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Development of the diagnostic methods to predict the development and the prognosis of autoimmune diseases based on the genome and epigenome informations

Research Project

Project/Area Number 17H04111
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Laboratory medicine
Research InstitutionOsaka University

Principal Investigator

IWATANI Yoshinori  大阪大学, 医学系研究科, 名誉教授 (60168581)

Co-Investigator(Kenkyū-buntansha) 日高 洋  大阪大学, 医学系研究科, 准教授 (30243231)
渡邉 幹夫  大阪大学, 医学系研究科, 教授 (50294088)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2019: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2018: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2017: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Keywords自己免疫疾患 / 甲状腺 / 病因・病態 / 発症予測 / 遺伝子多型 / エピジェネティクス / マイクロRNA / DNAメチル化 / IFNG遺伝子 / CD58遺伝子 / IL6遺伝子 / CD80/CD86遺伝子 / VEGF/VEGFR2遺伝子 / メチル化 / 自己免疫性甲状腺疾患 / 橋本病 / バセドウ病 / ゲノム / エピゲノム / TNFA遺伝子 / ヨードサイロニン脱ヨウ素酵素 / Th2走化性関連遺伝子 / Th17関連遺伝子 / 予後予測 / 甲状腺自己抗原 / TLR / IL-18 / miR-146 / miR-27A / Argonate / TNFαメチル化 / 予防医学 / 発症予知
Outline of Final Research Achievements

In order to develop the predictive diagnostic method for the development and prognosis of autoimmune disease, we examined genetic and epigenetic factors in autoimmune thyroid disease (AITD). Then, we found that gene polymorphisms of thyroid-specific antigens (Tg and TPO) and costimulatory molecules which induce regulatory T cells (CD58) and helper T (Th) cells (CD80/CD86) were the genetic factors for the development of AITD, and that micro RNA (miR-146a), which suppresses NF-κB activity via TRAF6, and DNA methylation of TNFA gene polymorphisms were the environmental factors for the disease development. On the other hand, we found that gene polymorphisms of various factors which regulate Th1 and Th17 cells (IL18, MIR27A, CRTH2, IL17F, IL15, TLR7/TLR9, AGO2 and et al.) were the genetic factors for the prognosis (severity) of AITD, and that DNA methylations of IFNG and IL6 genes were the epigenetic factors for the disease prognosis.

Academic Significance and Societal Importance of the Research Achievements

単純に疾患と健常人を比較する今までのゲノムワイド関連解析等で解明された自己免疫疾患の遺伝因子はオッズ比が低く、疾患の発症予測等には利用できない。そこで、疾患の病態分類を厳密かつ詳細に行って解析した結果、オッズ比の高い結果が得られた。さらに、疾患の発症には、遺伝因子以外に環境因子も関与しているため、環境因子の影響を受けて遺伝子の発現を変化させるエピジェネティック因子(micro RNA、DNAメチル化など)を解明することにした。そして、これらのエピジェネティック因子の解明により、有用な自己免疫疾患の発症・予後予測診断法の開発が可能になった。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (20 results)

All 2020 2019 2018 2017 2016 Other

All Journal Article (19 results) (of which Int'l Joint Research: 9 results,  Peer Reviewed: 19 results,  Open Access: 3 results,  Acknowledgement Compliant: 3 results) Remarks (1 results)

  • [Journal Article] Association of CD58 Polymorphisms and its Protein Expression with the Development and Prognosis of Autoimmune Thyroid Diseases.2020

    • Author(s)
      Yamamoto M, Watanabe M, Inoue N, Watanabe A, Ozaki H, Ohsaki M, Hidaka Y, Iwatani Y.
    • Journal Title

      Immunol Invest

      Volume: 49(1-2) Issue: 1-2 Pages: 106-119

    • DOI

      10.1080/08820139.2019.1659811

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Increases of CD80 and CD86 Expression on Peripheral Blood Cells and their Gene Polymorphisms in Autoimmune Thyroid Disease.2020

    • Author(s)
      Watanabe A, Inoue N, Watanabe M, Yamamoto M, Ozaki H, Hidaka Y, Iwatani Y.
    • Journal Title

      Immunol Invest

      Volume: 49(1-2) Issue: 1-2 Pages: 191-203

    • DOI

      10.1080/08820139.2019.1688343

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Gene polymorphisms of <i>VEGF</i> and <i>VEGFR2</i> are associated with the severity of Hashimoto’s disease and the intractability of Graves’ disease, respectively2020

