Immune-related gene polymorphisms as risk factors for the development of Factor VIII inhibitors in hemophilia A patients: a sibling-pair association analysis (HUM1P.257)

Abstract

Abstract Inhibitors are one of the most feared complications in hemophilia, occurring in 15-30% of individuals with severe forms of Hemophilia A Human Leukocyte Antigen (HLA) haplotype, and polymorphism of genes regulating the immune response have been indicated as risk factors for inhibitor development. However, it is still unclear the extent to which each of these genetic variants contribute to inhibitor formation as a function of the F8 gene mutation. Here, 96 patients clustered in 45 sibling-pairs and 2 sibling-triplets of which 15 are discordant and the remaining are concordant for inhibitors were considered in a case-control analysis. Next Generation Sequencing on patients’ genomic DNA was performed for detection of FVIII mutation, genotyping of HLA-DRB1 allele and for TNF-α, IL-10, CTLA4, DOCK2 and MAPK9. Our results demonstrate a higher frequency of DRB1*15 allele in inhibitor patients [odds ratio (OR) 2.57; P = 0.022]. In TNF-α, the A allele of the -308G>A polymorphism was found with higher frequency in the inhibitor cohort. This finding was ore evident for the homozygous A/A genotype (7.7% vs 1.8% in inhibitor patient group vs. non-inhibitor respectively, p=0.028). For IL-10, the -1082G allele was observed more frequently in patients with inhibitors (59% vs. 37.5%; P = 0.0037). Our data validate the hypothesis that specific genomic haplotypes affect the development of FVIII inhibitors and can support inhibitor prediction for prognostic and therapeutic applications.