Functional analysis of susceptibility genes for diabetes: gene-gene and gene-environment interaction

• Project/Area Number: 16390264
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kinki University (2006); Osaka University (2004-2005)
• Principal Investigator: IKEGAMI Hiroshi Kinki University, School of Medicine, Professor, 医学部, 教授 (20221062)
• Co-Investigator(Kenkyū-buntansha): YAMATO Eiji Osaka University, Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (20273667) ; FUJISAWA Tomomi Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (10324766)
• Project Period (FY): 2004 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥14,000,000 (Direct Cost: ¥14,000,000); Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000); Fiscal Year 2005: ¥4,100,000 (Direct Cost: ¥4,100,000); Fiscal Year 2004: ¥8,500,000 (Direct Cost: ¥8,500,000)
• Keywords: diabetes mellitus / gene / multifactorial disease / animal models / congenic strain / gene-gene interaction / gene-environment interaction

Research Abstract

To clarify genetic basis of diabetes mellitus for better understanding of molecular mechanisms of the disease pathogenesis and for the development of effective methods for prevention and intervention, molecular genetic studies on both type 1 and type 2 diabetes were performed in inbred animal models for type 1(NOD mice) and type 2 (NSY mice) diabetes, respectively with particular focus on gene-gene and gene-environmental interaction Analysis of consomic and congenic strains with NSY derived diabetogenic chromosomes introgressed onto control C3H/He genetic background revealed the existence of diabetogenic genes on mouse chromosome 11 and 14, respectively. Gene-gene interaction was demonstrated for obesity between chromosomes 11 and 14. Diabetogenic genes on both chromosomes 11 and 14 showed gene-environment interaction with markedly deteriorated phenotypes with supplementation of 30% sucrose in drinking water. Sub-congenic analysis demonstrated that diabetogenic genes on chromosome 11 consist of multiple components.
Sub-congenic analysis of NOD mice congenic for Iddl6 region on chromosome 17 revealed that Iddl6 consists of multiple components and one of them is located in class I K region.
Multi-center collaborative study team, termed the Japanese Study Group on Type 1 Diabetes Genetics was established and made it possible to perform large-scale genetic association studies with sufficient power on candidate genes for type 1 diabetes. Taking advantage of these valuable resources, contribution of INS, CTLA4, PTPN22 and SUMO4 on susceptibility to type 1 diabetes in Japanese was confirmed. The data generated from the present study provides valuable information on genetics of diabetes for future development of tailored medicine in the treatment of diabetes mellitus.

