Post-GWAS study for identification of druggable target of AF

2017 Fiscal Year Annual Research Report

• Project/Area Number: 26293052
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 古川 哲史 東京医科歯科大学, 難治疾患研究所, 教授 (80251552)
• Project Period (FY): 2014-04-01 – 2018-03-31
• Keywords: 心房細動 / GWAS / 1塩基多型 / 酸化ストレス / 交感神経

Outline of Annual Research Achievements

平成28年度までの研究で、exon-wide association study(EWAS)から同定された2つのレアSNPと心房細動との関連が心房筋由来細胞株HL-1を使ったin vitroの検討を行った。一方は、心筋細胞においてアンジオテンシン-II受容体－NADPH-oxidaseの経路を介して活性酸素の産生に関与する分子で、心房細動感受性1塩基多型(SNP)があると、活性酸素の産生がより増加することが明らかとなった。また同分子は単球－マクロファージ系にも発現しており、単球をフォルボールエステルで活性化すると発現が増加すること、スクラッチアッセイなどから単球の移動に関係すること、すなわち単球の組織に侵入する時に重要な働きをすることが明らかとなった。すなわち同分子は、心筋細胞と単球-マクロファージの両者で心房細動の発現に関与することが分かった。もう一方の分子を神経細胞に発現させると、チロシンヒドロキシラーゼの発現が増え、交感神経への分化を誘導することが分かった。さらに、心房細動感受性SNPを持つ同分子を発現させると、チロシンヒドロキシラーゼの発現がさらに増加することが分かった。そこで、同分子のノックアウトマウスをゲノム編集技術CRISPR/Cas9を用いて作製したが、繁殖に問題があった。これは、自律神経が繁殖に関係するためと考えられる。平成29年度末になってやっとマウスの頭数がある程度に達して、実験が可能な段階に達した。

