Polymorphisms in the TGF-β1 (rs1982037) and IL-2 (rs2069762, rs4833248) genes are not associated with inhibitor development in Iranian patients with hemophilia A

Abstract

Objectives Development of neutralizing antibodies against factor VIII is the major complication in hemophilia care which makes replacement therapies ineffective. The reports showed that inflammatory cytokines play an important role in inhibitor production. In the present study, the relationship between inhibitor development and the polymorphisms of two cytokine genes was studied in severe hemophiliac patients from Iran. Methods In this case-control study, three polymorphisms of immune regulatory genes [TGF-β (rs1982037) and IL-2 (rs2069762, rs4833248)] were analyzed in 100 Iranian hemophilia A patients divided into 55 inhibitor positive and 45 inhibitor negative patients using Tetra primer ARMS PCR, and DNA sequencing. Results The analysis of polymorphisms in the TGF-β and IL-2 genes showed no association between the genotypes and the production of inhibitors (p> 0.05). Also, comparison of allele frequencies for TGF-β and IL-2 genes between two groups indicated no significant differences associated with the development of FVIII inhibitors (p > 0.05). Discussion In contrast with some reports involving the correlation between polymorphisms of the TGF-β1 and IL-2 genes and inhibitor development in the world, no statistically significant differences in analysis of the alleles and genotypes for TGF-β and IL-2 genes were found between the inhibitor and non-inhibitor Iranian patients. Thus, other genetic markers influencing the immune response to replacement therapy in patients with hemophilia should be identified. Conclusions Regarding our results in molecular predisposition for inhibitor development, further studies of effective genetic markers are required as a prerequisite for the development of novel immunogenic therapeutic approaches in the future.

Association between interleukin-2 (rs2069762) gene polymorphism and FVIII inhibitor development in Indonesian patients with severe hemophilia A

“…Similarly, FVIII inhibitor development was not related to IL-2 SNPs of rs2069762 (p = 0.321) and allele frequency (p = 0.217) in the Iranian population. 14 This lack of association may be due to the functional SNPs of transforming growth factor-β1 (TGF-β1) at several sites. 19 TGF-β1 gene structure has been linked to functional implications, as it binds to transcription factors, leading to decreased protein production in several autoimmune diseases.…”

Impacto do desenvolvimento de inibidores no tratamento e qualidade de vida de pacientes com hemofilia: uma revisão de literatura

“…Todos eles relacionados à apresentação de peptídeos de FVIII às células CD41 T-helper. Alguns polimorfismos genéticos, como os do TGF-β, da e IL10, em CD44, receptor de fator 1 estimulante de colônias (CSF1R), DOCK2, proteína MAPK9 e IQGAP2 os genes TNFalfa e CTLA4 foram sugeridos em alguns estudos como contribuintes ao risco de inibidor na hemofilia A, contudo o estudo que evidenciou essas relações envolveu poucos indivíduos (Astermark, 2015;Lai et al, 2016;Naderi et al, 2018;Zhao et al, 2019).…”

Polymorphisms in FCGR2A (131H/R) and FCGR2B (232I/T) are associated with the development of inhibitors in Chinese hemophilia A patients

“…Inhibitor titres ≧0.6BU/mL at any time were considered to be inhibitor positive [16]. Antibody titers <5BU/mL was de ned as low-response inhibitors, while inhibitor titres persistently ≧5BU/mL were de ned as high-response inhibitors [17]. Severity of haemophilia was classi ed according to the criteria of White et al [18].…”