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Molecular biological analysis of thrombotic tendency: Study of FV R2 frequency and its molecular

Research Project

Project/Area Number 15591039
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionNational Hospital Organization, Nagoya Medical Center (Clinical Research Center)

Principal Investigator

YAMAZAKI Tomio  National Hospital Organization, Nagoya Medical Center (Clinical Research Center), Department of Hemostasis and Thrombosis, Division chief, 止血血栓研究部, 室長 (00282202)

Co-Investigator(Kenkyū-buntansha) SAITO Hidehiko  SAITO,Hidehiko, 院長 (20153819)
HAMAGUCHI Motohiro  HAMAGUCHI,Motohiro, 部長 (30393177)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2003: ¥2,600,000 (Direct Cost: ¥2,600,000)
KeywordsFactor V / Factor V R2 haplotype / polymorphism / venous thrombosis / risk factor / anticoagulant activity / glycosylation / thrombotic tendency
Research Abstract

A mutant factor V, FV-R2 is a polymorphic molecule of coagulation factor V (FV). Its origin is supposed to be very old in the history of human being. Although it has been expected that FV-R2 exists in Japanese people as well as western populations, its frequency in Japan has not yet been determined. Several previous studies have suggested that FV-R2 is a risk factor of venous thrombosis. However, contravercial results have also been obtained and relationship between FV-R2 and venous thrombosis has not yet been clarified.
After informed consent was obtained, we analyzed genomic DNA samples from healthy volunteers and found that allelic frequency of FV-R2 in Japanese population is approximately 10%. We also performed expression studies and functional analyses by in vitro expression systems to study molecular biological relationship between FV-R2 and venous thrombosis. The expression study showed that expression level of FV-R2 was lower than that of wild type FV, and revealed impaired intracellular transport and intracellular degradation of FV-R2. In the functional analyses, no abnormality was found in thromobin-activation and activated protein C (APC)-inactivation of FV-R2. However, FV-R2 had impaired anticoagulant activity (APC cofactor activity) due to combinations of amino acid substitutions in FV-R2 (either M385T + D2194G or H1299R + M1736V). We also found that D2194G mutation affected molecular conformation of C-terminal region of FV molecule and increased efficiency of partial N-glycosylation at N2180. Presence of N-glycan at N2180 results in increased thrombin generation. Thus, the increased efficiency of partial N-glycosylation at N2180 by D2194G mutation, as well as impaired anticoagulant activity, is supposed to be one of the molecular mechanisms by which FV-R2 causes thrombotic tendency.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (5 results)

All 2005 2003 Other

All Journal Article (3 results) Book (1 results) Publications (1 results)

  • [Journal Article] Factor V2005

    • Author(s)
      Tomio Yamazaki
    • Journal Title

      Thrombosis, Hemostasis, and Vascular Sciences(Chugai Igaku CO.)

      Pages: 347-352

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Factor Vを見直そう : Factor V R2 haplotrypeと血栓症2003

    • Author(s)
      山崎鶴夫
    • Journal Title

      日本血栓止血学会誌 14

      Pages: 310-315

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Pay attention again to Factor V: Factor V R2 Haplotype and Thrombosis2003

    • Author(s)
      Tomio Yamazaki
    • Journal Title

      Jap J Thromb Hemost 14(4)

      Pages: 310-315

    • NAID

      130000106362

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] 血栓・止血・脈管学(第V因子)2005

    • Author(s)
      山崎鶴夫
    • Total Pages
      834
    • Publisher
      中外医学社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] 山崎鶴夫: "Factor Vを見直そう:Factor V R2 haplotypeと血栓症"日本血栓止血学会誌. 14・4. 310-315 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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