Thiopurine metabolism associated with NUDT15 gene and clincal application.

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17443
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kitasato 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
• Keywords: 炎症性腸疾患 / チオプリン / NUDT15

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.

Free Research Field

消化器内科学

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。