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Genetic background of thrombophilia using third generation DNA sequencing

Research Project

Project/Area Number 19K08875
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionNational Cardiovascular Center Research Institute

Principal Investigator

MIYATA Toshiyuki  国立研究開発法人国立循環器病研究センター, 病院, 客員研究員 (90183970)

Co-Investigator(Kenkyū-buntansha) 根木 玲子  国立研究開発法人国立循環器病研究センター, 病院, 室長 (90600594)
辻 明宏  国立研究開発法人国立循環器病研究センター, 病院, 医師 (70598367)
関根 章博  国立研究開発法人国立循環器病研究センター, 研究所, その他(移行) (30425631)
小亀 浩市  国立研究開発法人国立循環器病研究センター, 研究所, 部長 (40270730)
Project Period (FY) 2019-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords静脈血栓塞栓症 / 血栓性素因 / 凝固制御因子 / 特発性血栓症 / modifier / 登録研究 / プロトロンビンバリアント / 次世代シーケンサー / 第三世代シーケンサー / 血栓症修飾遺伝子
Outline of Research at the Start

静脈血栓塞栓症の遺伝子解析に、10 kb-50 kb のDNA断片を決定できる”long read”の第三世代のシーケンサーを導入し、これまでのシークエンサーでは見逃していた遺伝子バリアントの同定を目指す。非典型溶血性尿毒症症候群の発症を修飾する遺伝子バリアントの研究を行う。日本人の血栓症の原因となるバリアントや血栓症を修飾するバリアントを解明し、血栓症の再発予防・予知や診断・治療に応用する。

Outline of Final Research Achievements

Unprovoked venous thromboembolism (VTE) is characterized by thrombosis at a relatively young age, a strong family history, recurrent episodes, and involvement of unusual sites. In this study, we conducted a genetic analysis of unprovoked VTE using next-generation sequencing (NGS) and third-generation sequencing (TGS), utilizing a candidate gene approach including three coagulation regulators and six clotting factors. When the sequences obtained by NGS and TGS were compared with the reference sequence, there were a small number of nucleotides that did not match. Among them, the PROS1 gene analyzed by the TGS method had a relatively large number of unmatched nucleotides, and these were judged to be miscalls.

Academic Significance and Societal Importance of the Research Achievements

次世代DNAシークエンス(NGS)法はヒト遺伝子解析に広く使用されているが、構造バリアントなどの大きなバリアントの同定は困難である。本研究では、静脈血栓塞栓症の遺伝子解析に、長いDNA配列を決定できるlong readの第3世代DNAシークエンス(TGS)法を導入した。結果として、NGS では同定できず、TGS法で同定できるバリアントがあった。一方で、偽遺伝子をもつPROS1遺伝子では標準配列に一致しない塩基が見られたことから、さらに検討を加える必要があると考えられた。

Report

(5 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (35 results)

All 2023 2022 2021 2020 2019 Other

All Journal Article (17 results) (of which Peer Reviewed: 15 results,  Open Access: 9 results) Presentation (14 results) (of which Int'l Joint Research: 3 results,  Invited: 4 results) Book (3 results) Remarks (1 results)

  • [Journal Article] Three Cases of Unprovoked Venous Thromboembolism with Prothrombin p.Arg596Gln Variant and a Literature Review of Antithrombin Resistance2023

    • Author(s)
      Tsuji A, Miyata T, Sekine A, Neki R, Kokame K, Tomita T, et al.
    • Journal Title

      Internal Medicine

      Volume: 62 Issue: 6 Pages: 885-888

    • DOI

      10.2169/internalmedicine.9718-22

    • ISSN
      0918-2918, 1349-7235
    • Year and Date
      2023-03-15
    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] P2Y12 Reaction Units and Clinical Outcomes in Acute Large Artery Atherosclerotic Stroke: A Multicenter Prospective Study2023

