The majority of associations with inhibitor production are related to HLA class

II alleles: HLA-DRB1*14, DRB1*15, HLA-DQB1*06:02, DQB1*06:03. A positive association of the DRB1*15:01/DQB1*06:02 haplotype and inhibitor prevalence was reported in severe haemophilia patients. On the contrary DRB1*16 and DQB1*05:02 alleles were found to lower inhibitor risk [23-26]. The weak association of HLA types with inhibitor development suggests that the ability of a patient’s MHC class II to present one or more FVIII-derived peptides is a necessary but Selleckchem RXDX-106 not sufficient condition to stimulate helper T cells and produce neutralizing antibodies. In attempts to find new markers allowing a stratification of the risk patients to develop inhibitors, single-nucleotide polymorphisms (SNPs) in the regulatory regions of cytokine genes have been studied. Certain polymorphisms, mainly localized in the promoter regions, in the exons or in microsatellites of intron regions can affect the transcription and influence the production of cytokines and subsequently modify the profile of the immune response. Genetic polymorphisms

in immune-response associated genes, i.e. IL1b, IL4, IL10, TNF-α and CTLA4, have been analysed. The association between the −308A/A genotype in TNF-α gene and the formation of inhibitors was evident in several studies. For the cytogene IL10, the −1082G allele and 134 bp allele of a ‘CA’ dinucleotide repeat microsatellite in the promoter region of the IL10 see more gene were found to be more common in patients with inhibitors patients. A clear predominance of the high-producer GCC haplotype (0.55 vs. 0.32) and Methocarbamol a lower frequency of the low-producer ACC haplotype (0.20 vs. 0.32; P = 0.002) was observed in patients with inhibitors [26-28]. Furthermore, several new candidates as potentially predictors for inhibitor development (CD44, CSF1R, DOCK2, MAPK9 and IQGAP2) have been identified in Haemophilia

Inhibitor Genetic Study [29]. Ethnicity and family history have been shown to predispose for the development of FVIII inhibitors. The incidence of inhibitors is high in the subgroup of patients of African descent when compared with Caucasians (55.6% vs. 27.4%). As the F8 mutation spectrum does not differ between races this difference might be based on ethnic-specific genetic variants in immune response determinants. Another hypothesis is related to ethnic-specific F8 gene variants. Four common, non-synonymous SNPs within the F8 have been identified, which occur as six haplotypes in the human population (H1–H6). Three of these haplotypes (H3, H4 and H5) have been associated with an increased risk of inhibitor development and were detected mainly in black people [30]. The risk for the formation of inhibitors increases significantly in patients with a family history of inhibitors, where the absolute risk in such patients is determined to be 48%, whereas the risk in patients with no family history only 15%.