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Search for the pathogenesis and drug target of atrial fibrillation based on ExWAS

Research Project

Project/Area Number 18H02803
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 53020:Cardiology-related
Research InstitutionTokyo Medical and Dental University

Principal Investigator

Furukawa Tetsushi  東京医科歯科大学, 難治疾患研究所, 教授 (80251552)

Co-Investigator(Kenkyū-buntansha) 竹内 純  東京医科歯科大学, 難治疾患研究所, 准教授 (10451999)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2019: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2018: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Keywords心房細動 / 全エクソン相関解析 / 自律神経 / マクロファージ / 炎症 / 酸化ストレス / 個別化医療 / 1塩基多型 / 全ゲノム関連解析 / 全エクソン関連解析
Outline of Final Research Achievements

Whole-exon association analysis (ExWAS) of atrial fibrillation (AF) yeiled two
rare single nucleotide polymorphisms (SNPs) with high odds ratios and amino acid substitutions. Then, we carried out in vitro analysis with cultured cells and in vivo with genome-edited mice. We showed that the AF-sensitive sall 3 SNP, which was identified in AF ExWAS performed in the elderly poses a risk of developing AF by causing abnormal differentiation of the autonomic nerves into sympathetic and parasympathetic. In terms of the AF-sensitive SNP of Tks5, which was identified in ExWAS in young people, is at risk of developing AF by enhancing the migration and infiltration of macrophage, resulting in induction of inflammation.

Academic Significance and Societal Importance of the Research Achievements

心房細動は最も多い不整脈であり(患者数約100万人)、高頻度に脳卒中(心原性脳塞栓)を合併し、寝たきりの原因となるため、その治療が喫緊の社会問題となっている。全ゲノム関連解析では、1塩基多型が遺伝子外に存在することが多く、疾患との関連が低いことで創薬シーズを同定するに至っていない。全エクソン関連解析を用いることにより、疾患との関連が高く、アミノ酸置換を有する変異を2つ同定した。その機能解析から、これまで知られていなかった心房細動の新たな病態発現機構、創薬シーズを同定でき、心房細動の新たな治療戦略に役立つことが期待できる。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (22 results)

All 2021 2020 2019 2018

All Journal Article (13 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 13 results,  Open Access: 11 results) Presentation (7 results) (of which Invited: 1 results) Book (2 results)

  • [Journal Article] Sparsely methylated mitochondrial cell free DNA released from cardiomyocytes contributes to systemic inflammatory response accompanied by atrial fibrillation2021

    • Author(s)
      Yamazoe Masahiro、Sasano Tetsuo、Ihara Kensuke、Takahashi Kentaro、Nakamura Wakana、Takahashi Naomi、Komuro Hiroaki、Hamada Satomi、Furukawa Tetsushi
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 5837-5837

    • DOI

      10.1038/s41598-021-85204-7

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Functional Role of the L396R Mutation of Tks5 Identified by an Exome-Wide Association Study in Atrial Fibrillation2020

    • Author(s)
      Yang Xiaoxi、Sasano Tetsuo、Ebana Yusuke、Takeuchi Jun K.、Ihara Kensuke、Yamazoe Masahiro、Furukawa Tetsushi
    • Journal Title

      Circulation Journal

      Volume: 84 Issue: 12 Pages: 2148-2157

    • DOI

      10.1253/circj.CJ-20-0101

    • NAID

      130007942473

    • ISSN
      1346-9843, 1347-4820
    • Year and Date
      2020-11-25
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells2020

    • Author(s)
      Higashijima Y, Matsui Y, Shimamura T, Nakaki R, Nagai N, Tsutsumi S, Abe Y, Link VM, Osaka M, Yoshida M, Watanabe R, Tanaka T, Taguchi A, Miura M, Ruan X, Li G, Inoue T, Nangaku M, Kimura H, Furukawa T, Aburatani H, Wada Y, Ruan Y, Glass CK, Kanki Y
    • Journal Title

      The EMBO Journal

      Volume: 39 Issue: 7 Pages: 1-1

    • DOI

      10.15252/embj.2019103949

    • NAID

      120006902140

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] In vitro generation of functional murine heart organoids via FGF4 and extracellular matrix2020

