Identification of susceptibility genes for autoimmunity and beta-cell specificity of type 1 diabetes

• Project/Area Number: 15K09404
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kindai University
• Principal Investigator: IKEGAMI Hiroshi 近畿大学, 医学部, 教授 (20221062)
• Co-Investigator(Kenkyū-buntansha): 馬場谷 成 近畿大学, 医学部, 講師 (10449837) ; 廣峰 義久 近畿大学, 医学部, 講師 (30460851) ; 川畑 由美子 近畿大学, 医学部, 准教授 (80423185) ; 能宗 伸輔 近畿大学, 医学部, 講師 (90460849)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: １型糖尿病 / 自己免疫 / 遺伝子 / 疾患感受性 / 臓器特異性 / 自己免疫疾患 / 免疫寛容 / バセドウ病 / 円形脱毛症 / 標的臓器

Outline of Final Research Achievements

The purpose of this study was to identify genes responsible for both autoimmuninty and organ-specificity of type 1 diabetes. Type 1 diabetes and autoimmune thyroid diseases (AITD), alopecia areata and AITD, are often develop in the same individuals, whereas type 1 diabetes and AA are very rare to be observed in the same individuals. HLA-DR4 haplotype (DRB1*04:05-DQB1*04:01) was found to be responsible for beta-cell specificity in autoimmune diseases. targeted disruption of MafA in NOD mice resulted in protection, but not accerelation, of beta-cell autoimmunity and type 1 diabetes. Accumulation of regulatory T-cells in insulitis legion was suggested to be possible mechanism of protection from beta-cell autoimmunity and type 1 diabetes.

