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Estimation of Susceptibility to and Prognosis of Cardiovascular Diseases Based on Genetic Polymorphism and Its Application to Drug Discoveries

Research Project

Project/Area Number 12794012
Research Category

Grant-in-Aid for University and Society Collaboration

Allocation TypeSingle-year Grants
Research Field Circulatory organs internal medicine
Research InstitutionThe University of Tokyo

Principal Investigator

NAGAI Ryozo  Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Professor, 医学部附属病院, 教授 (60207975)

Co-Investigator(Kenkyū-buntansha) FURUYA Toshio  Pharmadesign, Inc., President, 代表取締役社長(研究職)
MAEMURA Koji  The University of Tokyo Hospital, Assistant Professor, 医学部附属病院, 助手 (90282649)
YAMAZAKI Tsutomu  Graduate School of Medicine, the University of Tokyo, Professor, 大学院・医学系研究科, 教授 (60251245)
SAKATA Tsuneaki  Shionogi & Co.,Ltd. Chief Researcher, 主管研究員
森田 啓行  東京大学, 医学部・附属病院, 助手 (60323573)
栗原 裕基  熊本大学, 発生医学研究センンター, 教授 (20221947)
古屋 利夫  ファルマデザイン(株), 代表取締役社長・(研究職)
Project Period (FY) 2000 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥40,100,000 (Direct Cost: ¥40,100,000)
Fiscal Year 2002: ¥19,100,000 (Direct Cost: ¥19,100,000)
Fiscal Year 2001: ¥21,000,000 (Direct Cost: ¥21,000,000)
KeywordsCardiovascular Diseases / Genetic polymorphism / Disease susceptibility / promoter region / Matrix metalloproteinase / ATP-binding cassete A1(ABCA1) / Glycoprotein Ia / KLF5 / 遺伝子マーカー / エクソン / SNP / マトリクスメタロプロテアーゼ / プロモーター
Research Abstract

The aim of this study is to identify useful genetic markers associated with susceptibility to or severity of cardiovascular diseases. At first we established clinical database system for the patients in our department and we obtained DNA samples from them after informed consent by the way approved by the institutional ethics committee. Using these clinical data and genetic samples we obtained the results mentioned as follows.
(l) The Met823Ile polymorphism in ABCA1 gene was one of the independent determinants of high-density lipoprotein in Japanese population. (2) The combination in the promoter SNPs of MMP1 and MMP3 was significantly associated with susceptibility to myocardial infarction. (3) The (GC)n polymorphism in HO-1 gene was associated with coronary artery diseases. (4) There was no association between glycoprotein Ia polymorphism and onset of myocardial infarction. (5) Mild hyperhomocyteinemia caused endothelial dysfunction resulting in more severe atherosclerotic lesions in rat balloon injury model. This is relevant to our previous report that genetic polymorphism in MTHFR was related to atherothrombotic diseases by affecting plasma homocysteine levels. (6) After immunohistchemical study of post-atherectomy specimens, the expression of KLF5 was shown to be a useful marker to predict post-angioplasty restenosis. Moreover we established and analyzed heterozygous KLF5-knockout mice, demonstrating that KLF5 is a key element linking external stress and cardiovascular remodeling.
By promoting the genetic analyzes about important genes in cardiovascular system, we will make personalized medicine a reality after applying useful genetic markers to clinical diagnosis or guidance.

Report

(4 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (30 results)

All Other

All Publications (30 results)

