Association of TNFAIP3 Polymorphisms With Bleeding Phenotypes and FVIII Inhibitor Development in Patients With Hemophilia A: A Case-Control Study.

Background

Hemophilia A is an X-linked bleeding disorder caused by factor VIII (FVIII) deficiency. While F8 gene mutations are the primary cause, immune and inflammatory pathways contribute to variability in clinical phenotype and FVIII inhibitor development. TNFAIP3, encoding the immune regulatory protein A20, negatively regulates NF-κB signaling, and its polymorphisms rs2230926 and rs10499194 may influence immune responses and inhibitor susceptibility.

Objectives

To investigate the association of TNFAIP3 rs2230926 and rs10499194 with clinical features and inhibitor formation in Hemophilia A patients.

Methods

A case-control study included 42 patients and 70 age- and sex-matched healthy controls. Genotyping was performed using tetra-primer ARMS-PCR. Associations between genotypes, haplotypes, and clinical characteristics such as disease severity, bleeding frequency, joint involvement, Treatment interval, and inhibitor formation were analyzed using chi-square and Fisher's exact tests.

Results

The rs2230926 TT genotype was predominant (97.6%). Among the 35 patients with available rs10499194 genotype data, the CC, CT, and TT genotypes were observed in 62.9%, 28.6%, and 8.6% of patients, respectively. No significant associations were observed between either polymorphism and clinical parameters or inhibitor formation. Haplotype analysis identified three major haplotypes (TC, TT, and GC), none of which was significantly associated with disease susceptibility or inhibitor risk.

Conclusion

TNFAIP3 rs2230926 and rs10499194 are unlikely to be major contributors to bleeding phenotype or inhibitor development in Hemophilia A. Phenotypic variability likely results from complex interactions among genetic, immunologic, and environmental factors, warranting larger multicenter studies with comprehensive profiling.