Impact of Interleukin-6 and Interleukin-10 Gene Polymorphisms on Inhibitor Development in Patients with Moderate and Severe Hemophilia a

Background:

An important complication of administration of factor VIII concentrates to treat or prevent bleeding,is the development of autoantibodies that block the activity of the relevant factor (inhibitors). These inhibitory antibodies occur in approximately 25 % of patients with severe hemophilia A. Inhibitors are much less common in patients with mild or moderate disease. Recently, significant progress has been made in our understanding of the mechanisms that lead to inhibitor formation. Polymorphisms of the immune response genes have been suggested to be contributing determinants of the inhibitor risk. Previous immunogenetic studies have shown the implication of human leukocyte antigen (HLA) alleles and some of the cytokine polymorphisms in inhibitors formation such as IL-6 and IL-10.

Aim:

This study aimed to investigate the associations between interleukin-6 gene promoter polymorphism at position (−174 G/C), interleukin-10 gene promoter polymorphism at position (-1082G/A) and susceptibility of patients with hemophilia A to develop factor VIII inhibitors.

Methods and subjects:

After medical ethical committee approval, the present study was conducted on 50moderate and severehemophilia A males aged ≤ 18 years who are attending hematology outpatient clinic of Alexandria University Children's Hospital at El-Shatby. The 50 children were undergoing a)Detailed history taking, with special emphasis on: Age of the patient at the time of diagnosis, clotting activity of factor VIII, Age at first exposure to factor VIII, Type and dose of administered factor VIII concentrate. Exposure days (EDs), Age at first surgical intervention, Detection of factor VIII inhibitors b)Laboratory investigations: Identification of genetic variant IL-6 (rs1800795) , IL-10 ( rs1800896 ) using real time PCR.

Results:

Thirtyone (72.1%) patients had severe hemophilia and 19 (27.9%) had moderate Hemophilia. Eight (16%) of the studied patients were inhibitor positive.

As regard interleukin-6 gene promoter polymorphism at position (−174 G/C), the frequency of G allele was greater than C allele in patients who developed inhibitors (χ²= 0.63) with P value = 1.000. regarding interleukin-10 gene promoter polymorphism at position (-1082G/A), the frequency of G allele was greater than A allele in patients who developed inhibitors (χ²0.75) with P value = 0.891.There was no statistically significantdifference as regards interleukin-6 polymorphism at position (−174 G/C), interleukin-10 polymorphism at position (-1082G/A) between inhibitor positive and inhibitor negative patients.

Conclusion:

There was no relation between interleukin-6 polymorphism at position (−174 G/C) , interleukin-10 polymorphism at position (-1082G/A)and the development of factor VIII inhibitors in patients with hemophilia A despite of the high frequency of G allele among inhibitors corresponding to the previous studies done . Further studies are recommended with larger cohort and other SNPs.