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Elucidation of pathophysiology and development of diagnosis method of non-alcoholic fatty liver disease by genomic and epigenomic analysis

Research Project

Project/Area Number 16K09781
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Metabolomics
Research InstitutionOsaka University

Principal Investigator

Hotta Kikuko  大阪大学, 医学部附属病院, 特任講師(常勤) (30360639)

Research Collaborator Nakajima Atsushi  横浜市立大学, 医学(系)研究科, 教授 (30326037)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords非アルコール性脂肪肝疾患 / RNAシークエンス / DNAメチル化 / 遺伝子共発現ネットワーク解析 / DMR / ネットワーク解析 / Co-methylation解析 / RNAシークエンシング / メチル化解析 / エクソンシークエンス / 次世代シークエンス / 遺伝子ネットワーク解析 / ゲノム / エピゲノム
Outline of Final Research Achievements

RNA-sequencing and subsequent weighted gene co-expression network analysis of non-alcoholic fatty liver disease (NAFLD) revealed 2 networks associated with NAFLD, one of which is a scale-free network with 4 hub genes and the other is a random network. The genomic region that is under epigenetic regulation during NAFLD progression were identified using differentially methylated region (DMR) analyses. The average values of topological overlap measures for the CpG matrix combining two different DMRs were calculated and two DMR networks correlated with the stages of fibrosis were identified. The annotated genes of one network included genes involved in fibrosis and cellular proliferation. The annotated genes of the second network were associated with metabolic pathways. The CpG methylation levels in these networks were strongly affected by age and fasting plasma glucose levels. The methylation status of five DMRs in the second network was reversible following weight loss.

Academic Significance and Societal Importance of the Research Achievements

非アルコール性脂肪肝疾患のゲノムワイドな発現解析、メチル化解析により病態進行に伴う変化が2-3個の遺伝子群に分類されることを明らかにすることが出来た。2-3個の遺伝子群の発現やメチル化レベルの変動には年齢、血糖値が重要であり、1つの遺伝子群は減量による可逆性が認められ、非アルコール性脂肪肝疾患における減量や血糖値コントロールの重要性が分子レベルで証明された。病態進行に関連する遺伝子群が少数のグループに分かれることから、メチル化レベルや発現量を調節する因子の存在が示唆された。それらの因子を同定することで新たな治療方法の開発が期待される結果となった。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (13 results)

All 2018 2017 2016

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 3 results,  Acknowledgement Compliant: 1 results) Presentation (9 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Identification of differentially methylated region (DMR) networks associated with progression of nonalcoholic fatty liver disease.2018

    • Author(s)
      Hotta K, Kitamoto A, Kitamoto T, Ogawa Y, Honda Y, Kessoku T, Yoneda M, Imajo K, Tomeno W, Saito S, Nakajima A
    • Journal Title

      Scientific Reports

      Volume: 8 Issue: 1 Pages: 13567-13567

    • DOI

      10.1038/s41598-018-31886-5

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of the genomic region under epigenetic regulation during non-alcoholic fatty liver disease progression.2018

    • Author(s)
      Hotta K, Kitamoto T, Kitamoto A, Ogawa Y, Honda Y, Kessoku T, Yoneda M, Imajo K, Tomeno W, Saito S, Nakajima A
    • Journal Title

      Hepatology Research

      Volume: 48 Issue: 3

    • DOI

      10.1111/hepr.12992

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Identification of core gene networks and hub genes associated with progression of nonalcoholic fatty liver disease by RNA sequencing2017

    • Author(s)
      Hotta K, Kikuchi M, Kitamoto T, Kitamoto A, Ogawa Y, Honda Y, Kessoku T, Kobayashi K, Yoneda, M, Imajo K, Tomeno W, Nakaya A, Suzuki Y, Saito S, and Nakajima A
    • Journal Title

      Hepatology Research

      Volume: 印刷中 Issue: 13 Pages: 1445-1448

    • DOI

      10.1111/hepr.12877

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] The characteristics of non-obese NAFLD: Effect of genetic and environmental factors.2016

