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CLONING OF SUSCEPTIBILITY GENES FOR NON-INSULIN-DEPENDENT DIABETES MELLITUS BY A NOVEL STRATEGY

Research Project

Project/Area Number 09470220
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 内分泌・代謝学
Research InstitutionOsaka University

Principal Investigator

IKEGAMI Hiroshi  Osaka University Medical School, Assisstant Professor, 医学部, 助手 (20221062)

Co-Investigator(Kenkyū-buntansha) KAWAGUCHI Yoshihiko  Osaka Unversity Medical School, Assistant Professor, 医学部, 助手 (20303943)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥8,600,000 (Direct Cost: ¥8,600,000)
Fiscal Year 1998: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1997: ¥6,800,000 (Direct Cost: ¥6,800,000)
KeywordsMULTIFACTORIAL DISEASE / GENETICS / DIABETES MELLITUS / SUSCEPTIBILITY
Research Abstract

Unlike monogenic diseases, classical linkage analysis is not feasible and therefore a novel strategy is required for genetic dissection of multifactorial diseases such as diabetes mellitus. In this study we constructed a novel strategy for genetic dissection for multifactorial diseases in general and diabetes mellitus in particular.
For genetic dissection of type 2 diabetes with low Xs values, methods with enough power are required. To increase the power of genetic analysis, we newly eatablished meta-analysis for association studies between genotypes and phenotypes, including quantitative traits. By using this method, we showes significant association between insertion/deletion polymorphism of the ACE gene and susuceptibility to diabetic nephropathy in more than 5000 subjects, and between a quantiative phenotype, body mass index, and mutation in beta 3 adrenergic receptor gene in more than 9000 subjects.
To make genetic analysis simpler, we used inbred animal models for diabetes mellitus (NOD mice for type 1 diabetes and NSY mice for type 2 diabetes). Quantiatative trait locus (QTL) mapping in F2 mice in crosses of NSY with contsol C3H/He mice mapped at least 3 QTL (Nidd1, NIdd2, NIdd3) on mouse chromosomes 11, 14 and 6. Nidd1 appears to affect glucose tolerance through imapired insulin secretion, whereas Nidd2 through insulin resistance. Nidd3 singnificantly affects insulin resistance and abdominal fat accumulation as well as glucose tolerance. Consomic and congenic strains for each of these loci are now in progress to further localization and functional analysis of these QTL.

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (23 results)

All Other

All Publications (23 results)

  • [Publications] Hotta M: "Pancreatic β cell-specific expression of thioredoxin an antioxidative and anti-apoptotic protein,prevents autoimmune and strptozotocin-induced diabetes." J Exp Med. 188. 1445-1451 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Fujisawa T: "Meta-analysis of the association of Trp64Arg polymorphism of β3-adrenergic receptor gene with body mass index." J Clin Endocrinol Metab. 83. 2441-2444 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Fujisawa T: "Meta-analysis of assocoation of Insertion/deletion polymorphism of angiotensin I-converting enzyme gene with diabetic nephrpathy and retinopathy." Diabetologia. 41. 47-53 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Fu J: "Association of distal chromosome2q with IDDM in Japanese subjects." Diabetologia. 41. 228-232 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shen G-Q: "Asp905Tyr polymorphism of skeletal muscle-specific gycogen-targeting subunit of protein phosphatase 1 gene in non-insulin-dependent diabetes mellitus." Diabetes Care. 21. 1086-1089 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ueda H: "Genetic analysis of late-onset type 2 diabetes in a model of human complex trait." Diabetes. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Ueda H,Ikegami H,Kawaguchi Y,Fujisawa T,Yamato E,Shibata M,Ogihara T: "Genetic analysis of late-onset type 2 diabetes in a mouse model of human complex trait." Diabetes. (in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hotta M,Tashiro F,Ikegami H,Niwa H,Ogihara T,Yodoi J,Miyazaki J-I: "Pancreatic beta-cell-specific expression of thioredoxin, an antioxidative and anti-apoptotic protein, prevents autoimmune and strptozotocin-induced diabetes." J Exp Med. 188. 1445-1451 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Fujisawa T,Ikegami H,Kawaguchi Y,Ogihara T: "Meta- analysis of the association of Trp64 Arg polymorphism of beta3- adrenergic receptor gene with body mass index." J Clin Endocrinol Metab. 83. 2441-2444 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Fujisawa T,Ikegami H,Kawaguchi Y,Hamada Y,Ueda H,Shintani M,Fukuda M,Ogihara T: "Meta- analysis of the association of Insertion/deletion polymorphism of angiotensin I-converting enzyme gene with diabetic nephropathy and retinopathy." Diabetologia. 41. 47-53 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Fu J,Ikegami H,Kawaguchi Y,Fujisawa T,Kawabata Y,Hamada Y,Ueda H,Shintani M,Nojima K,Babaya N,Shen Q-J,Uchigata Y,Urakami T,Omori Y,Shima K,Ogihara T: "Association of distal chromosome 2q with IDDM in Japanese subjects." Diabetologia. 41. 228-232 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Kawaguchi Y,Ikegami H,Shen G-Q,Nakagawa Y,Fujisawa T,Hamada Y,Ueda H,Fu J,Uchigata Y,Kaitagawa Y,Omori Y,Shima K,Ogihara T: "Insulin gene region contributes to genetic susceptibility to, but may not to low incidence of, insulin-dependent diabetes mellitus in Japanese." Biochem Biophys Res Commun. 233. 283-287 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shen GQ,Ikegami H,Fujisawa T,Hamada Y,Kamide K,Rakugi H,Higaki J,Murakami H,Shimamoto K,Ogihara T: "Asp905Tyr polymorphism of protein phosphatase 1G-subunit gene in hypertension." Hypertension. 30. 236-239 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Hotta M: "Pancreatic β cell-specific expression of thioredoxin, an antioxidative and anti-apoptotic protein, prevents autoimmune and strptozotocin-induced diabetes." J Exp Med. 188. 1445-1451 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fujisawa T: "Meta-analysis of the association of Trp64Arg polymorphism of β3-adrenergic receptor gene with body mass index." J Clin Endocrinol Metab. 83. 2441-2444 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fujisawa T: "Meta-analysis of association of Insertion/deletion polymorphism of angiotensin I-converting enzyme gene with diabetic nephropathy and retinopathy." Diabetologia. 41. 47-53 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fu J: "Association of distal chromosome 2q with IDDM in Japanese subjects." Diabetologia. 41. 228-232 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Shen G-Q: "Asp905Tyr polymorphism of skeletal muscle-specific glycogen-targeting subunit of protein phosphatase 1 gene in non-insulin-dependent diabetes mellitus." Diabetes Care. 21. 1086-1089 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Ueda H: "Genetic analysis of late-onset type 2 diabetes in a mouse model of human complex trait." Diabetes. (印刷中). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Shen,G-Q: "Asp905Tyr polymorphism of protein phosphatase 1G subunit gene in hypertension" Hypertension. 30. 236-239 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kawaguchi,Y: "Insulin gene region contributes to genetic susceptibility to,but may not to low incidence of,insulin dependent diabetes mellitus in Japanese" Biochemical and Biophysical Research Communication. 233. 283-287 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Fujisawa,T: "Meta-analysis of association of insertion/deletion polymorphism of ACE gene with diabetic nephropathy and retinopathy" Diabetologia. 41. 47-53 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] Fu,J: "Association of distal chromosome 2q with IDDM in Japanese subjects" Diabetologia. 41. 228-232 (1998)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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