Identification of susceptibility genes for type 1 diabetes: whole-exome sequence analysis in rare multiplex families in Japanese

• Project/Area Number: 18K08530
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• 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, 准教授 (90460849)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: １型糖尿病 / 遺伝子 / 分子遺伝学 / 次世代シークエンス / 濃厚家系 / ゲノムワイド関連解析 / rare variant / common variant / 全エクソ－ムシークエンス / ※１型糖尿病

Outline of Final Research Achievements

To clarify pathogenesis of type 1 diabetes for the development of effective methods for prediction, prevention and cure of type 1 diabetes, we performed molecular genetic analysis of type 1 diabetes by using two approaches. 1) Common variants: genome-wide association study on fulminant type 1 diabetes, 2) Rare variants: whole-exome sequencing in rare multiplex families with type 1 diabetes in Japanese population. GWAS identified two loci associated with fulminant type 1 diabetes with genome-wide significance: HLA on chromosome 6 and CSAD/lnc-ITGB7-1 on chromosome 12q13.13. In multiplex families, existence of two categories of susceptibility genes, genes specific to each family and genes common in multiple families, were found to be present, indicating the importance of precision medicine based on susceptibility genes in each family.

Academic Significance and Societal Importance of the Research Achievements

欧米ではほとんど認めない我が国固有の劇症１型糖尿病のGWASで今回初めて同定した遺伝子は、１型糖尿病の劇症化や日本人固有の膵β細胞脆弱性に関する情報を提供する。また我が国では極めて稀な１型糖尿病濃厚発症家系におけるrare variantの同定は寄与率の高い遺伝子の機能解析を通じて１型糖尿病発症の根本に関する基盤情報を提供する。これらの成果は１型糖尿病の予知・予防・根治に不可欠の基盤情報であり、１型糖尿病の根本解決に資することが期待される。

