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

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-?1), and interferon gamma (IFN-?) 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-?1, and IFN-? 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.

SUBMITTER: Fidanc? ID

PROVIDER: S-EPMC3996645 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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

Fidancı Inanç Değer ID Zülfikar Bülent B Kavaklı Kaan K Ar M Cem MC Kılınç Yurdanur Y Başlar Zafer Z Cağlayan Server Hande SH

Turkish journal of haematology : official journal of Turkish Society of Haematology 20140305 1

<h4>Objective</h4>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 ...[more]

PMID: 24764725

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Project description:BackgroundDevelopment of inhibitors to transfused factor VIII in patients with hemophilia A continues to be a challenge for professionals involved in hemophilia care. The majority of patients in India receive 'on-demand' rather than prophylactic therapy. The present study was done to assess the prevalence of factor VIII inhibitors in patients with hemophilia A (PWHA) receiving 'on-demand' therapy in a North Indian population and to study the clinicopathological parameters influencing the development of inhibitors.MethodsThe study group comprised of 300 PWHA. Detailed clinical parameters, treatment history, bleeding profile including family history were recorded. Diagnosis of hemophilia A was confirmed by relevant coagulation tests. Inhibitors were screened using mixing based studies followed by quantification by Bethesda assay and Nijmegen modified Bethesda assay. Samples were collected from five cities in North India where a free supply of factor VIII was available and effectively used in three of these cities.ResultsIn the 300 PWHA, disease phenotype was severe in 219 (73%), moderate in 62 (20.67%) and mild in 19 (6.34%), based on the factor VIII bioassay. Inhibitor prevalence was 9.6% (n = 29) and seen only in the severe phenotype. Inhibitor titers ranged from 0.8 to 108.8 BU/ml. A total of 12 PWHA had low and 17 had high titers. Correlation of various clinicopathological parameters in inhibitor-positive versus negative PWHA showed significant correlation with age at onset of disease, severity of disease, age at first exposure to treatment, annual factor intake (IU/kg/year), intense treatment episodes and bleeding manifestations like central nervous system bleed and hematuria. The total study sample had blood group B in 33.34% PWHA, followed by O (27.34%), A (24.34%) and AB (15%), however, in inhibitor-positive samples, significant inhibitor formation was associated with the ABO subtype A (19/29, 65.51%).ConclusionsFactor VIII inhibitor prevalence in PWHA receiving 'on-demand' therapy was 9.6%. Clinicopathological correlates of inhibitor development in such PWHA have been analyzed in this novel study.

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

Publications

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

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