD) remains a significant challenge, with many prospective drugs failing in clinical trials. Etrolizumab, a humanized anti-β7 integrin monoclonal antibody, showed promise in pre-clinical studies but ultimately failed to meet primary endpoints in IBD phase 3 clinical trials1. One potential contributing factor to such failures is the limited understanding of the genetic and molecular mechanisms underlying patient heterogeneity in IBD. Methods We analysed genotype and clinical data from 452 ulcerative colitis (UC) patients enrolled in the etrolizumab phase 3 clinical trial. Using the previously validated integrated Single nucleotide polymorphism Network Platform (iSNP)2, we assessed the systems-level downstream impact of non-coding SNPs. iSNP generated patient-specific signalling and gene-regulatory networks, which we examined to identify key functional processes. This patient-level network modelling enabled us to dissect the molecular heterogeneity within the cohort. We then defined distinct patient subgroups based on their molecular network profiles and correlated these with clinical phenotypes to link genotype-driven functional processes to clinical outcomes. Results The functional modules were enriched in key molecular processes relevant to UC, including NFkB signalling and cell cycle, providing clear connection between genotype and pathomechanisms. Unsupervised clustering of patient-specific molecular networks stratified patients into distinct subgroups, which exhibited significant differences in gene expression and clinical outcomes, including disease severity and treatment response (Figure 1). Conclusion The presented approach enables the identification of patient subsets based on their disease-associated SNP fingerprints and uncovers distinct disease subgroups by coalescing GWAS signals that perturb downstream signalling, providing a mechanistic framework for understanding UC heterogeneity and guiding precision medicine strategies. This study underscores the value of network-based methodologies in elucidating genotype-phenotype relationships in IBD. References: 1. Peyrin-Biroulet L, Hart A, Bossuyt P, et al. Etrolizumab as induction and maintenance therapy for ulcerative colitis in patients previously treated with tumour necrosis factor inhibitors (HICKORY): a phase 3, randomised, controlled trial. Lancet Gastroenterol Hepatol. 2022;7(2):128-140. doi:10.1016/S2468-1253(21)00298-32. 2. Módos D, Thomas JP, Brooks-Warburton J, et al. Decoding Non-coding SNPs: Systems Genomics Modelling Dissects the Heterogeneity of IBD. medRxiv. October 30, 2024. doi:10.1101/2024.10.28.24316194; Molecular Systems Biology, in press. Conflict of interest: Liu, Yufan: Grant: Unilever, Roche Thomas, John P: Research support from Roche Modos, Dezso: Other: I worked as consultant for HEALX and IOVA Pharmaceuticals Research support from Roche Bohar, Balazs: Research support from Roche Powell, Nick: Grant: Takeda, BMS, Pfizer, Astra-Zeneca Personal Fees: Abbvie, Abivax, Allergan, Astra-Zeneca, Bristol-Myers Squibb, Celgene, Celltrion, Dr Falk Pharma UK Ltd, Ferring, Galapagos, GSK, Janssen, MSD, Roche, Pfizer, Sobi, Takeda, Tillotts Paun, Alexandra: Employed by F Hoffmann - La-Roche AG Basel McBride, Jacqueline: Employed by Genentech Dr. Korcsmaros, Tamas: Research support from Roche