    • Author(s)
      Lee Jiyoung、Sutani Akito、Kaneko Rin、Takeuchi Jun、Sasano Tetsuo、Kohda Takashi、Ihara Kensuke、Takahashi Kentaro、Yamazoe Masahiro、Morio Tomohiro、Furukawa Tetsushi、Ishino Fumitoshi
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 4283-4283

    • DOI

      10.1038/s41467-020-18031-5

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A missense mutation in the RSRSP stretch of Rbm20 causes dilated cardiomyopathy and atrial fibrillation in mice2020

    • Author(s)
      Ihara K, Sasano T, Hiraoka Y, Togo-Ohno M, Soejima Y, Sawabe M, Tsuchiya M, Ogawa H, Furukawa T, Kuroyanagi H
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 17894-17894

    • DOI

      10.1038/s41598-020-74800-8

    • NAID

      120007031666

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lysine demethylase 7a regulates murine anterior-posterior development by modulating the transcription of Hox gene cluster2020

    • Author(s)
      Higashijima Yoshiki、Nagai Nao、Yamamoto Masamichi、Kitazawa Taro、Kawamura Yumiko K.、Taguchi Akashi、Nakada Natsuko、Nangaku Masaomi、Furukawa Tetsushi、Aburatani Hiroyuki、Kurihara Hiroki、Wada Youichiro、Kanki Yasuharu
    • Journal Title

      Communications Biology

      Volume: 3 Issue: 1 Pages: 725-725

    • DOI

      10.1038/s42003-020-01456-5

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mutant KCNJ3 and KCNJ5 potassium channels as novel molecular targets in bradyarrhythmias and atrial fibrillation.2019

    • Author(s)
      Yamada N, Asano Y, Fujita M, Yamazaki S, Inanobe A, Matsuura N, Kobayashi H, Ohno S, Ebana Y, Tsukamoto O, Ishino S, Takuwa A, Kioka H, Yamashita T, Hashimoto N, Zankov DP, Shimizu A, Asakura M, Asanuma H, Kato H, Nishida Y, Miyashita Y, Shinomiya H, Naiki N, Hayashi K, Makiyama T, Ogita H, et al.
    • Journal Title

      Circulation

      Volume: In press Issue: 18 Pages: 2157-2169

    • DOI

      10.1161/circulationaha.118.036761

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Networking analysis on superior vena cava arrhythmogenicity in atrial fibrillation2019

    • Author(s)
      Ebana Yusuke、Furukawa Tetsushi
    • Journal Title

      IJC Heart & Vasculature

      Volume: 22 Pages: 150-153

    • DOI

      10.1016/j.ijcha.2019.01.007

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pathway analysis with genome-wide association study (GWAS) data detected the association of atrial fibrillation with the mTOR signaling pathway2019

    • Author(s)
      Ebana Yusuke、Sun Yihan、Yang Xiaoxi、Watanabe Taiju、Makita Satoru、Ozaki Kouichi、Tanaka Toshihiro、Arai Hirokuni、Furukawa Tetsushi
    • Journal Title

      IJC Heart & Vasculature

      Volume: 24 Pages: 100383-100383

    • DOI

      10.1016/j.ijcha.2019.100383

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Combined Analysis of Human and Experimental Murine Samples Identified Novel Circulating MicroRNAs as Biomarkers for Atrial Fibrillation2018

    • Author(s)
      Natsume Y, Oaku K, Takahashi K, Nakamura W, Oono A, Hamada S, Yamazoe M, Ihara K, Sasaki T, Goya M, Hirao K, Furukawa T, Sasano T.
    • Journal Title

      Circulation Journal

      Volume: 82 Issue: 4 Pages: 965-973

    • DOI

      10.1253/circj.CJ-17-1194

    • NAID

      130006528576

    • ISSN
      1346-9843, 1347-4820
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Electrophysiological Assessment of Murine Atria with High-Resolution Optical Mapping2018

    • Author(s)
      Ihara Kensuke、Sugiyama Koji、Takahashi Kentaro、Yamazoe Masahiro、Sasano Tetsuo、Furukawa Tetsushi
    • Journal Title