    • Author(s)
      Fukuma K, Yamagami H, Ihara M, Tanaka T, Miyata T, Miyata S, Kokame K, Nishimura K, Nakaoku Y, Yamamoto H, Hayakawa M, Kamiyama K, Enomoto Y, Itabashi R, Furui E, Manabe Y, Ezura M, Todo K, Hashikawa K, Uchiyama S, Toyoda K, Nagatsuka K, and the PRAISE Study Investigators
    • Journal Title

      Journal of Atherosclerosis and Thrombosis

      Volume: 30 Issue: 1 Pages: 39-55

    • DOI

      10.5551/jat.63369

    • ISSN
      1340-3478, 1880-3873
    • Year and Date
      2023-01-01
    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Biochemistry, molecular genetics, and clinical aspects of hereditary angioedema with and without C1 inhibitor deficiency2023

    • Author(s)
      Miyata T, Horiuchi T
    • Journal Title

      Allergol Int

      Volume: 72

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 血液凝固因子・凝固制御因子2022

    • Author(s)
      宮田敏行、和田晋一
    • Journal Title

      日本臨牀

      Volume: 80 Pages: 673-678

    • Related Report
      2021 Research-status Report
  • [Journal Article] Autoantibody-resistant ADAMTS13 variant2021

    • Author(s)
      Miyata, T
    • Journal Title

      Blood

      Volume: 137 Issue: 19 Pages: 2575-2576

    • DOI

      10.1182/blood.2021011147

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Current prophylactic plasma infusion protocols do not adequately prevent long-term cumulative organ damage in the Japanese congenital thrombotic thrombocytopenic purpura cohort2021

    • Author(s)
      Sakai, K. Fujimura, Y. Miyata, T. Isonishi, A. Kokame, K. Matsumoto, M.
    • Journal Title

      Br J Haematol,

      Volume: 194 Issue: 2 Pages: 444-452

    • DOI

      10.1111/bjh.17560

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Influence of renal impairment and genetic subtypes on warfarin control in Japanese patients.2021

    • Author(s)
      Tanaka T, Ihara M, Fukuma K, Yamamoto H, Washida K, Kimura S, Kada A, Miyata S, Miyata T, Nagatsuka K
    • Journal Title

      Genes (Basel)

      Volume: 12 Issue: 10 Pages: 1537-1537

    • DOI

      10.3390/genes12101537

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical guidance for peripartum management of patients with hereditary thrombophilia.2021

    • Author(s)
      Kobayashi T, Morishita E, Tsuda H, Neki R, Kojima T, Ohga S, Ochiai M, Adachi T, Miyata T
    • Journal Title

      J Obstet Gynaecol Res

      Volume: 47 Issue: 9 Pages: 3008-3033

    • DOI

      10.1111/jog.14879

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Complement-related thrombosis2021

    • Author(s)
      MIYATA Toshiyuki、INOUE Norimitsu
    • Journal Title

      Japanese Journal of Thrombosis and Hemostasis

      Volume: 32 Issue: 6 Pages: 695-707

    • DOI

      10.2491/jjsth.32.695

    • NAID

      130008134369

    • ISSN
      0915-7441, 1880-8808
    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] ジャーナルクラブ「ヘパリン抵抗性 臨床的視点からと管理戦略」2021

    • Author(s)
      根木玲子、宮田敏行
    • Journal Title

      日本血栓止血学会誌

      Volume: 32 Pages: 796-797

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Derlin-3 is required for changes in ERAD complex formation under ER stress2020

    • Author(s)
      Eura Y, Miyata T, Kokame K
    • Journal Title

      Int J Mol Sci

      Volume: 21 Issue: 17 Pages: 6146-6146

    • DOI

      10.3390/ijms21176146

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Success and limitations of plasma treatment in pregnant women with congenital thrombotic thrombocytopenic purpura2020

    • Author(s)
      Sakai Kazuya、Fujimura Yoshihiro、Nagata Yasuyuki、Higasa Satoshi、Moriyama Masato、Isonishi Ayami、Konno Mutsuko、Kajiwara Michiko、Ogawa Yoshiyuki、Kaburagi Shigehiko、Hara Tomoko、Kokame Koichi、Miyata Toshiyuki、Hatakeyama Kinta、Matsumoto Masanori
    • Journal Title

