TNF‑ α Gene Polymorphisms as Determinants of Alloantibody Emergence in Hemophilia: A Systematic Review and Meta‐Analysis

INTRODUCTION: Inhibitor development remains one of the most serious complications of replacement therapy in patients with hemophilia. Tumour necrosis factor-alpha (TNF-α) is a key pro-inflammatory cytokine, and its genetic variants have been implicated in immune-related conditions. The association between TNF-α gene polymorphisms and inhibitor formation in hemophilia has been explored. AIM: To systematically review and quantitatively synthesize available evidence on the association between TNF-α gene polymorphisms and the development of inhibitors in patients with hemophilia. METHODS: A comprehensive literature search was conducted in PubMed and SciELO from inception to 11 February 2025. Eligible studies evaluated TNF-α polymorphisms in patients with hemophilia and reported data on inhibitor status. Data extraction and quality assessment (using the Q-Genie tool) were performed independently by two reviewers. Meta-analyses were conducted using the Mantel-Haenszel method, where pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: Nineteen studies met the inclusion criteria for the systematic review, and ten were included in the meta-analysis. A significant association was observed between the rs1800629 (-308G>A) polymorphism and inhibitor development under the A-recessive model (OR = 2.00; 95% CI: 1.13-3.54). No significant associations were found for other TNF-α polymorphisms. CONCLUSION: This meta-analysis suggests that the TNF-α rs1800629 polymorphism may be associated with an increased risk of inhibitor development in patients with hemophilia. These findings highlight the potential role of inflammatory genetic variants in modulating the immune response to replacement therapy. Further large-scale, multi-ethnic studies are needed to confirm these results and better understand the underlying mechanisms.