THE ROLE OF INTERLEUKIN-10 GENE VARIANTS IN INHIBITOR DEVELOPMENT IN HEMOPHILIA: A SYSTEMATIC REVIEW AND META-ANALYSIS

A major therapeutic challenge in hemophilia is the development of inhibitors that neutralize replacement therapies. Interleukin-10 (IL-10), an anti-inflammatory cytokine, regulates immune responses and influences antibody production, suggesting a potential role in inhibitor formation. This systematic review aimed to investigate the association of IL-10 polymorphism with inhibitor formation in patients with hemophilia. Following PRISMA guidelines, the study was registered in PROSPERO (CRD42024590045). Genetic studies on IL-10 polymorphisms and inhibitors were included, while case reports, reviews, and animal studies were excluded. A comprehensive search was conducted in PubMed and Scielo, covering records up to June 16, 2025. Methodological quality was assessed using Q-genie, and a meta-analysis was performed for polymorphisms with data from at least three studies, using the Mantel-Haenszel method. Of 107 screened studies, 19 were included in the systematic review and 12 in the meta-analysis. Fifteen studies referred to hemophilia A patients only, with sample sizes ranging from 15 to 935, and inhibitor development rates varying from 6/50 (12%) to 130/260 (50%). High variability was observed among the studies, particularly regarding sampling locations, which included Europe (n = 6), Asia (n = 6), the Americas (n = 4), Africa (n = 1), and two multicentric studies spanning Europe and North America. All included studies investigated at least one IL-10 polymorphism potentially associated with the risk of inhibitor development. The most frequently studied variants were rs1800896 (n = 9 studies), rs1800871 (n = 7), and rs1800872 (n = 6), all located in the regulatory region of the IL-10 gene. No significant association was found between IL- 10 polymorphisms and inhibitor formation. To assess the impact of hemophilia type on the findings, studies involving hemophilia A and B were analyzed separately leading to the same results. In a subgroup analysis, the T-rs1800871 and A-rs1800872 recessive models were associated with protection against inhibitor development in subjects with severe hemophilia A. Although IL-10 polymorphisms do not appear to play a central role in inhibitor development across all hemophilia populations, protective associations identified in patients with severe hemophilia A suggest a potential immunomodulatory role in specific subgroups. These findings underscore the importance of further studies exploring IL-10-mediated mechanisms in immune tolerance and their implications for personalized treatment strategies in hemophilia.