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

Keiko Shinozawa*
1  Department of Laboratory Medicine, Tokyo Medical University, Shinjuku, Tokyo, Japan
,
Koji Yada*
2  Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
3  The Course of Hemophilia Education, Nara Medical University, Kashihara, Nara, Japan
,
Tetsuhito Kojima
4  Aichi Health Promotion Foundation, Nagoya, Aichi, Japan
5  Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
,
Keiji Nogami
2  Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
,
Masashi Taki
6  St. Marianna University School of Medicine, Yokohama City Seibu Hospital, Yokohama, Kanagawa, Japan
,
Katsuyuki Fukutake
1  Department of Laboratory Medicine, Tokyo Medical University, Shinjuku, Tokyo, Japan
,
Akira Yoshioka
2  Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
,
Akira Shirahata
7  Department of Pediatrics, University of Occupational and Environmental Health Japan, Kitakyushu, Fukuoka, Japan
,
Midori Shima
2  Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
3  The Course of Hemophilia Education, Nara Medical University, Kashihara, Nara, Japan
,
study group on JAPAN HEMOPHILIA INHIBITOR STUDY (J-HIS)› Author Affiliations
Funding This research was supported by Research Grant for Health Science, Health and Labor Sciences Research Grants for Research on HIV/AIDS, and Japan Agency for Medical Research and Development (AMED) under grant numbers JP17fk0410306 and JP20fk0410017.

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.

Study Group of J-HIS1 and J-HIS2 Consisting of Steering Committee and Collaborative Institutes


Steering Committee Members of J-HIS 1 and J-HIS 2

Teruhisa Fujii (Hiroshima University, Hiroshima), Katsuyuki Fukutake* (Tokyo Medical University, Tokyo), Isao Hamaguchi (National Institute of Infectious Diseases, Tokyo), Hideji Hanabusa** (Ogikubo Hospital, Tokyo), Satoshi Higasa (Hyogo College of Medicine, Hyogo), Yasuo Horikoshi (Shizuoka Children's Hospital, Shizuoka), Masue Imaizumi (Miyagi Children's Hospital, Miyagi), Fuminori Iwasaki (Kanagawa Children's Medical Center, Kanagawa), Kiyoshi Kawakami (Kagoshima City Hospital, Kagoshima), Masao Kobayashi (Hiroshima University, Hiroshima), Tetsuhito Kojima (Nagoya University, Aichi), Takeshi Matsumoto (Mie University Hospital, Mie), Yoko Matsuo (Kurume University Hospital, Fukuoka), Tadashi Matsushita (Nagoya University, Aichi), Hisaya Nakadate (National Center for Child Health and Development, Tokyo), Keiji Nogami (Nara Medical University, Nara), Shouichi Ohga (Kyushu University, Fukuoka), Yoshitoshi Otsuka (Hyogo College of Medicine, Hyogo), Toshiaki Oka (Sapporo Tokushukai Hospital, Hokkaido), Yuri Okimoto (Chiba Children's Hospital, Chiba), Michio Sakai (Hospital of the University of Occupational and Environmental Health, Fukuoka), Midori Shima (Nara Medical University, Nara), Keiko Shinozawa (Tokyo Medical University, Tokyo), Akira Shirahata (Kitakyushu Yahata Higashi Hospital, Fukuoka), Takashi Suzuki (Ogikubo Hospital, Tokyo), Junki Takamatsu (Japan Red Cross Aichi blood Center, Aichi), Hideyuki Takedani (The Institute of Medical Science, The University of Tokyo, Tokyo), Masashi Taki (St. Marianna University School of Medicine Yokohama City Seibu Hospital, Kanagawa), Maiko Taneichi (National Institute of Infectious Diseases, Tokyo), Koji Yada (Nara Medical University, Nara), and Akira Yoshioka (Nara Medical University, Nara).


*K.F. was a program supervisor of AMED and has resigned the committee before initiation of a grant from AMED in 2017. **We would like to offer our deepest sympathies to Dr. Hideji Hanabusa who passed away untimely in October 2016.


