Spectrum of F8 Genotype and Genetic Impact on Inhibitor Development in Patients with Hemophilia A from Multicenter Cohort Studies (J-HIS) in Japan

Abstract

Some genetic and treatment-related factors are risk factors for inhibitor development in patients with hemophilia A (PwHA). However, the genotype distribution of the factor VIII gene (F8) and genetic impact on inhibitor development in Japanese PwHA remain unknown. In 2007, the Japan Hemophilia Inhibitor Study 2 (J-HIS2) was organized to establish a nationwide registry system for hemophiliacs and to elucidate risk factors for inhibitor development, designed for prospective investigation following a retrospective study (J-HIS1) which had already finished. Patients, newly diagnosed after January 2007, were enrolled in J-HIS2 and followed up for inhibitor development and clinical environments since 2008 onward. In the present study, F8 genotypes of PwHA were investigated in the patients recruited from the J-HIS2 cohort as well as those with inhibitor from the J-HIS1 cohort. F8 variants identified in 59 PwHA with inhibitor in J-HIS1 were: 20 intron-22 inversions, 5 intron-1 inversions, 9 large deletions, 4 nonsense, 8 missense, 11 small in/del, and 2 splice-site variants. F8 variants identified in 267 (67 with inhibitor) PwHA in J-HIS2 were: 76(28) intron–22 inversions, 3(2) intron–1 inversion, 1(0) duplication, 8(5) large deletions, 21(7) nonsense, 109(7) missense, 40(11) small in/del, and 9(7) splice-site variants. Forty variants were novel. The cumulative inhibitor incidence rate in the severe group with null changes was 42.4% (95% confidence interval [CI]: 33.7–50.8), higher than that with nonnull changes (15.6% [95%CI: 6.8–27.8]), in J-HIS2. Relative risk for inhibitor development of null changes was 2.89. The spectrum of F8 genotype and genetic impact on inhibitor development in Japanese PwHA were consistent with the previous reports.

Translational readthrough at <i>F8</i> nonsense variants in the factor VIII B domain contributes to residual expression and lowers inhibitor association

“…8 Although it is well recognized that the more disruptive the F8 variant the more likely is the inhibitor development, nonsense variants confer lower risk for inhibitors than envisaged for a potentially null genetic condition. [8][9][10] Nonsense variants are characterized by the introduction of premature termination codons (PTCs) and are responsible for ~11% of human inherited disorders. 11,12 Their pathogenic effect is related to the synthesis of truncated molecules with decreased stability and/or loss-of-function features, coupled with nonsense-mediated decay of PTC-bearing transcripts.…”

Clinical conditions and risk factors for inhibitor‐development in patients with haemophilia: A decade‐long prospective cohort study in Japan, J‐HIS2 (Japan Hemophilia Inhibitor Study 2)

“…The RR of null type F8 variants for inhibitor-development was 2.06 (95% CI: 1.24-3.43), suggesting that F8 null variants are a risk-factor for inhibitor-development with statistically significant difference (P < .01) similar to the previous reports. 9,12,15 No statistically significant differences with other unmodifiable features were evident between patients with and without inhibitors (Table 2A).…”

“…Genomic DNA was purified from leukocytes in whole blood samples (4.5 mL) obtained by venipuncture. F8 in PwHA was sequenced as previously described 12 . All F9 exons and intron‐exon junctions in PwHB were amplified by polymerase chain reaction (PCR) using gene‐specific primers, and DNA sequences were determined using each PCR products 13,14 …”

“…We have recently reported that, of the unmodifiable patient‐related characteristics in both J‐HIS1 and J‐HIS2, the F8 genotype in PwHA was strongly associated with inhibitor‐development 12 . The present study aims to evaluate the multiple risk for inhibitor‐development in PwH.…”

“…We have recently reported that, of the unmodifiable patient-related characteristics in both J-HIS1 and J-HIS2, the F8 genotype in PwHA was strongly associated with inhibitor-development. 12 The present study aims to evaluate the multiple risk for inhibitor-development in PwH. To our knowledge, this is the first nationwide report clarifying the spectrum of treatment linked to the risk-factors for inhibitordevelopment in Japanese PwH.…”