      Journal of Visualized Experiments

      Volume: 132 Issue: 132 Pages: 56478-56478

    • DOI

      10.3791/56478

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Arrhythmic hazard map for a 3D whole-ventricles model under multiple ion channel block.2018

    • Author(s)
      Okada J, Yoshinaga T, Kurokawa J, Washio T, Furukawa T, K Sawada, Sugiura S, Hisada T
    • Journal Title

      Br J Pharmacol

      Volume: 175 Issue: 17 Pages: 3435-3452

    • DOI

      10.1111/bph.14357

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Important cardiac transcription factor genes are accompanied by bidirectional long non-coding RNAs2018

    • Author(s)
      Hori Yutaro、Tanimoto Yoko、Takahashi Satoru、Furukawa Tetsushi、Koshiba-Takeuchi Kazuko、Takeuchi Jun K.
    • Journal Title

      BMC Genomics

      Volume: 19 Issue: 1 Pages: 1-1

    • DOI

      10.1186/s12864-018-5233-5

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] スプライシング鮮魚因子RBM20変異を持つ心房細動モデルマウスの確立2020

    • Author(s)
      井原健介、黒柳秀人、平岡優一、笹野哲郎、古川哲史
    • Organizer
      心電学関連研究会2020
    • Related Report
      2020 Annual Research Report
  • [Presentation] 光学マッピング法による心不全モデルマウスにおける心房性不整脈の電気生理学的特性評価2020

    • Author(s)
      岩宮賢,井原健介,富井直輝,山﨑正俊,黒柳秀人,佐久間一郎,古川哲史,笹野哲郎
    • Organizer
      心電学関連研究会2020
    • Related Report
      2020 Annual Research Report
  • [Presentation] 肢誘導心電図のP波フラグメント解析による心房伝導障害の評価2020

    • Author(s)
      木藤穂高,佐々木奏絵,田中敏博,井原健介,古川哲史,笹野哲郎
    • Organizer
      心電学関連研究会2020
    • Related Report
      2020 Annual Research Report
  • [Presentation] Effects of hydrogel culture substrate on contractile properties and gene expression profiles of human iPS cell-derived cardiomyocytes.2018

    • Author(s)
      Kurokawa J, Fujizuka M, Hayashi E, Ashihara T, Kanda Y, Sekino Y, Furukawa T
    • Organizer
      日本薬学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Disease modeling using iPS cells2018

    • Author(s)
      Furukawa T, Okata S, Yuasa S, Suzuki T, Makita N, Kurokawa J, Egashira T, Yamakawa H, Seki T, Aizawa T, Hashimoto H, Kuroda Y, Tanaka A, Yae K, Murata M, Aiba T, Shimizu W, Horie M, Kodama I, Ogawa S, Fukuda K
    • Organizer
      第78回日本循環器学会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Impact of SNP on IL6R (rs7514452) for age at onset of atrial fibrillation2018

    • Author(s)
      Sato Y, Satoh A, Nitta J, Honda Y, Kuroda S, Sekigawa M, Kanoh M, Suzuki M, Inaba O, Muramatsu K, Yamato T, Matsumura Y, Asakawa K, Ebana Y, Furukawa T, Hirao K, Isobe M
    • Organizer
      第78回日本循環器学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Effect of SNP on 9q22 (rs6479562) on the progression from paroxysmal atrial fibrillation to persistent atrial fibrillation2018

    • Author(s)
      Sekigawa M, Satoh A, Nitta J, Sato Y, Honda Y, Kuroda S, Kanoh M, Suzuki M, Inaba O, Muramatsu K, Yamato T, Matsumura Y, Asakawa K, Ebana Y, Furukawa T, Hirao K, Isobe M
    • Organizer
      第78回日本循環器学会
    • Related Report
      2018 Annual Research Report
  • [Book] 心房細動のすべて2018

    • Author(s)
      古川哲史
    • Total Pages
      223
    • Publisher
      新潮社
    • ISBN
      4106107953
    • Related Report
      2018 Annual Research Report
  • [Book] ぜんぶわかる心臓・血管の事典2018

    • Author(s)
      古川哲史
    • Total Pages
      159
    • Publisher
      成美堂
    • ISBN
      9784415325774
    • Related Report
      2018 Annual Research Report

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Published: 2018-04-23   Modified: 2022-01-27  

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