RNF213-related vasculopathy and stroke: mechanisms and treatment strategies

2023 Fiscal Year Final Research Report

• Project/Area Number: 19K06922
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 46020:Anatomy and histopathology of nervous system-related
• Research Institution: National Hospital Organization Osaka National Hospital Institute for Clinical Reserch (2023); Osaka University (2019-2022)
• Principal Investigator: Okazaki Shuhei 独立行政法人国立病院機構大阪医療センター(臨床研究センター), その他部局等, 上席・主任研究員クラス (60623072)
• Co-Investigator(Kenkyū-buntansha): 猪原 匡史 国立研究開発法人国立循環器病研究センター, 病院, 部長 (00372590) ; 渡邊 光太郎 大阪大学, 医学部附属病院, 医員 (00836877) ; 北野 貴也 大阪大学, 大学院医学系研究科, 招へい教員 (70772193)
• Project Period (FY): 2019-04-01 – 2024-03-31
• Keywords: stroke / intracranial stenosis / RNF213 / gene polymorphism / risk factors

Outline of Final Research Achievements

The following analyses were conducted with the objective of elucidating the mechanism by which the RNF213 p.R4810K polymorphism causes cerebral infarction and developing therapeutic strategies. (1) The establishment of a multicenter stroke registry linked to electronic medical records (10 facilities, over 6000 cases), (2) MRI vessel wall imaging analyses demonstrated that mutation carriers exhibited structural changes in the vessel wall that differed from those observed in atherosclerosis, (3) Cross-sectional studies demonstrated that mutation carriers exhibited a lower cumulative risk of atherosclerosis and a distinct risk profile. (4) A long-term prospective study revealed that mutation carriers exhibited a more progressive narrowing of intracranial arteries, and that statins may inhibit this progression. (5) A subanalysis of a randomized controlled trial of statins showed the potential of statins to prevent cerebral infarction in carriers of the RNF213 mutation.

Free Research Field

脳血管障害

Academic Significance and Societal Importance of the Research Achievements

RNF213遺伝子変異は日本人の約2％が保因者であり、脳梗塞の最大の遺伝的リスクである。本研究成果により、RNF213変異保因者の放射線学的、疫学的特徴が明らかとなり、長期追跡調査においても脳動脈狭窄症の進行や脳血管障害の発症にこの変異が強く関連していることが示された。更にスタチンなどの脂質代謝系への介入による進行抑制の可能性が示され、今後の研究のさらなる発展により、東アジア地域全体における脳梗塞リスクの低下につながることが期待できる。