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Zhang Z, Li H, Wan Z, Su M, Zhang Y, Yang T, Ji X, Men J, Xing G, Han J, Ji Y, Zhang W, Chen H, Xu X, Fei J, Dong C, Yang Y, Wu Y, Yi Q, Pang W, Zhang M, Shi C, Zhen K, Wang D, Lei J, Wu S, Shu S, Zhang Y, Zhang S, Gao Q, Wan J, Xie W, Yang P, Zhang P, Zuo X, Jiang T, Zhai Z, Wang C. Whole genome sequencing identifies pathogenic genetic variants in Han Chinese patients with familial venous thromboembolism. Commun Biol 2025; 8:604. [PMID: 40221599 PMCID: PMC11993696 DOI: 10.1038/s42003-025-07935-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 03/13/2025] [Indexed: 04/14/2025] Open
Abstract
Genetic factors play a pivotal role in determining venous thromboembolism (VTE) risk, particularly in cases of unprovoked early-onset VTE and those with a family history. While genome-wide association studies (GWAS) has advanced our understanding, high-quality whole-genome sequencing (WGS) from family-based studies is essential to elucidate the role of rare variants. In this study, we performed WGS on 216 individuals from 35 Han Chinese VTE pedigrees and validated findings in 99 high-heritability VTE cases using whole-exome sequencing. Functional impact was assessed via qPCR and Western Blot in HEK293T cells. Classical genes explained partial familial inheritance (20/35), while non-classical genes showed comparable effects on VTE recurrence and CTEPH. From 36 rare variants, 34 pedigrees (97%) were interpreted, with 29 variants reported for the first time. Notably, three novel variants, GP6 (c.G1094A:p.R365H), TET2 (c.G3451T:p.E1151X), and JAK2 (c.G380A:p.G127D), shared in two unrelated pedigrees each and are classified as low frequency in East Asians. Functional analyses revealed significant changes in GP6 and TET2 expression compared to the wild type. These findings provide novel insights into the genetic architecture of VTE and highlight GP6, TET2, and JAK2 as potential risk factors in East Asian populations, underscoring the clinical relevance of rare variants in VTE pathogenesis.
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Affiliation(s)
- Zhu Zhang
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Haobo Li
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
- China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhaoman Wan
- State Key Laboratory of Common Mechanism Research for Major Diseases, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu, China
| | - Mingming Su
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Yu Zhang
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
- China-Japan Friendship Hospital, Capital Medical University, Beijing, China
| | - Tao Yang
- Department of Vascular Surgery, Shanxi Bethune Hospital, Shanxi, China
| | - Xiaofan Ji
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
- China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jianlong Men
- Precision Medicine Center, Tianjin Medical University General Hospital, Tianjin, China
| | - Guoqiang Xing
- Department of Pulmonary and Critical Care Medicine, Zibo First Hospital, Zibo, Shandong, China
| | - Jing Han
- Department of Pulmonary and Critical Care Medicine, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China
| | - Yingqun Ji
- Department of Pulmonary and Critical Care Medicine, Shanghai East Hospital, Tongji University, Shanghai, China
| | - Wei Zhang
- Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Second Military Medical University, Shanghai, China
| | - Hong Chen
- Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaomao Xu
- Department of Pulmonary and Critical Care Medicine, Beijing Hospital, Beijing, China
| | - Jianwen Fei
- Department of Pulmonary and Critical Care Medicine, Yantaishan Hospital, Yantai, Shandong, China
| | - Chunling Dong
- Department of Pulmonary and Critical Care Medicine, Second Hospital, Jilin University, Jilin, China
| | - Yuanhua Yang
- Department of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Yan Wu
- Department of Respiratory and Critical Care Medicine, Wuxi People's Hospital Affiliated to Nanjing, Wuxi, Jiangsu, China
| | - Qun Yi
- Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Wenyi Pang
- Department of Pulmonary and Critical Care Medicine, Beijing Jishuitan Hospital, Beijing, China
| | - Meng Zhang
- Department of Pulmonary and Critical Care Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Chong Shi
- Beijing University of Chinese Medicine, China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Kaiyuan Zhen
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
- Peking University China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Dingyi Wang
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Clinical research and Data management, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Jieping Lei
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Clinical research and Data management, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Sinan Wu
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Clinical research and Data management, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Shi Shu
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Yunxia Zhang
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Shuai Zhang
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Qian Gao
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Jun Wan
- Department of Pulmonary and Critical Care Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Wanmu Xie
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
| | - Peiran Yang
- State Key Laboratory of Respiratory Health and Multimorbidity, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College; National Center for Respiratory Medicine; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; National Clinical Research Center for Respiratory Diseases, Beijing, China
| | - Peng Zhang
- Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
| | - Xianbo Zuo
- Department of Dermatology, China-Japan Friendship Hospital, Beijing, China.
