A Polymorphism in the IL-5 Gene is Associated with Inhibitor Development in Severe Hemophilia A Patients.
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.


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.


CONCLUSIONS
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.
Boğaziçi University, Department of Molecular Biology and Genetics, İstanbul, Turkey.
Inanç Değer
ID
Fidancı
İstanbul University Medical School, Institute of Oncology, İstanbul, Turkey.
Bülent
B
Zülfikar
Ege University Medical School, Department of Pediatric Hematology, İzmir, Turkey.
Kaan
K
Kavaklı
İstanbul Training and Education Hospital, Department of Hematology, İstanbul, Turkey.
M Cem
MC
Ar
Çukurova University Medical School, Department of Pediatric Hematology, Adana, Turkey.
Yurdanur
Y
Kılınç
İstanbul University Cerrahpaşa Medical Faculty, Department of Internal Medicine, Division of Hematology, İstanbul, Turkey.
Zafer
Z
Başlar
Boğaziçi University, Department of Molecular Biology and Genetics, İstanbul, Turkey.
Server Hande
SH
Cağlayan
Association study; F8 gene mutation; Hemophilia A; Inhibitor formation; Interleukins/cytokines; Single nucleotide gene polymorphisms