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

Keiko Shinozawa; Koji Yada; Tetsuhito Kojima; Keiji Nogami; Masashi Taki; Katsuyuki Fukutake; Akira Yoshioka; Akira Shirahata; Midori Shima; study group on JAPAN HEMOPHILIA INHIBITOR STUDY (J-HIS)

doi:10.1055/s-0040-1721385

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2021; 121(05): 603-615
DOI: 10.1055/s-0040-1721385

Coagulation and Fibrinolysis

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

Authors

Keiko Shinozawa‡^*

¹Department of Laboratory Medicine, Tokyo Medical University, Shinjuku, Tokyo, Japan
Koji Yada‡^*

²Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan

³The Course of Hemophilia Education, Nara Medical University, Kashihara, Nara, Japan
Tetsuhito Kojima

⁴Aichi Health Promotion Foundation, Nagoya, Aichi, Japan

⁵Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
Keiji Nogami

²Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
Masashi Taki

⁶St. Marianna University School of Medicine, Yokohama City Seibu Hospital, Yokohama, Kanagawa, Japan
Katsuyuki Fukutake

¹Department of Laboratory Medicine, Tokyo Medical University, Shinjuku, Tokyo, Japan
Akira Yoshioka

²Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
Akira Shirahata

⁷Department of Pediatrics, University of Occupational and Environmental Health Japan, Kitakyushu, Fukuoka, Japan
Midori Shima

²Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan

³The Course of Hemophilia Education, Nara Medical University, Kashihara, Nara, Japan

study group on JAPAN HEMOPHILIA INHIBITOR STUDY (J-HIS)

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.

Keywords

hemophilia A - inhibitor - F8 - null variants - nonnull variants

Full Text

References

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