Research Products

• [Journal Article] Prevention and treatment of obesity, insulin resistance and diabetes by bile acid binding resin. (2007)
  • Author(s): Kobayashi M, Ikegami H et al.
  • Journal Title: Diabetes 56 Pages: 239-247
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Prevention and treatment of obesity, insulin resistance and diabetes by bile acid binding resin. (2007)
  • Author(s): Kobayashi M, Ikegami H, Fujisawa T, Nojima K, Kawabata Y, Noso S, Babaya N, Itoi-Babaya M, Yamaji K, Hiromine Y, Shibata M, Ogihara T
  • Journal Title: Diabetes 56 Pages: 239-247
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prevention and treatment of obesity, insulin resistance and diabetes by bile acid binding resin. (2007)
  • Author(s): Kobayashi M, Ikegami H. et al.
  • Journal Title: Diabetes 56 Pages: 239-247
• [Journal Article] Insulin gene/IDDM2 locus in Japanese type 1 diabetes : contribution of class I alleles and influence of class I subdivision in susceptibility to type 1 diabetes. (2007)
  • Author(s): Awata T, Kawasaki E, Ikegami H et al.
  • Journal Title: J Clin Endocrinol Metab (印刷中)
• [Journal Article] Molecular scanning of IL-21 gene and genetic susceptibility to type 1 diabetes. (2007)
  • Author(s): Asano K, Ikegami H et al.
  • Journal Title: Hum Immunol (印刷中)
• [Journal Article] The association of CTLA4 polymorphism with type 1 diabetes is concentrated in patients complicated with autoimmune thyroid disease : a multi-center collaborative study in Japan (2006)
  • Author(s): Ikegami H et al.
  • Journal Title: J Clin Endocrinol Metab 91 Pages: 1087-1092
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Japanese Study Group on Type 1 Diabetes Genetics : The association of CTLA4 polymorphism with type 1 diabetes is concentrated in patients complicated with autoimmune thyroid disease : a multi-center collaborative study in Japan. (2006)
  • Author(s): Ikegami H, Awata T, Kawasaki E, Kobayashi T, Maruyama T, Nakanishi K, Shimada A, Amemiya S, Kawabata Y, Kurihara S, Tanaka S, Kanazawa Y, Mochizuki M, Ogihara T
  • Journal Title: J Clin Endocrinol Metab 91 Pages: 1087-1092
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Major quantitative trait locus on chromosome 2 for glucose tolerance in diabetic SMXA-5 mouse established from nondiabetic SM/J and A/J strains. (2006)
  • Author(s): Kobayashi M et al.
  • Journal Title: Diabetologia 49 Pages: 486-495
• [Journal Article] Evidence for the role of small ubiquitin-like modifier 4 (SUMO4) as a general autoimmunity locus in Japanese population. (2006)
  • Author(s): Tsurumaru M et al.
  • Journal Title: J Clin Endocrinol Metab 91 Pages: 3138-3143
• [Journal Article] The association of CTLA4 polymorphism with type 1 diabetes is concentrated in patients complicated with autoimmune thyroid disease : a multi-center collaborative study in Japan. (2006)
  • Author(s): Ikegami H et al.
  • Journal Title: J Clin Endocrinol Metab (in press)
• [Journal Article] Common genetic bases between type 1 and type 2 diabetes mellitus indicated by interview-based assessment of family history. (2006)
  • Author(s): Fujisawa T, Ikegami H, et al.
  • Journal Title: Diab Res Clin Prac 66S Pages: 91-95
• [Journal Article] Genetics of type 1 diabetes : similarities and differences between Asian and Caucasian populations. (2006)
  • Author(s): Ikegami H, et al.
  • Journal Title: Ann NY Acad Sci (in press)
• [Journal Article] Genetic heterogeneity in association of SUMO4 M55V variant with susceptibility to type 1 diabetes. (2005)
  • Author(s): Noso S, Ikegami H et al.
  • Journal Title: Diabetes 54 Pages: 3582-3586
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Evidence for Cd101 but not Fcgr1 as candidate for type 1 diabetes locus, Idd10. (2005)
  • Author(s): Yamaji K, Ikegami H et al.
  • Journal Title: Biochem Biophys Res Commun 331 Pages: 536-542
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Susceptibility to streptozotocin-induced diabetes is mapped to mouse chromosome 11. (2005)
  • Author(s): Babaya N, Ikegami H, et al.
  • Journal Title: Biochem Biophys Res Commun 328 Pages: 158-164