  • [Publications] Shindo, T.: "Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling"Nature Medicine. 8・8. 856-863 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hoshino Y, et al.: "Regulated Expression of the BTEB2 Transcription Factor in Vascular Smooth Muscle Cells : Analysis of Developmental and Pathological Expression Profiles Shows Implications as a Predictive Factor for Restenosis"Circulation. 102. 2528-2534 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Morita H, et al.: "Lack of association between the platelet glycoprotein Ia C807T gene polymorphism and myocardial infarction in Japanese. An approach entailing melting curve analysis with specific fluorescent hybridization probes"Thromb Haemost. 85. 226-230 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Morita H, et al.: "Diet-induced hyperhomocysteinemia exacerbates neointima formation in rat carotid arteries after balloon injury"Circulation. 103. 133-139 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Imai Y, et al.: "Resistance to neointimal hyperplasia and fatty streak formation in mice with adrenomedullin overexpression"Arterioscler Thromb Vasc Biol. 22:13. 10-15 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nojiri T, et al.: "Genetic variations of matrix metalto-proteinase-1 and -3 promoter regions and their associations with susceptibility to myocardial infarction in Japanese"Int J Cardiol. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shindo T., et al.: "Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling"Nature Med. 8. 856-863 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hoshino Y, et al.: "Regulated Expression of the BTEB2 Transcription Factor in Vascular Smooth Muscle Cells : Analysis of Developmental and Pathological Expression Profiles Shows Implications as a Predictive Factor for Restenosis"Circulation. 102. 2528-2534 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Morita H, et al.: "Lack of association between the platelet glycoprotein Ia C807T gene polymorphism and myocardial infarction in Japanese. An approach entailing melting curve analysis with specific fluorescent hybridization probes"Thromb Haemost. 85. 226-230 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Morita H, et al.: "Mediation of unusually high concentrations of 1,25-dihydroxyvitamin D in homozygous klotho mutant mice by increased expression of renal 1alpha-hydroxylase gene"Circulation. 103. 133-139 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Imai Y, et al.: "Resistance to neointimal hyperplasia and fatty streak formation in mice with adrenomedullin overexpression"Arterioscler Thromb Vase Biol.. 22:13. 10-15 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nojiri T, et al.: "Genetic variations of matrix metallo-proteinase-1 and -3 promoter regions and their associations with susceptibility to myocardial infarction in Japanese"Int J Cardiol.. in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Shindo, T.: "Kruppel-like zinc-finger transcription factor KLF5/BTEB2 is a target for angiotensin II signaling and an essential regulator of cardiovascular remodeling"Nature Medicine. 8・8. 856-863 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kaneda H, et al.: "Heme oxygenase-1 gene promoter polymorphism is associated with coronary artery disease in Japanese patients with coronary risk factors"Arterioscler Thromb Vasc Biol.. 22:16. 80-85 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Harada T, et al.: "A common Ile823Met variant of ATP-binding cassette transporter A1 gene (ABCA1) alters high density lipoprotein cholesterol level in Japanese population"Atherosclerosis. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Maemura K, et al.: "Perrell MA. Nagai R. Lee ME. Molecular mechanisms of morning onset of myocardial infarction"Ann NYAcad Sci.. 947. 398-402 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] Imai Y, et al.: "Resistance to neointimal hyperplasia and fatty streak formation in mice with adrenomedullin overexpression"Arterioscler Thromb Vasc Biol. 22:13. 10-15 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nojiri T, et al.: "Genetic variations of matrix metallo-proteinase-1 and -3 promoter regions and their associations with susceptibility to myocardial infarction in Japanese"Int J Cardiol. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Morita H, Saito Y, Kurabayashi M, Nagai R.: "Diet-induced mild hyperhomocysteinemia and increased salt intake diminish vascular endothelial function in a synergistic manner"J Hypertens. 20. 55-62 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Oh-hashi Y, Shindo T, Kurihara Y, Imai T, Wang Y, Morita H, Imai Y, Kayaba Y, Nishimatsu H, Suematsu Y, Hirata Y, Yazaki Y, Nagai R, Kuwaki T, Kurihara H.: "Elevated sympathetic nervous activity in mice deficient in alpha CGRP."Circ Res.. 89. 983-990 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Shindo T, Kurihara Y, Nishimatsu H, Moriyama N, Kakoki M, Wang Y, Imai Y, Ebihara A, Kuwaki T, Ju KH, Minamino N, Kangawa K, Ishikawa T, Fukuda M, Akimoto Y, Kawakami H, Imai T, Morita H, Yazaki Y, Nagai R, Hirata Y, Kurihara H.: "Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene"Circulation. 104. 1964-1971 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kato N, Sugiyama T, Morita H, Kurihara H, Sato T, Yamori Y, Yazaki Y.: "Association analysis of beta(2)-adrenergic receptor polymorphisms with hypertension in Japanese"Hypertension. 37. 286-292 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Itoh T, Kikuchi K, Odagawa Y, Takata S, Yano K, Okada S, Haneda N, Ogawa S, Nakano O, Kawahara Y, Kasai H, Nakayama T, Fukutomi T, Sakurada H, Shimizu A, Yazaki Y, Nagai R, Nakamura Y, Tanaka T.: "Correlation of genetic etiology with response to b-adrenergic blockade among symptomatic patients with familial long-QT syndrome"J Hum Genet. 46. 38-40 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kuwasako K.Kitamura K.Ito K.Uemura T.Yanagita Y.Kato J.Sakata T.Eto T.: "The seven amino acids of human RAMP2 (86) and RAMP3 (59) are critical for agonist binding to human adrenomedullin receptors"J Biol Chem. 276. 49459-49465 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Morita H,: "Lack of association between the platelet glycoprotein Ia C807T gene polymorphism and myocardial infarction in Japanese:.\a approach entailing melting curve analysis with specific fluorescent hybridization probes"Thromb Haemost.. 85. 226-230 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sekiguchi K,: "Homeobox protein hex induces SMemb/Nonmuscle myosin heavy chain-B gene expression through the cAMP-responsive element."Circ Res.. 88・1. 52-58 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Kanai H,: "Transforming growth factor-β/Smads signaling induces transcription of the cell type-restricted ankyrin repeat protein CARP gene through CAGA motif in vascular smooth muscle cells."Circ Res.. 88・1. 30-36 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Morita H,: "Diet-induced hyperhomocysteinemia exacerbates neointima formation in rat carotid arteries after balloon injury."Circulation.. 103・1. 133-139 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Hoshino Y,: "Regulated expression of the BTEB2 transcription factor in vascular smooth muscle cells : analysis of developmental and pathological expression profiles shows implications as a predictive factor for restenosis"Circulation.. 102・20. 2528-2534 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sata M,: "A Mouse Model of Vascular Injury that Induces Rapid Onset of Medial Cell Apoptosis Followed by Reproducible Neointimal Hyperplasia."J Mol Cell Cardiol.. 32・11. 2097-2104 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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