Molecular biological analysis of thrombotic tendency: Study of FV R2 frequency and its molecular
| Project/Area Number |
15591039
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | National Hospital Organization, Nagoya Medical Center (Clinical Research Center) |
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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)
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| Co-Investigator(Kenkyū-buntansha) |
SAITO Hidehiko SAITO,Hidehiko, 院長 (20153819)
HAMAGUCHI Motohiro HAMAGUCHI,Motohiro, 部長 (30393177)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| 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)
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| Keywords | Factor V / Factor V R2 haplotype / polymorphism / venous thrombosis / risk factor / anticoagulant activity / glycosylation / thrombotic tendency |
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| 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.
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Report
(3 results)
Research Products
(5 results)
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[Journal Article] Factor V2005
Author(s)
Tomio Yamazaki
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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
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