    • Author(s)
      Okamoto M, Watanabe M, Inoue N, Ogawa K, Hidaka Y, Iwatani Y.
    • Journal Title

      Endocrine Journal

      Volume: 67 Issue: 5 Pages: 545-559

    • DOI

      10.1507/endocrj.EJ19-0480

    • NAID

      130007847996

    • ISSN
      0918-8959, 1348-4540
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Association of IFNG gene methylation in peripheral blood cells with the development and prognosis of autoimmune thyroid diseases.2019

    • Author(s)
      Hashimoto H, Watanabe M, Inoue N, Hirai N, Haga E, Kinoshita R, Hidaka Y, Iwatani Y.
    • Journal Title

      Cytokine

      Volume: 123 Pages: 154770-154770

    • DOI

      10.1016/j.cyto.2019.154770

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Association of IL6 gene methylation in peripheral blood cells with the development and prognosis of autoimmune thyroid diseases.2019

    • Author(s)
      Hirai N, Watanabe M, Inoue N, Kinoshita R, Ohtani H, Hidaka Y, Iwatani Y.
    • Journal Title

      Autoimmunity

      Volume: 52(7-8) Issue: 7-8 Pages: 251-255

    • DOI

      10.1080/08916934.2019.1669568

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Methylation levels of the TNFA gene are different between Graves’ and Hashimoto’s diseases and influenced by the TNFA polymorphism2018

    • Author(s)
      Morita Emi、Watanabe Mikio、Inoue Naoya、Hashimoto Hidemi、Haga Emi、Hidaka Yoh、Iwatani Yoshinori
    • Journal Title

      Autoimmunity

      Volume: 印刷中 Issue: 3 Pages: 118-125

    • DOI

      10.1080/08916934.2018.1448078

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Functional polymorphisms of the type 1 and type 2 iodothyronine deiodinase genes in autoimmune thyroid diseases2018

    • Author(s)
      Inoue, N., Watanabe, M., Katsumata, Y., Ishido, N., Hidaka, Y., Iwatani, Y.
    • Journal Title

      Immunol Invest

      Volume: 47 Issue: 5 Pages: 534-542

    • DOI

      10.1080/08820139.2018.1458861

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Association of the polymorphisms in Th2 chemotaxis-related genes with the development and prognosis of autoimmune thyroid diseases2018

    • Author(s)
      Omori N, Watanabe M, Inoue N, Taniguchi J, Hidaka Y, Iwatani Y
    • Journal Title

      Endocrine Journal

      Volume: 65 Issue: 8 Pages: 815-826

    • DOI

      10.1507/endocrj.EJ18-0050

    • NAID

      130007458402

    • ISSN
      0918-8959, 1348-4540
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Polymorphisms in Th17-related genes and the pathogenesis of autoimmune thyroid disease2018

    • Author(s)
      Kunisato T, Watanabe M, Inoue N, Okada A, Nanba T, Kobayashi W, Inoue Y, Katsumata Y, Omori N, Nobuhara T, Takemura K, Hidaka Y, Iwatani Y
    • Journal Title

      Autoimmunity

      Volume: 51 Issue: 7 Pages: 360-369

    • DOI

      10.1080/08916934.2018.1534963

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Genotype-Based Epigenetic Differences in Monozygotic Twins Discordant for Positive Antithyroglobulin Autoantibodies2018

    • Author(s)
      Watanabe Mikio、Takenaka Yoichi、Honda Chika、Osaka Twin Research Group、Iwatani Yoshinori
    • Journal Title

      Thyroid

      Volume: 28 Issue: 1 Pages: 110-123

    • DOI

      10.1089/thy.2017.0273

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Polymorphisms and expression of genes encoding Argonautes 1 and 2 in autoimmune thyroid diseases2018

    • Author(s)
      Tokiyoshi Ena、Watanabe Mikio、Inoue Naoya、Hidaka Yoh、Iwatani Yoshinori
    • Journal Title

      Autoimmunity

      Volume: 51 Issue: 1 Pages: 35-42

    • DOI

      10.1080/08916934.2017.1416468

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The IL15 +96522 A>T functional polymorphism is related to the differentiation of Th17 cells and the severity of Hashimoto’s disease.2017

