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. 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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.
Alkhalifa et al. (Thu,) studied this question.