| | - Taijiao Jiang
- State Key Laboratory of Respiratory Disease, The Key laboratory of Advanced Interdisciplinary Studies Center, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
- Guangzhou National Laboratory, Guangzhou, Guangdong, China.
| | - Zhenguo Zhai
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China.
| | - Chen Wang
- National Center for Respiratory Medicine; State Key Laboratory of Respiratory Health and Multimorbidity; National Clinical Research Center for Respiratory Diseases; Institute of Respiratory Medicine, Chinese Academy of Medical Sciences; Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, China
- Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Department of Respiratory Medicine, Capital Medical University, Beijing, China
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Wu YF, Huang Y, Weng BH, Deng S, Pan LY, Li Z. Systemic thrombosis with prothrombin Belgrade mutation in a Chinese patient: A case report. World J Clin Cases 2025; 13:98390. [PMID: 40191676 PMCID: PMC11670033 DOI: 10.12998/wjcc.v13.i10.98390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 10/29/2024] [Accepted: 12/05/2024] [Indexed: 12/19/2024] Open
Abstract
BACKGROUND Thrombophilia contributes to a significant increased risk of venous thromboembolism and can be either inherited or acquired. Hereditary thrombophilia may arise from various gene mutations, some of which have not even been adequately reported or poorly understood. Previous studies reported a rare and novel missense mutation in the prothrombin gene (p.Arg596Gln), known as prothrombin Belgrade. The mechanisms and therapeutic strategies associated with prothrombin Belgrade mutation have not been fully elucidated. CASE SUMMARY We present the case of a 26-year-old woman with recurrent systemic thrombosis induced by prothrombin Belgrade mutation. The patient suffered from cerebral venous sinus thrombosis that rapidly progressed to systemic thrombosis, alongside a family history of cerebral thrombosis, and no traditional risk factors or abnormal coagulation function. Whole-genome sequencing detected a novel and rare heterozygous prothrombin missense mutation, c.1787G>T (p.Arg596Gln), which was responsible for the major etiology of the systemic thrombosis. CONCLUSION This case strengthens our understanding about hereditary basis of thrombophilia and provokes considerations for therapeutic options on prothrombin Belgrade mutation.
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Affiliation(s)
- Yan-Feng Wu
- Department of Neurology, Liuzhou Worker’s Hospital, Liuzhou 545007, Guangxi Zhuang Autonomous Region, China
| | - Yan Huang
- Department of Neurology, Liuzhou Worker’s Hospital, Liuzhou 545007, Guangxi Zhuang Autonomous Region, China
| | - Bao-Hui Weng
- Department of Neurology, Liuzhou Worker’s Hospital, Liuzhou 545007, Guangxi Zhuang Autonomous Region, China
| | - Shan Deng
- Department of Neurology, Liuzhou Worker’s Hospital, Liuzhou 545007, Guangxi Zhuang Autonomous Region, China
| | - Li-Ya Pan
- Department of Neurology, Liuzhou Worker’s Hospital, Liuzhou 545007, Guangxi Zhuang Autonomous Region, China
| | - Zhen Li
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin 300052, China
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Imai Y, Kusano K, Aiba T, Ako J, Asano Y, Harada-Shiba M, Kataoka M, Kosho T, Kubo T, Matsumura T, Minamino T, Minatoya K, Morita H, Nishigaki M, Nomura S, Ogino H, Ohno S, Takamura M, Tanaka T, Tsujita K, Uchida T, Yamagishi H, Ebana Y, Fujita K, Ida K, Inoue S, Ito K, Kuramoto Y, Maeda J, Matsunaga K, Neki R, Sugiura K, Tada H, Tsuji A, Yamada T, Yamaguchi T, Yamamoto E, Kimura A, Kuwahara K, Maemura K, Minamino T, Morisaki H, Tokunaga K. JCS/JCC/JSPCCS 2024 Guideline on Genetic Testing and Counseling in Cardiovascular Disease. Circ J 2024; 88:2022-2099. [PMID: 39343605 DOI: 10.1253/circj.cj-23-0926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Affiliation(s)
- Yasushi Imai
- Division of Clinical Pharmacology and Division of Cardiovascular Medicine, Jichi Medical University
| | - Kengo Kusano
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
| | - Takeshi Aiba
- Department of Clinical Laboratory Medicine and Genetics, National Cerebral and Cardiovascular Center
| | - Junya Ako
- Department of Cardiovascular Medicine, Kitasato University School of Medicine
| | - Yoshihiro Asano
- Department of Genomic Medicine, National Cerebral and Cardiovascular Center
| | | | - Masaharu Kataoka
- The Second Department of Internal Medicine, University of Occupational and Environmental Health
| | - Tomoki Kosho
- Department of Medical Genetics, Shinshu University School of Medicine
| | - Toru Kubo
- Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University
| | - Takayoshi Matsumura
- Division of Human Genetics, Center for Molecular Medicine, Jichi Medical University
| | - Tetsuo Minamino
- Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University
| | - Kenji Minatoya
- Department of Cardiovascular Surgery, Graduate School of Medicine, Kyoto University