Research Progress Status

29年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

29年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Combined analysis of human and experimental murine samples identified novel circulating microRNAs as biomarker for atrial fibrillation (2018)
  • Author(s): Natusme 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: Circ. J. Volume: 82 Pages: 965-973
  • DOI: 10.1177/1358863X17724263.
  • Peer Reviewed
• [Journal Article] Flecainide ameliorates arrhythmogenicity through NCX flux in Andersen-Tawil syndrome-iPS cell-derived cardiomyocytes (2017)
  • Author(s): Kuroda Y, Yuasa S, Watanabe Y, Ito S, Egashira T, Seki T, Hattori T, Ohno S, Kodaira M, Suzuki T, Hashimoto H, Okata S, Tanaka A, Aizawa Y, Murata M, Aiba T, Makita N, Furukawa T, Shimizu W, Kodama I, Ogawa S, Kokubun N, Horigome H, Horie M, Kamiya K, Fukuda K
  • Journal Title: Biochem. Biophys. Rep. Volume: 9 Pages: 245-256
  • DOI: 10.1016/j.bbrep.2017.01.002
  • Peer Reviewed
• [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] Association of ZFHX3 gene variation with atrial fibrillation, cerebral infarction, and lung thromboembolism: An autopsy study (2017)
  • Author(s): Zaw KTT, Sato N, Ikeda S, Thu KS, Mieno MN, Arai T, Mori S, Furukawa T, Sasano T, Sawabe M, Tanaka M, Muramatsu M
  • Journal Title: J. Cardiol. Volume: 70 Pages: 180-184
  • DOI: 10.1016/j.jjcc.2016.11.005.
  • Peer Reviewed
• [Journal Article] Identification of six new genetic loci associated with atrial fibrillation in the 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: Nat. Genet. Volume: 49 Pages: 953-958
  • DOI: 10.1038/ng.3842.
  • Peer Reviewed / 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: J. Cardiol. Volume: 70 Pages: 366-373
  • DOI: 10.1016/j.jjcc.2016.11.016.
  • Peer Reviewed
• [Journal Article] Association of the clinical and genetic factors with superior vena cava arrhythmogenicity in atrial fibrillation (2017)
  • Author(s): Ebana Y, Nitta J, Takahashi Y, Miyazaki S, Suzuki M, Liu L, Hirao K, Kanda E, Isobe M, Furukawa T
  • Journal Title: Circ. J. Volume: 82 Pages: 71-77
  • DOI: 10.1253/circj.CJ-17-0350.
  • Peer Reviewed
• [Journal Article] Chromosome 4q25 variants and recurrence after second-generation cryoballoon ablation in patients with paroxysmal atrial fibrillation (2017)
  • Author(s): Miyazaki S, Ebana Y, Liu L, Nakamura H, Hachiya H, Taniguchi H, Takagi T, Kajiyama T, Watanabe T, Igarashi M, Kusa S, Niida T, Iesaka Y, Furukawa T
  • Journal Title: Int. J. Cardiol. Volume: 244 Pages: 151-157
  • DOI: 10.1016/j.ijcard.2017.06.046.
  • Peer Reviewed
• [Journal Article] Overexpression of KCNJ2 in induced pluripotent stem cell-derived cardiomyocytes for the assessment of QT-prolonging drugs (2017)
  • Author(s): Li M, Kanda Y, Ashihara T, Sasano T, Nakai Y, Kodama M, Hayashi E, Sekino Y, Furukawa T, Kurokawa J
  • Journal Title: J. Pharmacol. Sci. Volume: 134 Pages: 75-85
  • DOI: 10.1016/j.jphs.2017.05.004.
  • Peer Reviewed
• [Journal Article] Calcification of joints and arteries with novel NT5E mutations with involvement of upper extremity arteries (2017)
  • Author(s): Yoshioka K, Kuroda S, Takahashi K, Sasano T, Furukawa T, Matsumura A.
  • Journal Title: Vas. Med. Volume: 22 Pages: 541-543
  • DOI: 10.1253/circj.CJ-17-1194.
  • Peer Reviewed
• [Presentation] コモン不整脈の遺伝的リスク (2017)
  • Author(s): 古川哲史
  • Organizer: 第２４３回日本循環器学会関東甲信越地方会
  • Invited
• [Presentation] Common genetic variants indicate the risk of atrial fibrillation in Japanese population (2017)
  • Author(s): Liu L, Ebana Y, Nitta J, Takahashi Y, Miyazaki S, Tanaka T, Mokura M, Isobe M, Furukawa T
  • Organizer: 第６３回日本不整脈心電学会学術集会
  • Invited
• [Presentation] Effect of SNP 9q22 (rs6479562) on the progression from patoxysmal atrial fibrillation to persistent atrial fibrillation (2017)
  • 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: The 78th Annual Scientific Meeting of the Japanese Circulation Society
• [Presentation] Impact of SNP on IL6R (rs7514452) for age at onset of atrial fibrillation (2017)
  • Author(s): Sato Y, Satoh A, Nitta J, Honda Y, Kuroda S, Skigawa M, Kanoh M, Suzuki M, Inaba O, Muramatsu K, Yamato T, Matsumura Y, Asakawa K, Eban Y, Furukawa T, Hirao K, Isobe M
  • Organizer: The 78th Annual Scientific Meeting of the Japanese Circulation Society
• [Presentation] Disease modeling using iPS cells (2017)
  • 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, Kurata M, Aiba T, Shimizu W, Horie M, Kodama I, Ogawa S, Fukuda K
  • Organizer: The 78th Annual Scientific Meeting of the Japanese Circulation Society
  • Invited
• [Presentation] Effects of hydrogel culture substrate on contractile properties and gene expression profiles of human iPS cell-derived cardiomyocytes (2017)
  • Author(s): Kurokawa J, Fujizuka M, Hayashi E, Ashihara T, Kanda Y, Sekino Y, Furukawa T
  • Organizer: 日本薬学会