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

OBJECTIVES: 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. We aimed to confirm if a single nucleotide variation (SNV) in the TWSG1 gene is associated with clinical remission in inflammatory bowel disease (IBD) patients on ustekinumab. METHODS: A retrospective cohort study was conducted in ustekinumab-treated IBD patients. Participants underwent screening for the TWSG1 SNV rs7242593 and were assessed for clinical disease remission by Harvey-Bradshaw Index or partial Mayo score at 3 and 12 months. Ustekinumab dose and treatment duration were also assessed. RESULTS: A total of 125 IBD participants were included (wild-type 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] and 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 wild-type carriers, ustekinumab dose escalations were not associated with disease remission at any time. CONCLUSION: TWSG1 SNV was associated with early and persistent clinical remission in ustekinumab-exposed IBD patients. Wild-type carriers who did not achieve remission were not rescued with high-dose treatment.