| | - Hiroyuki Morita
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo
| | - Masakazu Nishigaki
- Department of Genetic Counseling, International University of Health and Welfare
| | - Seitaro Nomura
- Department of Frontier Cardiovascular Science, Graduate School of Medicine, The University of Tokyo
| | | | - Seiko Ohno
- Medical Genome Center, National Cerebral and Cardiovascular Center
| | - Masayuki Takamura
- Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences
| | - Toshihiro Tanaka
- Department of Human Genetics and Disease Diversity, Tokyo Medical and Dental University
| | - Kenichi Tsujita
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kumamoto University
| | - Tetsuro Uchida
- Department of Surgery II (Division of Cardiovascular, Thoracic and Pediatric Surgery), Yamagata University Faculty of Medicine
| | | | - Yusuke Ebana
- Life Science and Bioethics Research Center, Tokyo Medical and Dental University Hospital
| | - Kanna Fujita
- Department of Cardiovascular Medicine, The University of Tokyo Hospital
- Department of Computational Diagnostic Radiology and Preventive Medicine, Graduate School of Medicine, The University of Tokyo
| | - Kazufumi Ida
- Division of Counseling for Medical Genetics, National Cerebral and Cardiovascular Center
| | - Shunsuke Inoue
- Department of Cardiovascular Medicine, The University of Tokyo Hospital
| | - Kaoru Ito
- Laboratory for Cardiovascular Genomics and Informatics, RIKEN Center for Integrative Medical Sciences
| | - Yuki Kuramoto
- Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine
| | - Jun Maeda
- Department of Cardiology, Tokyo Metropolitan Children's Medical Center
| | - Keiji Matsunaga
- Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University
| | - Reiko Neki
- Division of Counseling for Medical Genetics, Department of Obstetrics and Gynecology, National Cerebral and Cardiovascular Center
| | - Kenta Sugiura
- Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University
| | - Hayato Tada
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kanazawa University
| | - Akihiro Tsuji
- Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center
| | | | | | | | - Akinori Kimura
- Institutional Research Office, Tokyo Medical and Dental University
| | - Koichiro Kuwahara
- Department of Cardiovascular Medicine, Shinshu University School of Medicine
| | - Koji Maemura
- Department of Cardiovascular Medicine, Nagasaki University Graduate School of Biomedical Sciences
| | - Tohru Minamino
- Department of Cardiovascular Biology and Medicine, Juntendo University Graduate School of Medicine
| | | | - Katsushi Tokunaga
- Genome Medical Science Project, National Center for Global Health and Medicine
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4
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Tsuji A, Miyata T, Sekine A, Neki R, Kokame K, Tomita T, Kashima Y, Asano R, Ueda J, Aoki T, Ogo T. Three Cases of Unprovoked Venous Thromboembolism with Prothrombin p.Arg596Gln Variant and a Literature Review of Antithrombin Resistance. Intern Med 2023; 62:885-888. [PMID: 35945029 PMCID: PMC10076131 DOI: 10.2169/internalmedicine.9718-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Antithrombin resistance (ATR) is a newly identified strong genetic predisposition to venous thromboembolism (VTE) caused by genetic variations in prothrombin with substitutions of Arg at position 596 with either Leu, Gln, or Trp. In the present report, we identified a missense variant p.Arg596Gln in 3 patients from 2 families with unprovoked VTE who each experienced their first VTE event at 19, 67, and 19 years old. The three patients did not show any positive markers for thrombophilia on routine testing, suggesting that patients with unprovoked VTE who have negative findings on thrombophilia tests may carry a prothrombin variant with ATR.
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Affiliation(s)
- Akihiro Tsuji
- Division of Pulmonary Circulation, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Japan
| | - Toshiyuki Miyata
- Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Japan
| | | | - Reiko Neki
- Division of Counseling for Medical Genetics, National Cerebral and Cardiovascular Center, Japan
| | - Koichi Kokame
- Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center, Japan
| | - Tsutomu Tomita
- Department of Clinical Research and Development, National Cerebral and Cardiovascular Center, Japan
| | - Yumi Kashima
- Division of Pulmonary Circulation, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Japan
| | - Ryotaro Asano
- Division of Pulmonary Circulation, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Japan
| | - Jin Ueda
- Division of Pulmonary Circulation, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Japan
| | - Tatsuo Aoki
- Division of Pulmonary Circulation, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Japan
| | - Takeshi Ogo
- Division of Pulmonary Circulation, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Japan
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