Genetic Polymorphisms on TNFA, TNFRSF1A, and TNFRSF1B Genes Predict the Effectiveness of Anti-TNF-α Treatment in Inflammatory Bowel Disease Patients

<b>Background/Objectives:</b> Tumor necrosis factor alpha (TNF-α) is the key inflammatory cytokine involved in the pathogenesis of inflammatory bowel diseases (IBDs). Anti-TNF-α therapy has been successfully used for IBD treatment, although the therapeutic response differs among patients due to the genetic background. The aim of this study was to investigate whether the presence of single nucleotide polymorphisms (SNPs) on <i>TNFA</i>, <i>TNFRSF1A</i>, and <i>TNFRSF1B</i> genes could affect anti-TNF-α treatment effectiveness in IBD patients. <b>Methods:</b> In this prospective cohort study, 83 European IBD patients treated with infliximab or adalimumab (with or without steroid bridge therapy) as first-line therapy were enrolled. Genomic DNA was extracted from peripheral blood, and <i>TNF-α</i> (rs1800629, rs361525, rs1799724), <i>TNFRSF1A</i> (rs767455), and <i>TNFRSF1B</i> (rs1061622, rs1061624, rs3397, rs976881) SNPs were assessed. Steroid-free remission (SFR) (clinical remission together with steroid interruption) and anti-TNF-α therapy persistence after 12 months of follow-up were evaluated. Patients who stopped anti-TNF-α therapy before the end of follow-up, due to side effects or treatment failure, were defined as discontinuers. <b>Results:</b> A higher frequency of the G/G genotype in rs1800629 and the A/A genotype in rs1061624 was observed in the SFR group compared to non-SFR (97.7% vs. 82.8%; <i>p</i> = 0.025 and 32.6% vs. 10.3%; <i>p</i> = 0.029, respectively). Moreover, carriers of the A/A genotype in rs361525 and the C/C genotype in rs767455 had a lower probability of achieving SFR than wild-type patients (OR = 0.14; 95% CI= 0.03-0.69; <i>p</i> = 0.016 and OR = 0.10; 95% CI = 0.02-0.60; <i>p</i> = 0.012, respectively). Furthermore, an increased frequency of rs1800629 A allele was observed in patients who discontinued treatment compared to completers (27.3% vs. 6.9%; <i>p</i> = 0.033), as well as a high risk of interrupting therapy (HR = 6.47; 95% CI = 1.15-36.38). <b>Conclusions:</b> These results suggest that the evaluation of SNPs in <i>TNF-α</i>, <i>TNFR1A</i>, and <i>TNFR1B</i> genes could improve the management of IBD, leading to more effective, individualized treatment plans and a reduction in healthcare costs associated with ineffective therapies and disease complications.