2002 Fiscal Year Final Research Report Summary
Estimation of Susceptibility to and Prognosis of Cardiovascular Diseases Based on Genetic Polymorphism and Its Application to Drug Discoveries
| Project/Area Number |
12794012
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| Research Category |
Grant-in-Aid for University and Society Collaboration
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| Allocation Type | Single-year Grants |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | The University of Tokyo |
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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)
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| 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
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| Project Period (FY) |
2000 – 2002
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| Keywords | Cardiovascular Diseases / Genetic polymorphism / Disease susceptibility / promoter region / Matrix metalloproteinase / ATP-binding cassete A1(ABCA1) / Glycoprotein Ia / KLF5 |
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| 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.
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