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 Erlotinib order [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 U0126 nmr 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 Buspirone HCl 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.