Research Products

• [Journal Article] Glucose Metabolism After Pancreatectomy: Opposite Extremes Between Pancreaticoduodenectomy and Distal Pancreatectomy (2021)
  • Author(s): Niwano Fumimaru、Babaya Naru、Hiromine Yoshihisa、Matsumoto Ippei、Kamei Keiko、Noso Shinsuke、Taketomo Yasunori、Takeyama Yoshifumi、Kawabata Yumiko、Ikegami Hiroshi
  • Journal Title: The Journal of Clinical Endocrinology & Metabolism Volume: - Issue: 5 Pages: e2203-e2214
  • DOI: 10.1210/clinem/dgab036
  • Peer Reviewed / Open Access
• [Journal Article] Relationship of continuous glucose monitoring-related metrics with HbA1c and residual β-cell function in Japanese patients with type 1 diabetes (2021)
  • Author(s): Babaya Naru、Noso Shinsuke、Hiromine Yoshihisa、Taketomo Yasunori、Niwano Fumimaru、Yoshida Sawa、Yasutake Sara、Kawabata Yumiko、Ikegami Hiroshi
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 4006-4006
  • DOI: 10.1038/s41598-021-83599-x
  • Peer Reviewed / Open Access
• [Journal Article] The SAGE study: Global observational analysis of glycaemic control, hypoglycaemia and diabetes management in T1DM (2021)
  • Author(s): Renard Eric、Ikegami Hiroshi、Daher Vianna Andr? Gustavo、Pozzilli Paolo、Brette Sandrine、Bosnyak Zsolt、Lauand Felipe、Peters Anne、Pilorget Valerie、Juri?i?‐Er?en Dubravka、Kesavadev Jothydev、Seufert Jochen、Wilmot Emma G.
  • Journal Title: Diabetes/Metabolism Research and Reviews Volume: - Issue: 7
  • DOI: 10.1002/dmrr.3430
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Glycemic Control and Insulin Improve Muscle Mass and Gait Speed in Type 2 Diabetes: The MUSCLES-DM Study (2021)
  • Author(s): Sugimoto Ken、Ikegami Hiroshi、Takata Yasunori、Katsuya Tomohiro、Fukuda Masahiro、Akasaka Hiroshi、Tabara Yasuharu、Osawa Haruhiko、Hiromine Yoshihisa、Rakugi Hiromi
  • Journal Title: Journal of the American Medical Directors Association Volume: 22 Issue: 4 Pages: 834-838.e1
  • DOI: 10.1016/j.jamda.2020.11.003
  • NAID: 120006952199
  • Peer Reviewed / Open Access
• [Journal Article] A Rare Case of Adrenal Cysts Associated With Bilateral Incidentalomas and Diffuse Hyperplasia of the Zona Glomerulosa (2020)
  • Author(s): Babaya Naru、Okuda Yuki、Noso Shinsuke、Hiromine Yoshihisa、Taketomo Yasunori、Niwano Fumimaru、Ueda Kazuki、Tanaka Yumiko、Yamazaki Yuto、Sasano Hironobu、Kawabata Yumiko、Ohno Yasuhiro、Ikegami Hiroshi
  • Journal Title: Journal of the Endocrine Society Volume: 5 Issue: 2
  • DOI: 10.1210/jendso/bvaa184
  • Peer Reviewed / Open Access
• [Journal Article] Clinical and genetic determinants of urinary glucose excretion in patients with diabetes mellitus (2020)
  • Author(s): Monobe Keisuke、Noso Shinsuke、Babaya Naru、Hiromine Yoshihisa、Taketomo Yasunori、Niwano Fumimaru、Yoshida Sawa、Yasutake Sara、Minohara Tatsuro、Kawabata Yumiko、Ikegami Hiroshi
  • Journal Title: Journal of Diabetes Investigation Volume: - Issue: 5 Pages: 728-737
  • DOI: 10.1111/jdi.13417
  • Peer Reviewed / Open Access
• [Journal Article] Type 2 diabetes susceptibility genes on mouse chromosome 11 under high sucrose environment (2020)
  • Author(s): Kobayashi Misato、Ueda Hironori、Babaya Naru、Itoi-Babaya Michiko、Noso Shinsuke、Fujisawa Tomomi、Horio Fumihiko、Ikegami Hiroshi
  • Journal Title: BMC Genetics Volume: 21 Issue: 1
  • DOI: 10.1186/s12863-020-00888-6
  • Peer Reviewed / Open Access
• [Journal Article] Flash glucose monitoring in type 1 diabetes: A comparison with self‐monitoring blood glucose (2020)
  • Author(s): Babaya Naru、Noso Shinsuke、Hiromine Yoshihisa、Taketomo Yasunori、Niwano Fumimaru、Yoshida Sawa、Yasutake Sara、Kawabata Yumiko、Ikegami Hiroshi
  • Journal Title: Journal of Diabetes Investigation Volume: - Issue: 5 Pages: 1222-1229
  • DOI: 10.1111/jdi.13229
  • Peer Reviewed / Open Access
• [Journal Article] Conditions, pathogenesis, and progression of diabetic kidney disease and early decliner in Japan (2020)
  • Author(s): Yoshida Y, Kashiwabara K, Hirakawa Y, Tanaka T, Noso S, Ikegami H, Ohsugi M, Ueki K, Mita T, Watada H, Koya D, Mise K, Wada J, Shimizu M, Wada T, Ito Y, Narita I, Kashihara N, Nangaku M, Matsuyama Y
  • Journal Title: BMJ Open Diabetes Research & Care Volume: 8 Issue: 1 Pages: 1-8
  • DOI: 10.1136/bmjdrc-2019-000902
  • Peer Reviewed / Open Access
• [Journal Article] Recommendations on the proper use of SGLT2 inhibitors (2020)
  • Author(s): The Committee on the Proper Use of SGLT2 Inhibitors (Abiru N, Ikegami H, Inagaki N, Ueki K, Kaku K, Kadowaki T, Sato S, Seino Y, Haneda M)
  • Journal Title: Diabetology International Volume: 11 Issue: 1 Pages: 1-5
  • DOI: 10.1007/s13340-019-00415-8
  • Peer Reviewed / Open Access
