Abstract
Objective: A severe complication in the replacement therapy of hemophilia A (HA) patients is the development of alloantibodies (inhibitors) against factor VIII, which neutralizes the substituted factor. The primary genetic risk factors influencing the development of inhibitors are F8 gene mutations. Interleukins and cytokines that are involved in the regulation of B-lymphocyte development are other possible targets as genetic risk factors. This study assesses the possible involvement of 9 selected single nucleotide gene polymorphisms (SNPs) with interleukins (IL-4, IL-5, and IL-10), transforming growth factor beta 1 (TGF-β1), and interferon gamma (IFN-γ) in inhibitor development in severely affected HA patients carrying a null mutation in the F8 gene. Materials and Methods: A total of 173 HA patients were screened for intron 22 inversion and null mutations (nonsense and deletions). Genotyping of a total of 9 SNPs in genes IL-4, IL-5, IL-10, TGF-β1, and IFN-γ in 103 patients and 100 healthy individuals was carried out. Results: An association analysis between 42 inhibitor (+) and 61 inhibitor (-) patients showed a significant association with the T allele of rs2069812 in the IL-5 gene promoter and patients with inhibitors (p=0.0251). The TT genotype was also significantly associated with this group with a p-value of 0.0082, odds ratio of about 7, and confidence interval of over 90%, suggesting that it is the recessive susceptibility allele and that the C allele is the dominant protective allele. Conclusion: The lack of other variants in the IL-5 gene of patients and controls suggests that rs2069812 may be a regulatory SNP and may have a role in B-lymphocyte development, constituting a genetic risk factor in antibody development.
Highlights
The major complication of replacement therapy is the development of antibodies, which inhibit factor VIII (FVIII) activity in hemophilia A (HA)
The lack of other variants in the IL-5 gene of patients and controls suggests that rs2069812 may be a regulatory
We have previously reported that the most prevalent F8 gene mutation in severe HA patients with inhibitors is intron 22 inversion, with a frequency of 50% [4]
Summary
The major complication of replacement therapy is the development of antibodies (inhibitors), which inhibit factor VIII (FVIII) activity in hemophilia A (HA). Risk of inhibitor development increases at times of severe bleeding, trauma, or surgery, especially when high doses of FVIII are used for treatment. This occurs as a result of complicated immune reactions leading to the up-regulation of T- and B-cell responses [5]. The aim of this study was to search for other genetic risk factors that may be associated with inhibitor development For this purpose, informative SNPs of cytokine genes (IL-4, IL-5, IL-10, TGF-β1, and IFN-γ) involved in the regulation of B-cell responses were studied in a group of HA patients with null mutations (mutations with a major effect)
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