Abstract Background Despite the identification of numerous genetic risk factors for Inflammatory Bowel Disease (IBD), the influence of genetic variants on therapeutic response remains insufficiently understood. Due to its involvement in various immunoregulatory signaling pathways, the ETS2 gene has become increasingly prominent. Given that many patients respond inadequately to immunomodulatory therapies or experience a secondary loss of efficacy, there is a high demand for predictive biomarkers. This study aimed to investigate the relevance of ETS2 polymorphism in its response to anti-TNF treatment in IBD and to evaluate its potential as a predictive marker. Methods A retrospective cohort of 123 patients diagnosed with Crohn’s disease or Ulcerative Colitis was genotyped for the ETS2 rs2836882 variant. All patients had received at least one course of TNF-α-inhibitor therapy. Genotype distribution was evaluated in relation to treatment duration. Clinical data, including therapy response and discontinuation, were extracted from medical records and analyzed using survival and regression methods. Results Treatment duration differed significantly between the genotypes in the overall cohort (Log-Rank p = 0.017; Breslow p = 0.040; Tarone-Ware p = 0.026). Homozygous GG carriers had the most extended median treatment duration (49.5 months) compared to GA (31 months) and AA (21 months), with mean durations also differing significantly (Kruskal-Wallis, p = 0.030). The presence of at least one non-risk allele (AA/GA) was associated with an increased risk of therapy discontinuation (OR 1.580; 95%-CI 1.116–2.238; p = 0.0010). Stratified analyses revealed a significant genotype effect in Ulcerative Colitis where GG carriers showed the longest median duration (43.5 months) in comparison to GA (24 months) and AA (6 months) (Log-Rank p = 0.011; Breslow p = 0.011; Tarone-Ware p = 0.010). AA/GA carriers had a significantly higher risk of therapy discontinuation compered to GG carriers (OR 2.429; 95%-Cl 1.251–4.714; p = 0.009). In Crohn’s disease, median treatment durations showed a numerically similar but less pronounced trend across the genotypes (GG: 50 months; GA: 38.5 months; AA: 35.5 months), with no corresponding differences in treatment persistence over time (Log-Rank p = 0.154; Breslow p = 0.218; Tarone-Ware p = 0.191). Conclusion The ETS2 polymorphism is significantly associated with treatment duration in patients receiving TNF-α-inhibitors. The GG genotype correlates with prolonged therapy, whereas non-risk allele carriers have a higher risk of discontinuation, particularly in Ulcerative Colitis. In Crohn’s disease, genotype-related differences were observed numerically but did not reach statistical significance. Reference: Stankey, C.T., Bourges, C., Haag, L.M. et al. A disease-associated gene desert directs macrophage inflammation through ETS2. Nature 630, 447–456 (2024) Conflict of interest: Ms. Brink, Miriam: No conflict of interest Büttner, Janine: No conflict of interest Bochow-Fitzner, Bettina: No conflict of interest Jochum, Christoph: study sponsorship and honoraria from Johnson & Johnson, Abbvie, Gilead, alphasigma, Granite Bio, Pfizer, Genentec, Lilly
Brink et al. (Thu,) studied this question.