Other genetic markers of potential importance for the immune response to the deficient factor include the human leucocyte antigen (HLA) class II (i.e. DRB1*15 and DQB1*0602) and immune regulatory genes [4-7]. A twofold higher incidence of inhibitors in those of African descent compared with Caucasians

further supports the importance of genetic factors [2, 8]. It has been suggested that this discrepancy may be due to the different distribution of F8 haplotypes by race, with a higher risk for inhibitors in the case of a mismatch between the proteins encoded by the endogenous F8 haplotype and those comprising replacement products used for treatment [9, 10]. The haplotypes consist of four non-synonymous single nucleotide polymorphisms (SNPs) located across Gemcitabine the gene. Each mutation results in a non-terminating amino acid change in the factor VIII protein construction. The biologic implications of the amino acid changes have not fully been explored, but two of the residues are located in immunodominant epitopes, i.e. R484H and M2238V, whereas R776G and D1241E are located in the B-domain. The haplotypes H3, OTX015 cell line H4 and H5 have only been found among blacks, whereas H1 and H2 are found primarily in whites and are most commonly present in infused recombinant products [10]. The Hemophilia Inhibitor Genetics MCE公司 Study (HIGS) Combined

Cohort was used to further explore the suggested relationship between haplotype and inhibitor status

among those of African ancestry, and mismatch of haplotype and product use on inhibitor development by adjustment for the type of F8 mutation and previously described HLA class II risk alleles among the subset of HIGS participants. Our data comprised three multicentre studies: the Hemophilia Inhibitor Genetics Study (HIGS), the Malmö International Brother Study (MIBS) and the Hemophilia Growth and Development Study (HGDS) (N = 833). The HIGS study group included in the current analysis is composed of brother pairs, one or both of whom has a history of an inhibitor, and singletons with a history of inhibitors, enrolled in Europe, North America, Latin America and South Africa. The MIBS is composed, almost exclusively, of siblings pairs enrolled in Europe and North America, and the HGDS is a population-based group enrolled in haemophilia treatment centres in the US. Data collection from all cohorts included demographics, severity of haemophilia, history of and current inhibitor status, maximum lifetime Bethesda titre and type of F8 mutation. Hemophilia Inhibitor Genetics Study data collection also included retrospective identification of the type(s) of replacement products used prior to development of the inhibitor. For those not having an inhibitor, i.e.