Quality control of protein in cardiomyochyte by atrial fibrillation associated gene, NEURL1

• Project/Area Number: 17K07251
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical genome science
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Ebana Yusuke 東京医科歯科大学, 統合研究機構, 講師 (60517043)
• Project Period (FY): 2017-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2017: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
• Keywords: 心房細動 / ゲノムワイド関連研究 / mTOR / ｍTOR / NEURL / タンパク質品質管理 / 機能解析 / 心筋細胞

Outline of Final Research Achievements

Pathway analysis was performed from all SNV data used in genome-wide association studies to identify the CTCF and mTOR pathways. In order to confirm the involvement of the CTCF pathway and the mTOR pathway, microarray analysis was performed using atrial muscle tissue specimens collected in Department of Cardiovascular Surgery. Examination of the involvement of the two pathways in patients with atrial fibrillation and non-atrial fibrillation showed that the mTOR pathway was suppressed in the atrial muscles collected from patients with atrial fibrillation.
By participating in multi-institutional joint research on atrial fibrillation, we have newly identified a genetic predisposition related to atrial fibrillation.

Academic Significance and Societal Importance of the Research Achievements

ゲノムワイド関連研究から同定された遺伝マーカーから、心房細動に関連する生物学的経路を同定した。トランスクリプトーム解析から心房細動においてはmTOR経路が抑制されている可能性があり、心筋細胞におけるエネルギー代謝障害や機能タンパク質の品質管理に障害が生じていることが示唆された。心房筋の細胞障害の原因に光を当てることで、心房細動の薬物的な治療への可能性を開いたという意義がある。
また国際共同研究を含む、様々な共同研究を通して新たに心房細動に関わる遺伝子や遺伝子座が同定され、結果として遺伝的リスク評価法が提案され、臨床的な意義があると考えられる。

Research Products

• [Journal Article] Functional Role of the L396R Mutation of Tks5 Identified by an Exome-Wide Association Study in Atrial Fibrillation (2020)
  • 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
  • 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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pathway analysis with genome-wide association study (GWAS) data detected the association of atrial fibrillation with the mTOR signaling pathway (2019)
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Networking analysis on superior vena cava arrhythmogenicity in atrial fibrillation (2019)
  • Author(s): Ebana Yusuke、Furukawa Tetsushi
  • Journal Title: IJC Heart & Vasculature Volume: 22 Pages: 150-153
  • DOI: 10.1016/j.ijcha.2019.01.007
  • Peer Reviewed
• [Journal Article] Association of the Clinical and Genetic Factors With Superior Vena Cava Arrhythmogenicity in Atrial Fibrillation (2018)
  • Author(s): Ebana Y, Nitta J, Takahashi Y, Miyazaki S, Suzuki M, Liu L, Hirao K, Kanda E, Isobe M, Furukawa T
  • Journal Title: Circulation Journal Volume: 82 Issue: 1 Pages: 71-77
  • DOI: 10.1253/circj.CJ-17-0350
  • NAID: 130006281956
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Genetic variants associated with susceptibility to atrial fibrillation in Japanese population (2017)
  • Author(s): Liu L, Ebana Y, Nitta J, Takahashi Y, Miyazaki S, Tanaka T, Komura M, Isobe M, Furukawa T
  • Journal Title: Can. J. Cardiol. Volume: 33 Pages: 443-449
  • DOI: 10.1016/j.ijcard.2017.06.046
  • Peer Reviewed
• [Journal Article] Endoscopic features and genetic background of inflammatory bowel disease complicated with Takayasu arteritis. (2017)
  • Author(s): Akiyama S, Fujii T, Matsuoka K, Yusuke E, Negi M, Takenaka K, Nagahori M, Ohtsuka K, Isobe M, Watanabe M.
  • Journal Title: J Gastroenterol Hepatol. Volume: 32 Issue: 5 Pages: 1011-1017
  • DOI: 10.1111/jgh.13640
  • Peer Reviewed
• [Journal Article] Identification of six novel genetic loci associated with atrial fibrillation in Japanese population. (2017)
  • Author(s): Low SK, Takahashi A, Ebana Y, Ozaki K, Christophersen IE, Ellinor PT, AFGen Consortium, Ogishima S, Yamamoto M, Satoh M, Sasaki M, Yamaji T, Iwasaki M, Tsugane S, Tanaka K, Naito M, Wakai K, Tanaka H, Furukawa T, Kubo M, Ito K, Kamatani Y, Tanaka T.
  • Journal Title: Nature Genetics Volume: - Issue: 6 Pages: 953-958
  • DOI: 10.1038/ng.3842
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical utility and functional analysis of variants in atrial fibrillation-associated locus 4q25. (2017)
  • Author(s): Ebana Y, Ozaki K, Liu L, Hachiya H, Hirao K, Isobe M, Kubo M, Tanaka T, Furukawa T.
  • Journal Title: Journal of Cardiology Volume: - Issue: 4 Pages: 366-373
  • DOI: 10.1016/j.jjcc.2016.11.016
  • Peer Reviewed
• [Journal Article] Effects of immunosuppressive and biological agents on refractory Takayasu arteritis patients unresponsive to glucocorticoid treatment. (2017)
  • Author(s): Ohigashi H, Tamura N, Ebana Y, Harigai M, Maejima Y, Ashikaga T, Isobe M.
  • Journal Title: J Cardiol Volume: 69 Issue: 5 Pages: 774-778
  • DOI: 10.1016/j.jjcc.2016.07.009
  • Peer Reviewed
• [Journal Article] Genetic variants associated with susceptibility to atrial fibrillation in Japanese population (2016)
  • Author(s): Liu L, Ebana Y, Nitta JI, Takahashi Y, Miyazaki S, Tanaka T, Komura M, Isobe M, Furukawa T
  • Journal Title: Canadean Journal of Cardiology Volume: 33 Issue: 4 Pages: 443-449
  • DOI: 10.1016/j.cjca.2016.10.029
  • Peer Reviewed / Open Access
• [Presentation] Genetics of atrial fibrillation in Japanese Population (2018)
  • Author(s): Yusuke Ebana
  • Organizer: The 11th Asia Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research / Invited