Human leukocyte antigen alleles associated with inhibitor development in severe hemophilia A: analysis of the “My Life, Our Future” hemophilia A cohort

Background An earlier analysis of the “My Life, Our Future” Repository indicated the risk of individuals with severe hemophilia A (HA) developing neutralizing antifactor (F)VIII antibodies (inhibitors) was (1) higher in Black and Hispanic cohorts and (2) similar in intron-22 inversion mutations vs other large structural changes in the F8 gene. Objectives This study determined whether specific human leukocyte antigen (HLA) alleles or haplotypes indicate either risk of or protection from inhibitor development in severe HA and if such associations correlate with race/ethnicity or F8 variant type. Methods HLA haplotypes were obtained from whole genome sequence data for 1841 subjects with severe HA and their racial/ethnic categories verified by principal component analysis. Pairwise and multivariable logistic regression analyses were performed for subcohorts of HLA alleles/haplotypes defined by HA mutation type and race/ethnicity. Results HLA-DRB1∗15:01 , DQB1∗06:02 , and DQA1∗01:02 and B∗07:02 were higher-risk alleles for the White/non–Hispanic cohort, while HLA-DRB∗14:01 , DQB1∗05:03 , DQB1∗03:01 , B∗38:01 , B∗44:02 , and C∗05:01 were lower-risk alleles. HLA-B∗15:03 and B∗58:01 were higher-risk alleles for the Black/non–Hispanic cohort, while HLA-A∗33:03 was a lower-risk allele. Additional alleles were associated with inhibitor risk across the following cohorts: all ( N = 1841), intron-22 inversion ( n = 836), missense ( n = 288), not-missense ( n = 1553). No associations of HLA with inhibitor risk were seen for the Hispanic/White cohort. Analysis of subjects carrying both higher-risk and lower-risk alleles revealed combinations affecting the risks associated with individual alleles. Conclusion Our results implicate both innate and adaptive immune mechanisms, possibly including multiallelic HLA-associated effects on FVIII processing/presentation or signaling pathways in the development of inhibitors vs peripheral tolerance to FVIII.