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genetic heterogeneity in association of SUMO4 M55V variant with susceptibility to type 1 diabetes. (2005)
  • Author(s): Noso S, Ikegami H, Fujisawa T, Kawabata Y, Asano K, Hiromine Y, Tsurumaru M, Sugihara S, Lee I, Kawasaki E, Awata T, Ogihara T
  • Journal Title: Diabetes 54 Pages: 3582-3586
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Evidence for Cd101 but not Fcgrl as candidate for type 1 diabetes locus, Idd10. (2005)
  • Author(s): Yamaji K, Ikegami H, Fujisawa T, Noso S, Nojima K, Babaya N, Itoi-Babaya M, Makino S, Sakamoto T, Ogihara T
  • Journal Title: Biochem Biophys Res Commun 331 Pages: 536-542
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Susceptibility to streptozotocin-induced diabetes is mapped to mouse chromosome 11. (2005)
  • Author(s): Babaya N, Ikegami H, Fujisawa T, Nojima K, Itoi-Babaya M, Inoue K, Ohno T, Shibata M, Ogihara T
  • Journal Title: Biochem Biophys Res Commun 328 Pages: 158-164
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional polymorphism in Z-DNA-forming motif of promoter of SLC11A1 gene and type 1 diabetes in Japanese subjects. (2005)
  • Author(s): Nishino M, Ikegami H, et al.
  • Journal Title: Metabolism 54 Pages: 628-633
• [Journal Article] Effect of two alfa-glucosidase inhibitors, voglibose and acarbose, on postprandial hyperglycemia correlates with subjective abdominal symptoms. (2005)
  • Author(s): Fujisawa T, Ikegami H, et al.
  • Journal Title: Metabolism 54 Pages: 387-390
• [Journal Article] Idd1 and Idd3 are necessary but not sufficient for development of type 1 diabetes in NOD mouse. (2005)
  • Author(s): Ikegami H, et al.
  • Journal Title: Diab Res Clin Prac 66S Pages: 85-90
• [Journal Article] Association of Pro12Ala polymorphism of PPAR γ gene with insulin resistance and related diseases. (2005)
  • Author(s): Horiki M, Ikegami H et al.
  • Journal Title: Diab Res Clin Prac 66S Pages: 63-67
• [Journal Article] Improvement of liver function parameters in patients with type 2 diabetes treated with thiazolidinediones. (2005)
  • Author(s): Ono M, Ikegami H, et al.
  • Journal Title: Metabolism 54 Pages: 529-532
• [Journal Article] Combination of half doses of angiotensin type 1 receptor antagonist and angiotensin converting enzyme inhibitor in diabetic nephropathy. (2005)
  • Author(s): Fujisawa T, Ikegami H, et al.
  • Journal Title: Am J Hypertens 18 Pages: 13-17
• [Journal Article] Allelic variation in class I K gene as candidate for second component of MHC-linked susceptibility to type 1 diabetes in NOD mouse. (2004)
  • Author(s): Inoue K, Ikegami H et al.
  • Journal Title: Diabetologia 47 Pages: 739-747
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Allelic variation in class I K gene as candidate for second component of MHC-linked susceptibility to type 1 diabetes in NOD mouse. (2004)
  • Author(s): Inoue K, Ikegami H, Fujisawa T, Noso S, Nojima K, Babaya N, Itoi-Babaya M, Makino S, Ogihara T
  • Journal Title: Diabetologia 47 Pages: 739-747
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Allelic variation in class I K gene as candidate for a second of MHC-linked susceptibility to type 1 diabetes in non-obese diabetic mice (2004)
  • Author(s): Inoue K, Ikegami H, et al.
  • Journal Title: Diabetologia 47 Pages: 739-747
• [Journal Article] Idd1 and Idd3 are necessary but not sufficient for development of type 1 diabetes in NOD mouse. (2004)
  • Author(s): Ikegami H, et al.
  • Journal Title: Diabet Res Clin Pract 66(supple)
• [Journal Article] Functional polymorphism in Z-DNA-forming motif of promoter of SLC11A1 gene and type 1 diabetes in Japanese subjects. (2004)
  • Author(s): Nishino M, Ikegami H, et al.
  • Journal Title: Metabolism (in press)
• [Journal Article] A common polymorphism of uncoupling protein 2 gene is associated with hypertension. (2004)
  • Author(s): Ji Q, Ikegami H, et al.
  • Journal Title: J Hypertens 22 Pages: 97-102
• [Journal Article] Mouse model of type 1 and type 2 diabetes derived from the same closed colony : genetic susceptibility shared between two types of diabetes (2004)
  • Author(s): Ikegami H, et al.
  • Journal Title: ILAR Journal 45 Pages: 268-277