P1315 TWSG1 variation identifies a ustekinumab-response phenotype in patients with inflammatory bowel disease

Abstract Background A genome wide association study identified that genetic variation in the twisted gastrulation protein homolog-1 gene (TWSG1 rs7242593) was linked to early clinical remission in ustekinumab-exposed patients in the UNITI clinical trials. Methods A retrospective cohort study was conducted in IBD patients treated with ustekinumab. All participants underwent screening for the SNV rs7242593 in the TWSG1 gene and were assessed for clinical disease remission by Harvey-Bradshaw index (HBI) or partial Mayo score at 3 months and at 12 months. Ustekinumab dose and treatment duration were also assessed. Results A total of 125 IBD participants were included in the analyses (wildtype genotype, CC, n = 108; variant genotype, CT, n = 17). Participants in the variant genotype group were more likely to achieve clinical remission at 3-months (odds ratio, OR 23. 11, 95% confidence interval, CI = 3. 92-449. 40, adjusted p = 0. 0043), at 12-months (OR = 17. 75, 95%CI = 2. 42-381. 0, adjusted p = 0. 016) on standard ustekinumab dosing and less likely to discontinue therapy during the follow-up period (hazard ratio = 4. 20, 95%CI = 1. 94-9. 09, p = 0. 02). For wildtype genotypes, ustekinumab dose escalations were not associated with disease remission at any time. Conclusion TWSG1 SNV (rs7242593) was associated with early and persistent clinical remission in ustekinumab-exposed IBD patients. Wildtype participants who did not achieve remission were not rescued with high-dose treatment. This SNV may also serve as a useful molecular marker of patients who do not benefit from ustekinumab dose escalations. References: 1. Zhao J, Lu Q, Liu Y, et al. Th17 Cells in Inflammatory Bowel Disease: Cytokines, Plasticity, and Therapies. J Immunol Res. 2021;2021: 8816041. 2. Bourgonje AR, Ungaro RC, Mehandru S, Colombel JF. Targeting the Interleukin 23 Pathway in Inflammatory Bowel Disease. Gastroenterology. 2024. 3. Vuyyuru SK, Solitano V, Hogan M, et al. Efficacy and Safety of IL-12/23 and IL-23 Inhibitors for Crohn’s Disease: Systematic Review and Meta-Analysis. Dig Dis Sci. 2023;68 (9): 3702-3713. 4. Atreya R, Neurath MF. IL-23 Blockade in Anti-TNF Refractory IBD: From Mechanisms to Clinical Reality. Journal of Crohn’s 16 (Supplement₂): ii54-ii63. 5. Afif W, Arasaradnam RP, Abreu MT, et al. Efficacy and Safety of Ustekinumab for Ulcerative Colitis Through 4 Years: Final Results of the UNIFI Long-Term Maintenance Study. Official journal of the American College of Gastroenterology | ACG. 2024;119 (5). 6. Sandborn WJ, Rebuck R, Wang Y, et al. Five-Year Efficacy and Safety of Ustekinumab Treatment in Crohn’s Disease: The IM-UNITI Trial. Clin Gastroenterol Hepatol. 2022;20 (3): 578-590. e574. 7. Brusselle GG, Koppelman GH. Biologic Therapies for Severe Asthma. N Engl J Med. 2022;386 (2): 157-171. 8. Kim SH, Kim Y. Tailored Biologics Selection in Severe Asthma. Tuberc Respir Dis (Seoul). 2024;87 (1): 12-21. 9. Opina MTD, Moore WC. Phenotype-driven therapeutics in severe asthma. Curr Allergy Asthma Rep. 2017;17: 1-13. 10. Hart A, Li K, Gasink C, Jacobstein D, Brodmerkel C. DOP046 Genome-wide association study of baseline disease characteristics and response to Ustekinumab in moderate to severe Crohn’s disease. Journal of Crohn’s and Colitis. 2017;11 (suppl₁): S54-S54. 11. Lewis JD, Chuai S, Nessel L, Lichtenstein GR, Aberra FN, Ellenberg JH. Use of the noninvasive components of the Mayo score to assess clinical response in ulcerative colitis. Inflamm Bowel Dis. 2008;14 (12): 1660-1666. 12. Harvey RF, Bradshaw JM. A simple index of Crohn’s-disease activity. Lancet. 1980;1 (8167): 514. 13. Suzuki E, Fukuda T. Multifaceted Functions of TWSG1: From Embryogenesis to Cancer Development. Int J Mol Sci. 2022;23 (21). 