Research Products

• [Journal Article] Congenic mapping and candidate gene analysis for streptozotocin-induced diabetes susceptibility locus on mouse chromosome 11 (2018)
  • Author(s): Maegawa Tomoki、Miyasaka Yuki、Kobayashi Misato、Babaya Naru、Ikegami Hiroshi、Horio Fumihiko、Takahashi Masahide、Ohno Tamio
  • Journal Title: Mammalian Genome Volume: 29 Issue: 3-4 Pages: 273-280
  • DOI: 10.1007/s00335-018-9742-y
  • NAID: 120006517666
  • Peer Reviewed / Open Access
• [Journal Article] Insulin deficiency with and without glucagon: A comparative study between total pancreatectomy and type 1 diabetes. (2018)
  • Author(s): Niwano F, Hiromine Y, Noso S, Babaya N, Ito H, Yasutake S, Matsumoto I, Takeyama Y, Kawabata Y, Ikegami H.
  • Journal Title: J Diabetes Investig. Volume: 9 Issue: 5 Pages: 1084-1090
  • DOI: 10.1111/jdi.12799
  • Peer Reviewed / Open Access
• [Journal Article] Effects of dosage and dosing frequency on the efficacy and safety of high-dose metformin in Japanese patients with type 2 diabetes mellitus. (2018)
  • Author(s): Kanto K, Ito H, Noso S, Babaya N, Hiromine Y, Taketomo Y, Toma J, Niwano F, Yasutake S, Kawabata Y, Ikegami H.
  • Journal Title: J Diabetes Investig. Volume: 9 Issue: 3 Pages: 587-593
  • DOI: 10.1111/jdi.12755
  • Peer Reviewed / Open Access
• [Journal Article] 自己免疫疾患の標的臓器を決定する因子 －なぜ膵β細胞だけが攻撃されるのか－ (2018)
  • Author(s): 池上博司、能宗伸輔、川畑由美子
  • Journal Title: 日本体質医学会雑誌 Volume: 80
  • NAID: 40021496848
  • Peer Reviewed
• [Journal Article] Common phenotype and different non-HLA genes in Graves' disease and alopecia areata (2017)
  • Author(s): Taketomo Y, Noso S, Babaya M, Hiromine Y, Ito H, Kanto K, Niwano F, Oiso N, Kawada A, Kawabata Y, Ikegami H
  • Journal Title: Hum Immunol Volume: 78 Issue: 2 Pages: 185-189
  • DOI: 10.1016/j.humimm.2016.10.019
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A rare HLA genotype in two siblings with type 1 diabetes in a Japanese family clustered with type 1 diabetes (2017)
  • Author(s): Ina Y, Kawabata Y, Sakamoto R, Sekiguchi N and Ikegami H
  • Journal Title: J Diabetes Investig Volume: 印刷中 Issue: 6 Pages: 762-765
  • DOI: 10.1111/jdi.12628
  • Peer Reviewed / Open Access
• [Journal Article] Clinical features of cases of seroconversion of anti-glutamic acid decarboxylase antibody during the clinical course of type 2 diabetes: a nationwide survey in Japan (2017)
  • Author(s): Oikawa Y, Shimada A, Awata T, Fukui T, Ikegami H, Imagawa A, Kajio H, Kawabata Y, Kawasaki E, Miura J, Osawa H, Takahashi K, Tanaka S, Uchigata Y, Yasuda H, Yasuda K, Hanafusa T, Kobayashi T
  • Journal Title: Diabetol Int Volume: 8 Issue: 3 Pages: 306-315
  • DOI: 10.1007/s13340-017-0312-4
  • NAID: 40021293601
  • Peer Reviewed / Open Access
• [Journal Article] A case of fulminant type 1 diabetes mellitus with a precipitous decrease in pancreatic volume, induced by nivolmab for malignant melanoma: analysis of HLA and CTLA4 porymorphism. (2017)
  • Author(s): Ishikawa K, Shono-Saito T, Yamate T, Kai Y, Sakai T, Shimizu F, Yamada Y, Mori H, Noso S, Ikegami H, Kojima H, Tanaka H, Fujiwara S, Hatano Y
  • Journal Title: Eur J Dermatol Volume: 27 Issue: 2 Pages: 184-185
  • DOI: 10.1684/ejd.2016.2923
  • Peer Reviewed / Open Access
• [Journal Article] Case report: schwannoma arising from the unilateral adrenal area with bilateral hyperaldosteronism. (2017)
  • Author(s): Babaya N, Makutani Y, Noso S, Hiromine Y, Ito H, Taketomo Y, Ueda K, Ushijima H, Komoike Y, Yamazaki Y, Sasano H, Kawabata Y, Ikegami H.
  • Journal Title: BMC Endocr Disord. Volume: 17 Issue: 1 Pages: 74-74
  • DOI: 10.1186/s12902-017-0225-z
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and Genetic Characteristics of Non-Insulin-Requiring Glutamic Acid Decarboxylase (GAD) Autoantibody-Positive Diabetes: A Nationwide Survey in Japan (2016)
