メタボリック症候群の病態解明と予防法・治療法の開発

• Project/Area Number: 19659149
• Research Category: Grant-in-Aid for Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Hygiene
• Research Institution: Mie University
• Principal Investigator: 山田 芳司 Mie University, 生命科学研究支援センター, 教授 (90333286)
• Co-Investigator(Kenkyū-buntansha): 市原 佐保子 三重大学, 生命科学研究支援センター, 助教 (20378326) ; 西田 有 三重大学, 生命科学研究支援センター, 助教 (50287463)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2008: ¥1,300,000 (Direct Cost: ¥1,300,000); Fiscal Year 2007: ¥2,000,000 (Direct Cost: ¥2,000,000)
• Keywords: 遺伝子 / ゲノム / 多型 / メタボリック症候群 / 肥満 / 脂質代謝異常 / 高血圧 / 糖尿病

Research Abstract

研究参加施設の協力により、患者対照集団5,500例(メタボリック症候群2,500例、対照3,000例)のDNAサンプルおよび臨床データを収集した。202遺伝子多型について、メタボリック症候群1,017例、対照771例の関連解析を行い、メタボリック症候群の発症と関連する(P<0.05)遺伝子多型を14個検出した。これらの多型の中で、apolipoprotein A-V遺伝子のプロモーター領域に位置する-1131T→C多型がメタボリック症候群の発症に強く関連する(P=0.000002)ことを明らかにした。さらに、98遺伝子多型についてメタボリック症候群1,522例、対照895例の関連解析を行い、メタボリック症候群の発症と有意に(FDR<0.05)関連する遺伝子多型を6個検出した。これらの多型の中で、apolipoprotein A-V遺伝子の-3A→C多型(P=0.00000001)と553G→T(Gly185Cys)多型(P=0.0007)がメタボリック症候群の発症に強く関連することを明らかにした。今後は、SNPチップを用いたゲノム全領域関連解析によりメタボリック症候群の発症に関連する遺伝子およびその多型を同定する予定である。
メタボリック症候群のモデル動物であるSHR/NDmcr-cpについてcDNAマイクロアレイによる解析を行った結果、6週齢のSHR/NDmcr-cpでは対照ラットに比較し、肝臓ならびに脂肪組織でそれぞれ253個と535個の遺伝子の発現が亢進し、244個と508個の遺伝子の発現が抑制されていた。また、25週齢のSHR/NDmcr-cpでは対照ラットに比較し、肝臓ならびに脂肪組織でそれぞれ163個と277個の遺伝子の発現が亢進し、184個と224個の遺伝子の発現が抑制された。現在それらの遺伝子発現の変化について再現性を確認すると共に、階層的クラスター解析を行っている。