14. Kumar KSP, Narahari JM, Narayana P, Prashant A. The Role of Twisted Gastrulation 1 (TWSG1) Gene in TGF-β Signaling Linked to Cancer: A Comprehensive Review. Asian Pac J Cancer Prev. 2025;26 (4): 1129-1138. 15. Ihara S, Hirata Y, Koike K. TGF-β in inflammatory bowel disease: a key regulator of immune cells, epithelium, and the intestinal microbiota. J Gastroenterol. 2017;52 (7): 777-787. 16. Kapizioni C, Desoki R, Lam D, et al. Biologic Therapy for Inflammatory Bowel Disease: Real-World Comparative Effectiveness and Impact of Drug Sequencing in 13 222 Patients within the UK IBD BioResource. Journal of Crohn’s and Colitis. 2023;18 (6): 790-800. 17. GG BEK. 2023 Impact of Inflammatory Bowel Disease in Canada. In: Canada CsC ed. , Vol. 1, 2023: 278. 18. Coenen MJH, de Jong DJ, van Marrewijk CJ, et al. Identification of Patients With Variants in TPMT and Dose Reduction Reduces Hematologic Events During Thiopurine Treatment of Inflammatory Bowel Disease. Gastroenterology. 2015;149 (4): 907-917. e907. 19. Wilson A, Jansen LE, Rose RV, et al. HLA-DQA1-HLA-DRB1 polymorphism is a major predictor of azathioprine-induced pancreatitis in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2018;47 (5): 615-620. 20. Wilson A, Wang Q, Choi Y-H, et al. Pretreatment HLADQA1-HLADRB1 Testing for the Prevention of Azathioprine-Induced Pancreatitis in Inflammatory Bowel Disease: A Prospective Cohort Study. Clinical and Translational Gastroenterology. 2021;12 (4). 21. Heap GA, Weedon MN, Bewshea CM, et al. HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants. Nat Genet. Letter. 2014;46 (10): 1131-1134. 22. Wilson A, Peel C, Wang Q, Pananos AD, Kim RB. HLADQA1*05 genotype predicts anti-drug antibody formation and loss of response during infliximab therapy for inflammatory bowel disease. Aliment Pharmacol Ther. 2020;51 (3): 356-363. 23. Sazonovs A, Kennedy NA, Moutsianas L, et al. HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn’s Disease. Gastroenterology. 2020;158 (1): 189-199. 24. Wilson A, Chande N, Ponich T, Gregor JC, Choi YH, Kim RB. HLADQA1∗05GA Genetic Screening Promotes the Safe Delivery of Combination Therapy in Inflammatory Bowel Disease. Clin Gastroenterol Hepatol. 2023. 25. Noor NM, Lee JC, Bond S, et al. A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn’s disease (PROFILE): a multicentre, open-label randomised controlled trial. The Lancet Gastroenterology 9 (5): 415-427. 26. Lee JC, Lyons PA, McKinney EF, et al. Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. J Clin Invest. 2011;121 (10): 4170-4179. 27. Chen R, Zhang S. Treatment strategies and biomarkers in Crohn’s disease: the PROFILE trial. The Lancet Gastroenterology 9 (7): 592. 28. Meserve J, Ma C, Dulai PS, Jairath V, Singh S. Effectiveness of Reinduction and/or Dose Escalation of Ustekinumab in Crohn’s Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2022;20 (12): 2728-2740. e2721. Conflict of interest: Dr. Alkhalifa, Mohammed: No conflict of interest Dela Cruz, Gio: No conflict of interest Ponich, Terry: TP has served as a consultant for Bristol Myers Squibb, Celltrion, Eli Lilly and Pfizer recently. He currently serves as an investigator on clinical research studies for Abivax, Alimentiv, AnaptysBio, Eli Lilly, Merck, Morphic Therapeutic, Pfizer/Kanyos Bio, Spyre Therapeutics and Takeda. Gregor, James: James C. Gregor has received speaking honoraria from AbbVie, Pfizer, Takeda, Celltrion consulting honoraria from Fresinius Kabi educational grants from Janssen, AbbVie, Organon Yan, Brian: No conflict of interest Khanna, Reena: Reena Khanna reports fees for consulting/speaking from: AbbVie, Amgen, BMS, Celltrion, Encycle, Innomar, Gilead, Janssen, Jamp, Lilly, Merck, Pendopharm, Pfizer, Roche/Genentech, Alimentiv (formerly Robarts Clinical Trials), Shire, and Takeda Canada outside the submitted work. McIntosh, Keith: Keith McIntosh has received honoraria for speaking/consulting from AbbVie, Pfizer, Avir Pharma, Celltrion, Organon, Sanofi, Bausch, Lupin.