      Journal of Thrombosis and Haemostasis

      Volume: 18 Issue: 11 Pages: 2929-2941

    • DOI

      10.1111/jth.15064

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Low-Dose Activated Protein C Suppresses the Development of Cerebral Infarction and Neurological Deficits in Mice2020

    • Author(s)
      Yamato Keiko、Nakajo Yukako、Yamamoto-Imoto Hitomi、Kokame Koichi、Miyata Toshiyuki、Takahashi Jun C、Kataoka Hiroharu、Yanamoto Hiroji
    • Journal Title

      Neurosurgery Open

      Volume: 1 Issue: 4 Pages: 1-12

    • DOI

      10.1093/neuopn/okaa014

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 凝固系と血小板の活性化への補体の関わり2020

    • Author(s)
      宮田敏行
    • Journal Title

      Thrombosis Medicine

      Volume: 10 Pages: 258-262

    • Related Report
      2020 Research-status Report
  • [Journal Article] 遺伝性血栓性素因患者の妊娠分娩管理に関する診療の手引きQ&A2020

    • Author(s)
      厚生労働科学研究費補助金 難治性疾患政策研究事業 血液凝固異常症等に関する研究 特発性血栓症研究グループ、小林隆夫、森下英理子、津田博子、根木玲子、小嶋哲人、大賀正一、落合正行、安達知子、宮田敏行
    • Journal Title

      日本産婦人科・新生児血液学会誌

      Volume: 30 Pages: 5-54

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Knock‐in mice bearing constitutively active αIIb(R990W) mutation develop macrothrombocytopenia with severe platelet dysfunction2019

    • Author(s)
      Akuta Keigo、Kiyomizu Kazunobu、Kashiwagi Hirokazu、Kunishima Shinji、Nishiura Nobuko、Banno Fumiaki、Kokame Koichi、Kato Hisashi、Kanakura Yuzuru、Miyata Toshiyuki、Tomiyama Yoshiaki
    • Journal Title

      Journal of Thrombosis and Haemostasis

      Volume: 18 Issue: 2 Pages: 497-509

    • DOI

      10.1111/jth.14678

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic factors associated with elevation of uric acid after treatment with thiazide-like diuretic in patients with essential hypertension2019

    • Author(s)
      Ohta Yuko、Kamide Kei、Hanada Hironori、et al. (37人中31番目)
    • Journal Title

      Hypertension Research

      Volume: 43 Issue: 3 Pages: 220

    • DOI

      10.1038/s41440-019-0356-x

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] 機械弁置換術後妊婦に対する治療量抗凝固療法の自施設プロトコールの検証2022

    • Author(s)
      根木玲子、光黒真菜、岡本章、中島康太、伊田和史、塩野入規、中西篤史、神谷千津子、宮田敏行、吉松淳
    • Organizer
      第44回日本血栓止血学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 補体系の血栓・凝固異常症への関わり2021

    • Author(s)
      宮田敏行
    • Organizer
      第57回日本補体学会学術集会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] アンチトロンビン抵抗性を示すプロトロンビン変異を伴う3症例の検討2021

    • Author(s)
      辻明宏、関根章博、浅野遼太郎、上田仁、青木竜男、保山美由紀、根木玲子、小亀浩市、宮田敏行、大郷剛
    • Organizer
      第43回日本血栓止血学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 遺伝カウンセリング外来来談者における遺伝性血栓性素因の遺伝子解析および患者背景に関する検討2021

    • Author(s)
      根木玲子、伊田和史、丸山慶子、辻明宏、宮田敏行、小亀浩市
    • Organizer
      第43回日本血栓止血学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] プロテインS(PS)比活性検査およびPS-K196E変異検出ELISAのPS-K196E変異予測精度に関する検討2020

    • Author(s)
      三好剛一、丸山慶子、根木玲子、吉松 淳、浅原彩子、奥久人、小亀浩市、宮田敏行
    • Organizer
      第42回日本血栓止血学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] 特発性血栓症患者のゲノム情報を用いた層別化による病態解明研究2020

