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

• Project/Area Number: 12794012
• Research Category: Grant-in-Aid for University and Society Collaboration
• Allocation Type: Single-year Grants
• Research Field: Circulatory organs internal medicine
• Research Institution: The 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: ¥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)
• Keywords: Cardiovascular 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.

Research Products

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