Inflammatory and immune response genes: A genetic analysis of inhibitor development in Iranian hemophilia A patients

Pediatr Hematol Oncol. 2019 Feb;36(1):28-39. doi: 10.1080/08880018.2019.1585503. Epub 2019 Mar 19.


A major problem of hemophilia A (HA) treatment is the development of factor VIII (FVIII) inhibitor, which usually occurs shortly after initiating replacement therapy. Several studies showed the correlation between inhibitor development and polymorphisms in inflammatory and immune response genes of HA patients; however, literature data are not available to prove this association in Iranian population. The aim of this study was to investigate a possible association between FVIII inhibitor formation and the polymorphisms of 16 inflammatory and immune response genes in Iranian severe HA patients (FVIII activity < 1%). This case-control study was performed on 55 patients with severe HA inhibitors and 45 samples without inhibitors from Iranian Comprehensive Hemophilia Care center. After extraction of whole genomic DNA from blood samples and design of primers for 16 genes, the genotyping was performed by Tetra primer ARMS PCR, and the validation of single nucleotide polymorphisms was determined by DNA sequencing. The data indicated that there was a significant association between inhibitor development, and F13A1 (TT), DOCK2 (CC& CT), and MAPK9 (TT) genotypes. Moreover, a considerably increased inhibitor risk carrying T, C, and T allele for F13A1, DOCK2, and MAPK9 genes was observed in patients with inhibitors, respectively. In contrast, there was no statistically significant difference between the genotypic and allelic frequencies for other genes in patients with inhibitors compared to patients without inhibitors. These results demonstrate that only polymorphisms in F13A1, DOCK2, and MAPK9 genes are associated with the risk of developing FVIII inhibitors in Iranian HA patients.

Keywords: Hemophilia A; factor VIII; immune response genes; inflammatory genes; inhibitor; single nucleotide polymorphism.

Publication types

  • Clinical Trial

MeSH terms

  • Adult
  • Alleles*
  • Blood Coagulation Factor Inhibitors / genetics*
  • Factor VIII / genetics
  • GTPase-Activating Proteins
  • Gene Frequency*
  • Guanine Nucleotide Exchange Factors / genetics*
  • Hemophilia A / genetics*
  • Humans
  • Iran
  • Male
  • Mitogen-Activated Protein Kinase 9 / genetics*
  • Polymorphism, Genetic*


  • Blood Coagulation Factor Inhibitors
  • DOCK2 protein, human
  • GTPase-Activating Proteins
  • Guanine Nucleotide Exchange Factors
  • F8 protein, human
  • Factor VIII
  • Mitogen-Activated Protein Kinase 9