Genome-Wide Association Study and Gene-Based Analysis of Participants With Hemophilia A and Inhibitors in the My Life, Our Future Research Repository.

INTRODUCTION

Up to 30% of individuals with hemophilia A develop inhibitors to replacement factor VIII (FVIII), rendering the treatment ineffective. The underlying mechanism of inhibitor development remains poorly understood. The My Life, Our Future Research Repository (MLOF RR) has gathered and mutational information, phenotypic data, and biological material from over 11,000 participants with hemophilia A (HA) and B as well as carriers enrolled across US hemophilia treatment centers, including over 5,000 whole-genome sequences. Identifying genes associated with inhibitors may contribute to our understanding of why certain patients develop those neutralizing antibodies.

AIM AND METHODS

Here, we performed a genome-wide association study and gene-based analyses to identify genes associated with inhibitors in participants with HA from the MLOF RR.

RESULTS

We identify a genome-wide significant association within the human leukocyte antigen (HLA) locus in participants with HA with intronic inversions. HLA typing revealed independent associations with the HLA alleles major histocompatibility complex, class II, DR beta 1 (HLA DRB115:01) and major histocompatibility complex, class II, DQ beta 1 (DQB103:03). Variant aggregation tests further identified low-frequency variants within (glutamate receptor, ionotropic, delta 2 [] interacting protein 1) significantly associated with inhibitors.

CONCLUSION

Overall, our study confirms the association of DRB115:01 with FVIII inhibitors and identifies a novel association of DQB103:03 in individuals with HA carrying intronic inversions of . In addition, our results implicate , encoding -interacting protein, with the development of inhibitors, and suggest an unrecognized role of this gene in autoimmunity.