    • Author(s)
      Arakawa, Y. Watanabe, M., Takemura, K., Inoue, N., Hidaka, Y., Iwatani, Y.
    • Journal Title

      International Journal of Immunogenetics

      Volume: 44 Issue: 2 Pages: 41-50

    • DOI

      10.1111/iji.12305

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Intraindividual variation of microRNA expression levels in plasma and peripheral blood mononuclear cells and the associations of these levels with the pathogenesis of autoimmune thyroid diseases.2017

    • Author(s)
      Otsu, H., Watanabe, M., Inoue, N., Masutani, R., Iwatani, Y.
    • Journal Title

      Clin Chem Lab Med

      Volume: 55 Issue: 5 Pages: 626-635

    • DOI

      10.1515/cclm-2016-0449

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Functional polymorphisms affecting Th1 differentiation are associated with the severity of autoimmune thyroid diseases2017

    • Author(s)
      Inoue Naoya、Watanabe Mikio、Nakaguchi Azusa、Ueda Daishi、Kawaguti Hayaka、Hidaka Yoh、Iwatani Yoshinori
    • Journal Title

      Endocrine Journal

      Volume: 64 Issue: 7 Pages: 695-703

    • DOI

      10.1507/endocrj.EJ16-0551

    • NAID

      130005866013

    • ISSN
      0918-8959, 1348-4540
    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Association of the polymorphisms in the gene encoding thyroglobulin with the development and prognosis of autoimmune thyroid disease2017

    • Author(s)
      Mizuma Tomoyo、Watanabe Mikio、Inoue Naoya、Arakawa Yuya、Tomari Saki、Hidaka Yoh、Iwatani Yoshinori
    • Journal Title

      Autoimmunity

      Volume: 50 Issue: 6 Pages: 386-392

    • DOI

      10.1080/08916934.2017.1344971

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Association of IL-10-Regulating MicroRNAs in Peripheral Blood Mononuclear Cells with the Pathogenesis of Autoimmune Thyroid Disease2017

    • Author(s)
      Takuse Yukina、Watanabe Mikio、Inoue Naoya、Ozaki Ritsuko、Ohtsu Hiroshi、Saeki Minori、Katsumata Yuka、Hidaka Yoh、Iwatani Yoshinori
    • Journal Title

      Immunological Investigations

      Volume: 46 Issue: 6 Pages: 590-602

    • DOI

      10.1080/08820139.2017.1322975

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The polymorphisms in the thyroid peroxidase gene were associated with the development of autoimmune thyroid disease and the serum levels of anti-thyroid peroxidase antibody2017

    • Author(s)
      Tomari Saki、Watanabe Mikio、Inoue Naoya、Mizuma Tomoyo、Yamanaka Chika、Hidaka Yoh、Iwatani Yoshinori
    • Journal Title

      Endocrine Journal

      Volume: 64 Issue: 10 Pages: 1025-1032

    • DOI

      10.1507/endocrj.EJ17-0191

    • NAID

      130006186082

    • ISSN
      0918-8959, 1348-4540
    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Frequency-specific genetic influence on inferior parietal lobule activation commonly observed during action observation and execution2017

    • Author(s)
      Araki Toshihiko、Onishi Mai、Yanagisawa Takufumi、Hirata Masayuki、Watanabe Yoshiyuki、Ogata Soshiro、Hayakawa Kazuo、Honda Chika、Watanabe Mikio、Iwatani Yoshinori、Yorifuji Shiro
    • Journal Title

      Scientific Reports

      Volume: 7 Issue: 1 Pages: 17660-17660

    • DOI

      10.1038/s41598-017-17662-x

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Polymorphisms in and expression of Toll-like receptors in autoimmune thyroid diseases.2016

    • Author(s)
      Inoue, N., Katsumata, Y., Watanabe, M., Ishido, N., Manabe, Y., Watanabe, A., Masutani, R., Hidaka, Y., Iwatani, Y.
    • Journal Title

      Autoimmunity

      Volume: 26 Issue: 3 Pages: 1-10

    • DOI

      10.1080/08916934.2016.1261835

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Remarks] 大阪大学大学院医学系研究科保健学専攻生体情報科学講座 予防診断学研究室

    • URL

      http://sahswww.med.osaka-u.ac.jp/~prevdiag/

    • Related Report
      2017 Annual Research Report

URL: 

Published: 2017-04-28   Modified: 2021-02-19  

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