Research Products

• [Journal Article] Association of a polymorphism of apolipoprotein E gene with chronic kidney disease in Japanese individuals with metabolic syndrome (2009)
  • Author(s): Yoshida T, Kato K, Fujimaki T, Yokoi K, Oguri M, Watanabe S, Metoki N, Yoshida H, Satoh K, Aoyagi Y, Nishigaki Y, Tanaka M, Nozawa Y, Yamada Y
  • Journal Title: Genomics 93 Pages: 221-226
  • Peer Reviewed
• [Journal Article] Genetic risk for metabolic syndrome : examination of candidate gene polymorphisms related to lipid metabolism in Japanese individuals (2008)
  • Author(s): Yamada Y, Kato K, Yoshida T, Yokoi K, Matsuo H, Watanabe S, Metoki N, Yoshida H, Satoh K, Ichihara S, Aoyagi Y, Yasunaga A, Park H, Tanaka M, Lee W, Nozawa Y
  • Journal Title: J Med Genet 45 Pages: 22-28
  • Peer Reviewed
• [Journal Article] Association of genetic variants with atherothrombotic cerebral infarction among Japanese individuals with metabolic syndrome (2008)
  • Author(s): Yamada Y, Kato K, Oguri M, Yoshida T, Yokoi K, Watanabe S, Metoki N, Yoshida H, Satoh K, Ichihara S, Aoyagi Y, Yasunaga A, Park H, Tanaka M, Nozawa Y
  • Journal Title: Int J Mol Med 21 Pages: 801-808
  • Peer Reviewed
• [Journal Article] Genetic risk for metabolic syndrome: examination of candidate gene polymorphisms related to lipid metabolism in Japanese individuals (2008)
  • Author(s): Yoshiji Yamada, Kiinihiko Kato, Tetsuro Yoshida, Kiyoshi Yokoi, Hitoshi Matsuo, Sachiro Watanabe, Norifumi Metoki, Hidemi Yoshida, Kei Satoh, Watanabe, Norifumi Metoki, Hidemi Yoshida, Kei Satoh, Sahoko Ichihara, Yukitoshi Aoyagi, Akitomo Yasunaga, Hyuntae Park, Masashi Tanaka, Wan Lee, Yoshinori Nozawa
  • Journal Title: J Med Genet 45 Pages: 22-28
  • Peer Reviewed
• [Journal Article] Women with mitochondrial haplogroup N9a are protected against metabolic syndrome (2007)
  • Author(s): Masashi Tanaka, Noriyuki Fuku, Yutaka Nishigaki, Hitoshi Matsuo, Tomonori Segawa, Sachiro Watanabe, Kimihiko Kato, Kiyoshi Yokoi, Masafumi Ito, Yoshinori Nozawa, Yoshiji Yamada
  • Journal Title: Diabetes 56 Pages: 518-521
  • Peer Reviewed
• [Journal Article] Prediction of genetic risk for metabolic syndrome (2007)
  • Author(s): Yoshiji Yamada, Kimihiko Kato, Takeshi Hibino, Kiyoshi Yokoi, Hitoshi Matsuo, Tomonori Segawa, Sachiro Watanabe, Sahoko Ichihara, Hidemi Ybshida, Kei Satoh, Yoshinori Nozawa
  • Journal Title: Atherosclerosis 191 Pages: 298-304
  • Peer Reviewed
• [Journal Article] Association of genetic variants with myocardial infarction in Japanese individuals with metabolic syndrome
  • Author(s): Oguri M, Kato K, Yokoi K, Itoh T, Metoki N, Yoshida H, Satoh K, Aoyagi Y, Nishigaki Y, Tanaka M, Nozawa Y, Yamada Y
  • Journal Title: Atherosclerosis (In press)
  • Peer Reviewed
• [Journal Article] Association of candidate gene polymorphisms with atherothrombotic cerebral infazction among Japanese indivuduals with metabolic syndrome
  • Author(s): Yoshiji Yamada, Kimihiko Kato, Mitsutoshi Oguri, Tetsuro Yoshida, Kiyoshi Yokoi, Sachiro Watanabe, Norifumi Metoki, Hidemi Yoshida, Kei Satoh, Sahoko Ichihara, Yukitoshi Aoyagi, Akitomo Yasunaga, Hyuntae Park, Masashi Tanaka, Yoshinori Nozawa
  • Journal Title: Int J Mol Med (In press)
  • Peer Reviewed
• [Presentation] Identification of polymorphisms of the apolipoprotein A-V gene as genetic risk factors for metabolic syndrome (2009)
  • Author(s): Kimihiko Kato, Tetsuo Fujimaki, Toshiki Kawamiya, Satoru Tanaka, Kazuhiro Yajima, Takeshi Hibino, Kiyoshi Yokoi, Sachiro Watanabe, Toyoaki Murohara, Genjiro Kimura, Yoshiji Yamada
  • Organizer: 第73回日本循環器学会総会・学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2009-03-21
• [Presentation] Genetic risk for metabolic syndrome, chronic kidney disease, and cardiovascular disease (2008)
  • Author(s): Yoshiji Yamada
  • Organizer: The 2008 Scientific Conference of the Korean Society of Lipiodology and Atherosclerosis
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2008-09-06
• [Presentation] Genetic risk for metabolic syndrome (2008)
  • Author(s): Kazuhiro Yajima, Yoshiji Yamada, Kimihiko Kato, Takeshi Hibino, Kiyoshi Yokoi, Sachiro Watanabe, Sahoko Ichihara, Yoshinori Nozawa, Toyoaki Murohara, Genjiro Kimura
  • Organizer: European Society of Cardiology Congress 2008
  • Place of Presentation: Munich, Germany
  • Year and Date: 2008-09-01
• [Presentation] Identification of genetic risk and development of personalized prevention systems for cardiovascular diseases (2008)
  • Author(s): 山田 芳司
  • Organizer: 第72回日本循環器学会総会・学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2008-03-29
• [Presentation] Genetic risk for metabolic asyndrome: emxamination of candidate gene polymorphisms related to lipid metabolism in Japanese individuals (2008)
  • Author(s): Mitsutoshi Oguri, Kimihiko Kato, Tetsuro Yoshida, Tetsuo Fujimaki, Kazuhiro Yajima, Takeshi Hibino, Kiyoshi Yokoi, Sachiro Watanabe, Sahoko Ichihara, Toyoaki Murohara, Yoshiji Yamada
  • Organizer: 第72回日本循環器学会総会・学術集
  • Place of Presentation: 福岡
• [Presentation] Prediction of genetic risk for metabolic syndrome and atherosclerotic disease (2007)
  • Author(s): Yoshiji Yamada
  • Organizer: The 4th International Joint Symposium of Korea Biomedial Genomic Research Association and Center for Genomic Science
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2007-12-07
• [Presentation] Genetic risk for metabolic syndrome and atherosclerotic diseases (2007)
  • Author(s): Yoshiji Yamada
  • Organizer: 10th Cardiovascular Genomics and Atherosclerosis Symposium
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2007-04-13
• [Presentation] Prediction of genetic risk for myocardial infarction and stroke (2007)
  • Author(s): Yoshiji Yamada
  • Organizer: 12th World Congress on Advances in Oncology and 10th International Symposium on Molecular Medicine
  • Place of Presentation: Crete, Greece
• [Presentation] Prediction of genetic risk for metabolic syndrome (2007)
  • Author(s): Sahoko Ichihara, Yoshiji Yamada, Kimihiko Kato, Takeshi Hibino, Kiyoshi Yokoi, Hitoshi Matsuo, Tomonori Segawa, Sachiro Watanabe, Hidemi Yoshida, Kei Satoh, Yoshinori Nozawa
  • Organizer: 第71回日本循環器学会学術集会
  • Place of Presentation: 神戸
• [Remarks]
  • URL: http://www.lsrc.mie-u.ac.jp/human/