Analysis of cytokine genes polymorphism as markers for inhibitor development in haemophilia A

Abstract

Antibodies that block factor VIII (FVIII) activity appear in some haemophilia A patients treated with FVIII replacement therapy and severely impaired treatment. To date, the mechanisms that lead to this immune response are unknown. In this work, haplotypes of cytokine interleukin 10 (IL-10) gene have been associated with the presence of FVIII inhibitors in a group of Brazilian haemophilia A patients. The coexistence of a haplotype defining high IL-10 synthesis and one defining an intermediate production of cytokines is found to be associated with the group of patients who have a history of inhibitor development. Additionally, the coexistence of haplotypes defining high and low IL-10 syntheses is strongly associated with the group of negative inhibitors. These results have shown that the simple association considering only the presence or the absence of a haplotype and the development of inhibitors in haemophilia A is not sufficient. Data obtained in this work sustain the idea that the genetic studies may partly explain why only approximately 25% of haemophilia A patients develop FVIII inhibitors. Other genetic issues and details of the protein replacement therapy should be considered to measure the chances of a patient to develop anti-FVIII antibodies.

The polygenic nature of inhibitors in hemophilia A: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

“…22 Again, the present analysis has not considered treatment-related factors, which may in some cases modulate the inhibitor risk. The SNPs located in immunoregulatory genes previously associated with inhibitor risk in independent cohorts [6][7][8][9][10][11][12] were not consistently associated with risk in this investigation and in the meta-analysis combining all 3 cohorts. Among these previously described candidates, the SNP at location Ϫ1082A/G in the promoter region of IL-10 is the most frequently reported finding.…”

“…Indeed, genetic markers have been reported, independent of the type of F8 mutation, such as single nucleotide polymorphisms (SNPs) in the genes coding for IL-1, IL-2, IL-10, TNFA, TGF␤, and CTLA-4. [6][7][8][9][10][11][12] Because several of the SNPs characterized in immunoregulatory molecules coded by the human genome will influence the level of immune modulators, immune system challenges in conjunction with replacement therapy and a genetic predisposition might interact. This is supported by the observations of brother pairs and monozygotic twins with discordant inhibitor status 5 and the formation of inhibitors in association with significant inflammatory reactions among patients considered to be at low risk.…”

Violating the Theory of Single Gene-Single Disorder: Inhibitor Development in Hemophilia

“…Haplotypes GCC, ACC and ATA resulting from IL-10 (-1082, -819 T/C, -592 A/C) were shown to be associated with higher, intermediate and low production of cytokines respectively. A combination of high/intermediate IL-10 haplotype was specifically associated with susceptibility to inhibitor development in hemophilia [37]. IL-10 haplotypes were also found to be associated with inhibitor development in Caucasian and Chinese population [23,39].…”

“…Recently, genetic markers within IL-10 gene were associated with antibody production in hemophiliacs [37,38]. Haplotypes GCC, ACC and ATA resulting from IL-10 (-1082, -819 T/C, -592 A/C) were shown to be associated with higher, intermediate and low production of cytokines respectively.…”

From Genotype to Phenotype - When the Parents Ask the Question

“…In cases when one haemophilic child with antibodies to the deficient clotting factor is already born, families are typically very reluctant to opt for another child as the presence of inhibitors seem to compromise the only possible therapy option. It is up to the genetic counselor to explain the risks of another case of antibody-complicated haemophilia to the family and to order additional tests if needed, such as HLA typing and/or IL-10 and TNFalpha polymorphism typing Pavlova et al, 2009;Chaves at al., 2010). In one of our cases, there was a 21 g. w. pregnancy with a male foetus in a woman who has had already one son with severe haemophilia A complicated by high-titer antibodies to Factor VIII.…”