• [Journal Article] Contribution of Asian Haplotype of KCNJ18 to Susceptibility to and Ethnic Differences in Thyrotoxic Periodic Paralysis (2019)
  • Author(s): Noso Shinsuke、Babaya Naru、Hiromine Yoshihisa、Ito Hiroyuki、Taketomo Yasunori、Yoshida Sawa、Niwano Fumimaru、Monobe Keisuke、Minohara Tatsuro、Okada Takuya、Tsugawa Mamiko、Kawabata Yumiko、Ikegami Hiroshi
  • Journal Title: The Journal of Clinical Endocrinology & Metabolism Volume: 104 Issue: 12 Pages: 6338-6344
  • DOI: 10.1210/jc.2019-00672
  • Peer Reviewed / Open Access
• [Journal Article] Hyperglycemia in non-obese patients with type 2 diabetes is associated with low muscle mass: The MUSCLES-DM study. (2019)
  • Author(s): Sugimoto K, Tabara Y, Ikegami H, Takata Y, Kamide K, Ikezoe T, Kiyoshige E, Makutani Y, Onuma H, Gondo Y, Ikebe K, Ichihashi N, Tsuboyama T, Matsuda F, Kohara K, Kabayama M, Fukuda M, Katsuya T, Osawa H, Hiromine Y, Rakugi H.
  • Journal Title: J Diabetes Investig. Volume: 10: Issue: 6 Pages: 1471-1479
  • DOI: 10.1111/jdi.13070
  • Peer Reviewed / Open Access
• [Journal Article] Fulminant type 1 diabetes associated with Isolated ACTH deficiency induced by anti-programmed cell death 1 antibody—insight into the pathogenesis of autoimmune endocrinopathy— (2019)
  • Author(s): Okahata S, Sakamoto K, Mitsumatsu T, Kondo Y, Noso S, Ikegami H, Shiba T
  • Journal Title: Endocrine Journal Volume: 66 Issue: 4 Pages: 295-300
  • DOI: 10.1507/endocrj.EJ18-0328
  • NAID: 130007636467
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] Genome-Wide Association Study Confirming a Strong Effect of HLA and Identifying Variants in CSAD/lnc-ITGB7-1 on Chromosome 12q13.13 Associated With Susceptibility to Fulminant Type 1 Diabetes. (2019)
  • Author(s): Kawabata Y, Nishida N, Awata T, Kawasaki E, Imagawa A, Shimada A, Osawa H, Tanaka S, Takahashi K, Nagata M, Yasuda H, Uchigata Y, Kajio H, Makino H, Yasuda K, Kobayashi T, Hanafusa T, Tokunaga K, Ikegami H.
  • Journal Title: Diabetes Volume: 68 Issue: 3 Pages: 665-675
  • DOI: 10.2337/db18-0314
  • NAID: 40022000187
  • Peer Reviewed / Open Access
• [Journal Article] Diffusion-weighted Magnetic Resonance Imaging in the Pancreas of Fulminant Type 1 Diabetes (2018)
  • Author(s): 日本１型糖尿病の成因，診断，病態，治療に関する調査研究委員会（徳永あゆみ、今川彰久、西尾博、早田敏、下村伊一郎、阿比留教生、粟田卓也、池上博司、内潟安子、及川洋一、大澤春彦、梶尾裕、川﨑英二、川畑由美子、小澤純二、島田朗、高橋和眞、田中昌一郎、中條大輔、福井智康、三浦順之助、安田和基、安田尚史、小林哲郎、花房俊昭）
  • Journal Title: Journal of the Japan Diabetes Society Volume: 61 Issue: 12 Pages: 840-849
  • DOI: 10.11213/tonyobyo.61.840
  • NAID: 130007599010
  • ISSN: 0021-437X, 1881-588X
  • Year and Date: 2018-12-30
  • Peer Reviewed / Open Access
• [Journal Article] Early-Onset Diabetes Mellitus in a Patient With a Chromosome 13q34qter Microdeletion Including IRS2. (2018)
  • Author(s): Babaya N, Noso S, Hiromine Y, Ito H, Taketomo Y, Yamamoto T, Kawabata Y, Ikegami H.
  • Journal Title: J Endocr Soc. Volume: 11 Issue: 10 Pages: 1207-1213
  • DOI: 10.1210/js.2018-00175
  • Peer Reviewed / Open Access
• [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] Characteristics and clinical course of type 1 diabetes mellitus related to anti-programmed cell death-1 therapy. (2018)
  • Author(s): Baden MY, Imagawa A, Abiru N, Awata T, Ikegami H, Uchigata Y, Oikawa Y, Osawa H, Kajio H, Kawasaki E, Kawabata Y, Kozawa J, Shimada A, Takahashi K, Tanaka S, Chujo D, Fukui T, Miura J, Yasuda K, Yasuda H, Kobayashi T, Hanafusa T
  • Journal Title: Diabetol Int. Volume: 10 Issue: 1 Pages: 58-66
  • DOI: 10.1007/s13340-018-0362-2
  • NAID: 40021806480
  • Peer Reviewed / Open Access
• [Journal Article] Verification That Mouse Chromosome 14 Is Responsible for Susceptibility to Streptozotocin in NSY Mice. (2018)
  • Author(s): Babaya N, Ueda H, Noso S, Hiromine Y, Itoi-Babaya M, Kobayashi M, Fujisawa T, Ikegami H.
  • Journal Title: Int J Endocrinol. Volume: 21 Pages: 7654979-7654979
  • DOI: 10.1155/2018/7654979
  • Peer Reviewed / Open Access
• [Journal Article] Diffusion-weighted magnetic resonance imaging in the pancreas of fulminant type 1 diabetes (2018)
  • Author(s): Tokunaga A, Imagawa A, Nishio H, Hayata S, Shimomura I, Abiru N, Awata T, Ikegami H, Uchigata Y, Oikawa Y, Osawa H, Kajio H, Kawasaki E, Kawabata Y, Kozawa J, Shimada A, Takahashi K, Tanaka S, Chujo D, Fukui T, Miura J, Yasuda K, Yasuda H, Kobayashi T, Hanafusa T
  • Journal Title: Diabetology International Volume: 9 Pages: 257-265
  • NAID: 40021687155
  • 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
• [Presentation] Pathogenesis and treatment of insulin-dependent state (2018)
  • Author(s): Ikegami H
  • Organizer: the XiJing Diabetes and Endocrine Forum
  • Invited