Collaborative Institutes (65)

Aichi Sannomaru Hospital (Aichi), Anjo Kosei Hospital (Aichi), Nagoya University (Aichi), Akita University Hospital (Akita), Odate Municipal General Hospital (Akita), Aihara Internal Medical Clinic (Aomori), Kuroishi General Hospital (Aomori), Kameda General Hospital (Chiba), Matsudo City General Hospital (Chiba), Ehime University Hospital (Ehime), Tsuruga Medical Center (Fukui), Fukuoka University Hospital (Fukuoka), Hospital of the University of Occupational and Environmental Health Japan (Fukuoka), Kurume University Hospital (Fukuoka), Kyushu University Hospital (Fukuoka), Hiroshima University Hospital (Hiroshima), Asahikawa Medical University Hospital (Hokkaido), Iwamizawa Municipal General Hospital (Hokkaido), Kushiro Red Cross Hospital (Hokkaido), Sapporo Hokuyu Hospital (Hokkaido), Sapporo Medical University Hospital (Hokkaido), Sapporo Tokushukai Hospital (Hokkaido), Hyogo College of Medicine (Hyogo), Hyogo Prefectural Amagasaki General Medical Center (Hyogo), Kobe University Hospital (Hyogo), Ibaraki Children's Hospital (Ibaraki), Iwate Prefectural Ofunato Hospital (Iwate), Shikoku Medical Center for Children and Adults (Kagawa), Kagoshima City Hospital (Kagoshima), St. Marianna University School of Medicine Yokohama City Seibu Hospital (Kanagawa), St. Marianna University School of Medicine Hospital (Kanagawa), Japanese Red Cross Kochi Hospital (Kochi), Japanese Red Cross Kumamoto Hospital (Kumamoto), Ayabe City Hospital (Kyoto), Kyoto University Hospital (Kyoto), Mie University Hospital (Mie), Hasegawa Pediatric Clinic (Miyagi), Miyagi Children's Hospital (Miyagi), Sendai Medical Center (Miyagi), Sendai Nishitaga Hospital (Miyagi), Tohoku University Hospital (Miyagi), University of Miyazaki Hospital (Miyazaki), Japanese Red Cross Nagano Hospital (Nagano), Nara Medical University (Nara), Niigata Cancer Center Hospital (Niigata), Oita Memorial Hospital (Oita), Oita Prefectural Hospital (Oita), Kitano Hospital (Osaka), Osaka Rosai Hospital (Osaka), Saga University Hospital (Saga), Japanese Red Cross Otsu Hospital (Shiga), Seirei Hamamatsu General University (Shizuoka), Shizuoka Children's Hospital (Shizuoka), Dokkyo Medical University Hospital (Tochigi), Japanese Red Cross Ashikaga Hospital (Tochigi), National Center for Child Health and Development (Tokyo), National Center for Global Health and Medicine (Tokyo), Ogikubo Hospital (Tokyo), Teikyo University Hospital (Tokyo), University of Tokyo, Institute of Medical Science (Tokyo), Tokyo Medical University (Tokyo), Tokyo Metropolitan Children's Medical Center (Tokyo), Japanese Red Cross Wakayama Medical Center, (Wakayama), Naga Municipal Hospital (Wakayama), Tsuruoka Municipal Shonai Hospital (Yamagata).


Note

This study was presented in an abstract form at the Congress of World Federation of Hemophilia, Orlando, Florida, United States, July 2016, and the Congress of International Society on Thrombosis and Haemostasis (ISTH), Melbourne, Australia, July 2019.


Authors' Contributions

K.S.: genotyping, clinical laboratory testing, analyzed data, interpreted the data, wrote manuscript; K.Y.: clinical work, blood sampling, genotyping, interpreted the data, made figures and tables, analyzed data, wrote manuscript; T.K.: clinical work, blood sampling, advised the study, and edited manuscript; K.N.: clinical work, interpreted the data, wrote and edited manuscript; M.T.: clinical work, blood sampling; K.F.: clinical work, blood sampling, advised the study, study design, interpretation of data, and revision of the manuscript; A.Y. and A.S.: organized and initiated the study; M.S.: clinical work, supervised the study. K.S. and K.Y. equally contributed to this work, and both of them have the right to list herself (himself) first in bibliography.


* These authors contributed equally to this study as first authors.


Supplementary Material



Publication History

Received: 05 June 2020

Accepted: 21 October 2020

Publication Date:
30 November 2020 (online)

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