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Thiopurine metabolism associated with NUDT15 gene and clincal application.

Research Project

Project/Area Number 19K17443
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 53010:Gastroenterology-related
Research InstitutionKitasato University

Principal Investigator

Hiroki Kiyohara  北里大学, 北里研究所病院, 医師 (20626379)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords炎症性腸疾患 / チオプリン / NUDT15 / NUDT15遺伝子 / 白血球 / アポトーシス / チオプリン製剤 / 6-dTGTP / DNA
Outline of Research at the Start

炎症性腸疾患患者へのチオプリン製剤の使用により、白血球数が減少することがある。炎症を惹起する白血球数の減少が、治療予後にどのような影響を与えるのかについては不明な点が多く、本研究は観察研究によってこの点を明らかにする。また、日本人の約20%に存在するNudix Hydrolase 15(NUDT15)遺伝子変異を有する患者は白血球減少が起こりやすく、より少量のチオプリン製剤が投与されるが、本邦における至適投与量を判断する指標は確立されていない。本研究では、チオプリン製剤の代謝産物である6-デオキシチオグアノシン3リン酸の白血球DNA中濃度の、至適投与量の判断指標としての有用性について検証する。

Outline of Final Research Achievements

The aim of this research was to investigate why severe leukocytopenia is induced by thiopurine particularly in patients with NUDT15 genetic variant (R139C). Deoxy-thioguanosine (dTG) is a metabolite of thiopurine, and the incorporation of dTG into lymphocytes was accelerated in patients with NUDT15 genetic variant (R139C). Furthermore, dTG concentration in the DNA of peripheral mononuclear cells was inversely correlated with leukocyte count in peripheral blood. Finally, a thiopurine derivative, 6-thioguanine, was co-cultured with CD4+ lymphocytes derived from patients without thiopurine treatment, and the apoptosis of the lymphocytes was accelerated in NUDT15 (R139C) variant.

Academic Significance and Societal Importance of the Research Achievements

本研究によりNUDT15遺伝子変異(R139C)の存在によって、白血球減少が相対的に低用量の免疫調節薬の使用でも起こりやすい機序の一つが明らかとなった。将来的に、リンパ球DNA中のdTG濃度が、個体差の大きいIMの至適投与量の評価として有用である可能性が示されたことに加え、NUDT15遺伝子多型(R139C)を有する患者においては、特にこのdTGのリンパ球DNAへの取り込みを介したアポトーシスが促進されており、IMの薬理学的な作用とアポトーシスとの間に関連がある可能性が示され、これまで十分に明らかとなっていなかったIMの作用機序解明の一助となりうる。

Report

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

    (2 results)

All 2021 2020

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (1 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Increased DNA-incorporated thiopurine metabolite as a possible mechanism for leukocytopenia through cell apoptosis in inflammatory bowel disease patients with NUDT15 mutation2021

    • Author(s)
      Toyonaga Takahiko、Kobayashi Taku、Kuronuma Satoshi、Ueno Aito、Kiyohara Hiroki、Okabayashi Shinji、Takeuchi Osamu、Redfern Christopher P. F.、Terai Hideki、Ozaki Ryo、Sagami Shintaro、Nakano Masaru、Coulthard Sally A.、Tanaka Yoichi、Hibi Toshifumi
    • Journal Title

      Journal of Gastroenterology

      Volume: 56 Issue: 11 Pages: 999-1007

    • DOI

      10.1007/s00535-021-01820-0

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] NUDT15 variance increases DNA-incorporated thiopurine metabolites and lymphocyte apoptosis in patients with inflammatory bowel disease.2020

    • Author(s)
      Hiroki Kiyohara, Taku Kobayashi, Takahiko Toyonaga, Satoshi Kuronuma, Aito Ueno, Shinji Okabayashi, Osamu Takeuchi, Sally A. Coulthard, Christopher P. F. Redfern, Hideki Terai, Yoichi Tanaka, Ryo Ozaki, Masaru Nakano, Toshifumi Hibi
    • Organizer
      15th Congress of ECCO
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research

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Published: 2019-04-18   Modified: 2023-01-30  

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