Among the families enrolled in MIBS, approximately 70% were found to be concordant in which either all or none of the siblings had a history of inhibitors AZD9668 cell line [6]. The con- and discordancies in each subgroup of mutation are shown in Fig. 1. The concordance in the families with inhibitors was approximately 40%. The corresponding figures for the families with intron 22 inversions were 63% and 40%, respectively. In two families with large gene deletions, none of the siblings had an inhibitor history, and although only a small proportion of the families with missense mutations, small deletions/insertions and splice site mutations experienced inhibitors,

all siblings in some of these families had high-responding inhibitors. The family data clearly indicate that additional inherited genetic determinants, other than the type of causative fVIII mutation, will be of major VX-809 manufacturer importance in predicting the immunological outcome of replacement therapy. The HLA class

I alleles A3, B7 and C7, as well as the class II alleles DQA0102, DQB0602, DR15 have all been associated with higher risk for inhibitor development in unrelated patients [relative risk (RR) of 1.9–4.0], whereas the HLA C2, DQA0103, DQB0603 and DR13 alleles seem to be protective [7,8]. The reported associations were, however, weak and not statistically consistent. In the MIBS study, these alleles were equally distributed between the two patient groups [10].

Instead, significant associations were identified for two of the other class I alleles, i.e. HLA A26 and B44, but after correction for multiple comparisons no significant differences remained. IL-10 is an important anti-inflammatory cytokine exerting a broad spectrum of activities. IL-10 also enhances the in vitro production of all types of immunoglobulins by peripheral blood mononuclear cells in patients with autoimmune diseases and the serum concentration of IL-10 has been correlated to the disease activity in these patients [12,13]. The most interesting STK38 polymorphism with a functional implication described in the IL-10 gene is a 134 bp long variant of a CA microsatellite in the promoter region (IL-10.G) [14–16]. In the MIBS study, the allele 134 bp was identified in 44 of all 164 patients with haemophilia A (26.8%) [9]. Thirty-two of these 44 patients (72.7%) developed inhibitors compared with 45 of the 120 patients (37.5%) without the allele. Among all 77 patients with a history of inhibitors, allele 134 was found in 32 patients (41.6%) compared with 12 of the 87 inhibitor negative patients (13.8%; P < 0.001). This corresponds to an odds ratio (OR) of 4.4 with a 95% confidence interval (CI) of 2.1–9.5. A significant association between the allele and the development of inhibitors was also found in a subgroup analysis of patients with severe haemophilia A, i.e.