Effect of CTLA-4 and TNF-α Gene Polymorphisms on Inhibitor Development in a Turkish Cohort of Severe Hemophilia A Cases with Intron 22 Inversion Mutation: An Analytical Study

Objective: The development of neutralizing antibodies against infused factor VIII called inhibitor is the most challenging treatment complication in hemophilia A (HA) patients. Associated factors for inhibitor development are classified into 2 groups (genetics and non-genetics). Genetic factors other than mutation type of F8 gene include family history, ethnical origin, human leucocyte antigen haplotype, and a number of polymorphisms in genes which play role in immune system. In this study, we aimed to analyze the association between 3 variants in 2 genes [c.-318C>T; rs5742909 and c.49A>G; rs231775 in CTLA-4 and c.-308G>A; rs1800629 in tumor necrosis factor alpha (TNF-α)] and inhibitor development in a cohort of severe HA patients with intron 22 inversion (inv22) mutation. Material and Methods: The study included in 94 severe HA patients with inv22. Two groups were established according to the inhibitor status: inhibitor positive and inhibitor negative. We investigated 2 single nucleotide polymorphisms in CTLA-4 (c.- 318C>T; rs5742909 and c.49A>G; rs231775) and one in TNF-α (c.-308G>A; rs1800629) using Sanger sequencing in both groups. Results: In this study, no significant relationship between CTLA-4 polymorphisms and inhibitor development was observed in severe HA patients with inv22 mutation. However, the A allele for c.-308G>A variant in TNF-α was found to be associated with the increased risk for inhibitor development in those patients. Conclusion: In Turkish severe HA patients with inv22 mutation, c.-318C>T and c.49A>G variants in CTLA-4 gene are not associated with the inhibitor development, whereas c.-308G>A variant in TNF-α, the A allele is related to the risk of inhibitor development.