  • Author(s): Yasui J, Kawasaki E, Tanaka S, Awata T, Ikegami H, Imagawa A, Uchigata Y, Osawa H, Kajio H, Kawabata Y, Shimada A, Takahashi K, Yasuda K, Yasuda H, Hanafusa T, Kobayashi T, Japan Diabetes Society Committee on Type 1 Diabetes Mellitus Research
  • Journal Title: PLoS ONE Volume: 11 Issue: 5 Pages: 1-12
  • DOI: 10.1371/journal.pone.0155643
  • Peer Reviewed / Open Access
• [Journal Article] Risk factors of sudden death and cardiac arrest at the onset of fulminant type 1 diabetes mellitus. (2016)
  • Author(s): Yamaguchi aden MY, Imagawa A, Iwahashi H, Shimomura I, Awata T, Ikegami H, Uchigata Y, Osawa H, Kajio H, Kawasaki E, Kawabata Y, Shimada A, Takahashi K, Tanaka S, Yasuda K, Yasuda H, Kobayashi T, Hanafusa T
  • Journal Title: Diabetology Int Volume: なし Issue: 3 Pages: 281-288
  • DOI: 10.1007/s13340-015-0247-6
  • Peer Reviewed / Open Access
• [Journal Article] Immune checkpoint therapy and type 1 diabetes (2016)
  • Author(s): Ikegami H, Kawabata Y, Noso S
  • Journal Title: Diabetol Int Volume: 7 Issue: 3 Pages: 221-227
  • DOI: 10.1007/s13340-016-0276-9
  • NAID: 40020934033
  • Peer Reviewed
• [Journal Article] Organ specificity in autoimmune diseases: thyroid and islet autoimmunity in alopecia areata. (2015)
  • Author(s): Noso S, Park C, Babaya N, Hiromine Y, Harada T, Ito H, Taketomo Y, Oiso N, Kawada A, Suzuki T, Kawabata Y, Ikegami H
  • Journal Title: J Clin Endocrinol Metab Volume: 100 Issue: 5 Pages: 1976-1983
  • DOI: 10.1210/jc.2014-3985
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Low PD-1 expression in peripheral CD4+ T-cells in Japanese patients with autoimmune type 1 diabetes. (2015)
  • Author(s): Fujisawa R, Haseda F, Tsutsumi C, Hiromine Y, Noso S, Kawabata Y, Mitsui S, Terasaki J, Ikegami H, Imagawa A, Hanafusa T.
  • Journal Title: Clin Exp Immunol Volume: Feb 12 Issue: 3 Pages: 452-457
  • DOI: 10.1111/cei.12603
  • Peer Reviewed / Open Access
• [Presentation] Identification of genetic variants co-segregated with islet-autoimmunity in multiplex families of type 1 diabetes by genome-wide exome analysis (2017)
  • Author(s): Noso S, Hosomichi K, Hiromine Y, Ito H, Taketomo Y, Kawabata Y, Ikegami H
  • Organizer: Immunology of Diabetes Society, 15th International Congress 2017
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2017-01-20
  • Int'l Joint Research
• [Presentation] Whole-exome sequencing in rare families identified novel genetic variants for familial type 1 diabetes (2017)
  • Author(s): Noso S, Hosomichi K, Babaya N, Hiromine Y, Ito H, Taketomo Y, Kawabata Y, Ikegami H
  • Organizer: 53rd Annual Meeting of the European Association for the Study of Diabetes
  • Int'l Joint Research
• [Presentation] Insulin dependency with and without glucagon: marked difference in insulin requirement between patients with total pancreatectomy and type 1 diabetes (2017)
  • Author(s): Hiromine Y, Noso S, Babaya N, Ito H, Niwano F, Matsumoto I, Takeyama Y, Kawabata Y, Ikegami H
  • Organizer: 53rd Annual Meeting of the European Association for the Study of Diabetes
  • Int'l Joint Research
• [Presentation] 糖尿病の体質：予防と治療の個別化へむけて (2015)
  • Author(s): 池上博司
  • Organizer: 第65回日本体質医学会総会 シンポジウム
  • Place of Presentation: 札幌（札幌コンベンションセンター）
  • Year and Date: 2015-07-04
• [Presentation] １型糖尿病の遺伝：common variantからrare variantまで (2015)
  • Author(s): 川畑由美子、能宗伸輔、池上博司
  • Organizer: 第58回日本糖尿病学会年次学術集会 シンポジウム
  • Place of Presentation: 下関（ぱしふぃっくびぃなす）
  • Year and Date: 2015-05-21
• [Presentation] Identification of genetic loci linked to type 1 diabetes susceptibility by linkage analysis with whole exome sequencing in clustered family (2015)
  • Author(s): Noso S, Kawabata Y, Babaya N, Hiromine Y, Hosomichi K, Ikegami H
  • Organizer: Immunology of Diabetes Society, 14th International Congress
  • Place of Presentation: Munich, Germany（Hilton Munich Park）
  • Year and Date: 2015-04-12
  • Int'l Joint Research