An earlier analysis of data from the “My Life, Our Future” (MLOF) Research Repository (Ahmed and Pratt, 2023, PMID 36696179) indicated the risk of individuals with severe hemophilia A (HA) developing neutralizing anti-factor(F)VIII antibodies (“inhibitors”) was higher in Black and Hispanic cohorts, consistent with earlier reports. In that analysis, inhibitor risk associated with intron-22 inversion mutations was not significantly different from risk associated with other large structural changes in the F8 gene, in contrast to some earlier studies. Our objectives were to determine if 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 mutation type.

Clinical, demographic, self-identified race and ethnicity, and genetic data from 1,841 severe HA individuals were available for analysis. HLA haplotypes were obtained from their whole genome sequence (WGS) data. Principal component analysis (PCA) of WGS data was carried out for the following self-identified racial/ethnic groups: Black/Non-Hispanic, White/Non-Hispanic and White/Hispanic. The final groups included all individuals with PCA scores within 3 standard deviations from the mean of their respective racial/ethnic group. A total of 1165 of 1175 of the self-identified White/Non-Hispanic (99.2%), 214/216 of the self-identified Black/Non-Hispanic (99.1%) and 200/242 (82.6%) of the self-identified White/Hispanic subjects met this criterion and were therefore included in the subsequent analyses. Pairwise and multivariable logistic regression analyses of associations with HLA alleles/haplotypes were performed for sub-cohorts defined by HA mutation type as well as by race/ethnicity.

HLA-DRB1*15:01, DQB1*06:02, DQA1*01:02 and B*07:02 were found to be higher-inhibitor-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*05:01were associated with a lower risk of developing an inhibitor, compared to the overall severe HA population. HLA-B*15:03 and B*58:01 were higher-risk for the Black/Non-Hispanic severe HA cohort, while HLA-A*33:03 was lower-risk for this group. Additional alleles were associated with inhibitor risk across the following cohorts: All Severe HA (N=1841), Intron-22 Inversion (N=836), Missense Mutations (N=288) and Not Missense Mutations (N=1553). No associations of HLA with inhibitor risk were seen for the Hispanic/White cohort. Analysis of inhibitor risk for subjects carrying more than one of the HLA alleles associated with either higher or lower inhibitor risk revealed several pairs of alleles with either enhanced or decreased inhibitor risk compared to risks associated with the individual HLA alleles.

The associations of both Class I and Class II alleles implicate innate and adaptive immune mechanisms, possibly including multi-allelic HLA-associated effects on FVIII processing/presentation or signaling pathways, in the development of inhibitors versus peripheral tolerance to FVIII in severe HA.

Disclaimer: The opinions or assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Department of Defense or the Uniformed Services University of the Health Sciences or the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc.

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2025
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