    • Author(s)
      辻明宏、和田英夫、森下英理子、野上恵嗣、荻原義人、松下正、小嶋哲人、大郷剛、根木玲子、小亀浩市、安田聡、関根章博、宮田敏行
    • Organizer
      第42回日本血栓止血学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] Kindkin-3欠損血小板の血栓形成が明らかにする血栓形成メカニズム2020

    • Author(s)
      加藤恒、伊藤康彦、柏木浩和、西浦伸子、芥田敬吾、小亀浩市、宮田敏行、保仙直毅、金倉譲、冨山佳昭
    • Organizer
      第42回日本血栓止血学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] 当院の遺伝カウンセリング外来来談者における遺伝性血栓性素因の遺伝子解析の検討2020

    • Author(s)
      伊田和史、丸山慶子、辻明宏、宮田敏行、小亀浩市、根木玲子
    • Organizer
      第44回日本遺伝カウンセリング学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] Genetic study for idiopathic venous thromboembolism in Japanese using short-read and long read sequencers, a pilot study of Japanese Group of Idiopathic Thromboembolism2020

    • Author(s)
      Tsuji A, Sekine A, Wada H, Morishita E. Ogihara Y, Nogami K, Kojima T, Matsushita T, Yamada N, Ogo T, Neki R, Kokame K, Yasuda S, MiyataT
    • Organizer
      The XXVIII Congress of the International Society on Thrombosis and Haemostasis (ISTH 2020)
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Biochemical and genetic analyses of complement-related factors in Japanese patients with hypertensive disorders of pregnancy2020

    • Author(s)
      Neki R, Miyata T, Ohtani K, Hidaka Y, Ida K, Yokouchi-Konishi T, Nakanishi A, Yoshimatsu J, Kokame K, Wakamiya N, Inoue N
    • Organizer
      The XXVIII Congress of the International Society on Thrombosis and Haemostasis (ISTH 2020)
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Venous thromboembolism and TTP, aHUS2019

    • Author(s)
      Toshiyuki Miyata
    • Organizer
      The 41th Congress of the Japanese Society on Thrombosis and Hemostasis
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] 補体制御異常によるTMAの診断と治療, 補体と凝固のクロストーク2019

    • Author(s)
      宮田敏行
    • Organizer
      第41回日本血栓止血学会学術集会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Effects of Low-dose Combined Oral Contraceptives and Protein S K196E Mutation on Anticoagulation Factors: A Prospective Observational Study2019

    • Author(s)
      T. Miyoshi, H. Oku, S. Asahara, A. Okamoto, K. Kokame, M. Nakai, K. Nishimura, F. Otsuka, A. Higashiyama, J. Yoshimatsu, T. Miyata
    • Organizer
      The 27th Congress of the International Society on Thrombosis and Haemostasis
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 静脈血栓塞栓症と血液凝固制御能2019

    • Author(s)
      宮田敏行
    • Organizer
      第71回日本産婦人科学会学術集会
    • Related Report
      2019 Research-status Report
    • Invited
  • [Book] 第67回Scientific Standardization Committee 学術報告、Genomics in Thrombosis and Hemostasis2022

    • Author(s)
      宮田敏行
    • Total Pages
      14
    • Publisher
      血栓止血情報センター
    • Related Report
      2021 Research-status Report
  • [Book] 2020年度国際血栓止血学会SSC報告書、41-46頁2021

    • Author(s)
      宮田敏行
    • Total Pages
      197
    • Publisher
      血栓止血情報センター
    • Related Report
      2020 Research-status Report
  • [Book] 標準下肢静脈エコー、30-32頁2020

    • Author(s)
      宮田敏行、光黒真菜
    • Total Pages
      272
    • Publisher
      日本医事新報社
    • Related Report
      2020 Research-status Report
  • [Remarks] 宮田敏行研究所元部長が国際血栓止血学会Esteemed Career Awardを受賞

    • URL

      https://www.ncvc.go.jp/pr/release/pr_33926/

    • Related Report
      2022 Annual Research Report

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Published: 2019-04-18   Modified: 2024-01-30  

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