Polymorphisms in the Promoter Region of the IL-10 Gene Is Associated with Inhibitor Development in Hemophilia A.

The development of inhibitory antibodies is a severe and costly complication to replacement therapy occurring in 10–15% of patients with hemophilia A, and the aim of the Malmo International Brother Study (MIBS) is to evaluate host genetic factors associated with this adverse effect of treatment. In the present study, factor VIII mutations, HLA genotypes and polymorphisms of the interleukin IL-1beta, IL-4 and IL-10 genes known to influence antibody production in autoimmune diseases, were analyzed in 164 patients with hemophilia A (120 severe, 30 moderate and 14 mild) belonging to 78 unrelated families. Seventy-seven (47.0%) of the subjects had a history of inhibitors (57 high-responding, 20 low-responding) in 54 unrelated families (34 discordant, 20 concordant siblings). In 24 families, no inhibitor was reported in any of the siblings. Seventy-five patients (45.7%) in 36 families had an inversion. In this group, 40 patients (53.3%) in 28 families had inhibitors (17 concordant, 11 discordant). Weak associations between inhibitor development and the HLA alleles A26 and B44 were found. No association was found with the IL-1beta Taq 1 RFLP alleles in exon 5, and the −590 C/T SNP in the promoter region of IL-4. There was however, a strong association between an allele with 134 bp in one of the CA repeat microsatellites, IL-10G, located in the promoter region of the IL-10 gene, and development of inhibitor. Allele 134 was found in 32 (41.6%) of the patients with inhibitors compared with 12 (13.8%) of the inhibitor negative patients (p<0.001), corresponding to an odds ratio of 4.4 (95% CI 2.1–9.5, p<0.001). The association was consistent in the subgroup of families with severe hemophilia and an inversion of the factor VIII gene (p=0.002). Only one discordant inhibitor family was identified in which the subject without allele 134 developed an inhibitor, and the allele 134 positive brother did not. IL-10 is the first gene located outside the causative factor VIII gene mutation to be associated with inhibitor development in hemophilia and our data indicate this gene to be an important determinant for this side-effect of replacement therapy.