Genetic background of inhibitor development in patients with hemophilia in Japan: Trajectory of multi-center prospective cohort study Japan Hemophilia Inhibitor Study (J-HIS)

Abstract

The development of inhibitors is one of the most serious complications in patients with hemophilia (PwH). International studies have reported that certain genetic and treatment-related factors are associated with inhibitor development in PwH. However, the genotype distribution of the factor (F) VIII(IX) gene (F8 or F9) and its impact on inhibitor development in Japanese PwH remain unknown. In 2007, the Japan Hemophilia Inhibitor Study 2 (J-HIS2) was organized to establish a nationwide registry system for PwH and to elucidate the risk factors for inhibitor development; it was designed as a prospective investigation following a retrospective study, J-HIS1. Patients newly diagnosed after January 2007 were enrolled in the J-HIS2 and followed up for inhibitor development and clinical environments from 2008 to 2020. Of the 417 patients (340 PwHA and 77 PwHB) from the 46 facilities enrolled in the study, 83 (76 PwHA and 7 PwHB) were recorded with inhibitors. Inhibitors were observed in 31.0% of severe PwHA cases, 8.0% of moderate PwHB cases, 1.6% of mild PwHB cases, and 17.1% of severe PwHB cases. Most inhibitors (89.7% in severe PwHA and 71.4% in severe PwHB) were detected within 25 days of exposure. Genotyping of these patients revealed an association between inhibitor development and null variants of F8 (p<0.01) or F9 (p<0.05). Based on the final results of J-HIS2 and detailed information on the F8 genotype identified in PwHA enrolled in the J-HIS studies, the prospects of treatment in consideration of inhibitor development are discussed in this section.