    • Author(s)
      Honda Y, Yoneda M, Kessoku T, Ogawa Y, Tomeno W, Imajo K, Mawatari H, Fujita K, Hyogo H, Ueno T, Chayama K, Saito S, Nakajima A, Hotta K
    • Journal Title

      Hepatol Res

      Volume: - Issue: 10 Pages: 636-636

    • DOI

      10.1111/hepr.12648

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 非アルコール性脂肪肝疾患のゲノムワイドメチル化解析2018

    • Author(s)
      堀田紀久子、北本卓也、北本綾、小川祐二、本多靖、結束貴臣、米田正人、今城健人、中島淳
    • Organizer
      第61回日本糖尿病学会年次学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 非アルコール性脂肪肝疾患のゲノムワイドメチル化解析2018

    • Author(s)
      堀田紀久子、北本綾、北本卓也、小川祐二、本多靖、結束貴臣、米田正人、今城健人、留野渉、斉藤聡、中島淳
    • Organizer
      第39回日本肥満学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 非アルコール性脂肪肝疾患のゲノムワイドメチル化解析2018

    • Author(s)
      堀田紀久子、北本綾、北本卓也、小川祐二、本多靖、結束貴臣、米田正人、今城健人、留野渉、斉藤聡、中島淳
    • Organizer
      日本人類遺伝学会第63回大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 非アルコール性脂肪肝疾患の肝生検組織のRNAシークエン スと遺伝子共発現ネットワークの探索2017

    • Author(s)
      堀田紀久子,北本卓也,北本綾,小川祐二,本多靖, 米田正人,今城健人,鈴木穣,中島淳
    • Organizer
      第60 回日本糖尿病学会年次学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 非アルコール性脂肪肝疾患の肝生検組織のRNAシークエンスによる遺伝子共発現ネットワーク解析2017

    • Author(s)
      堀田紀久子、北本卓也、北本綾、小川祐二、本多靖、米田正人、今城健人、鈴木穣、中島淳
    • Organizer
      第38回日本肥満学会
    • Related Report
      2017 Research-status Report
  • [Presentation] 非アルコール性脂肪肝疾患の肝生検組織のRNAシークエンスと遺伝子共発現ネットワーク解析2017

    • Author(s)
      堀田紀久子、北本卓也、北本綾、小川祐二、本多靖、米田正人、今城健人、鈴木穣、中島淳
    • Organizer
      日本人類遺伝学会 第62回大会
    • Related Report
      2017 Research-status Report
  • [Presentation] CDH13遺伝子多型は内臓脂肪、アディポネクチン値と独立してメタボリックシンドロームに関連する2016

    • Author(s)
      堀田紀久子、和田淳、宮崎茂、徳永勝人、益崎裕章、浜口和之、山田研太郎、花房俊昭、及川眞一、田中喜代次、船橋徹、松澤佑次
    • Organizer
      第37回日本肥満学会
    • Place of Presentation
      東京ファッションタウン(東京都江東区)
    • Year and Date
      2016-10-07
    • Related Report
      2016 Research-status Report
  • [Presentation] CDH13とADIPOQ多型,内臓脂肪,アディポネクチン,メタボリックシンドロームとの関連2016

    • Author(s)
      堀田紀久子,小谷一晃,嶺尾郁夫,和田淳,宮崎滋,徳永勝人,益崎裕章,濱口和之,山田研太郎,花房俊昭,及川眞一,坂田利家,船橋徹,松澤佑次
    • Organizer
      第59 回日本糖尿病学会年次学術集会 会長
    • Place of Presentation
      京都国際会館(京都府京都市)
    • Year and Date
      2016-05-19
    • Related Report
      2016 Research-status Report
  • [Presentation] Targeted-bisulfite sequence analysis of the methylation of CpG islands in the PNPLA3, SAMM50, and PARVB of patients with nonalcoholic fatty liver disease: relationship to their mRNA expression and rs738409 genotype2016

    • Author(s)
      Hotta K, Ogawa Y, Honda Y, Imajo K, Sito S, Yoneda M, Nakajima A
    • Organizer
      The 13th International Congress of Human Genetics
    • Place of Presentation
      京都国際会館(京都府京都市)
    • Year and Date
      2016-04-03
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research

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Published: 2016-04-21   Modified: 2020-03-30  

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