QT延長症候群における遺伝子変異部位別チャネル機能異常と不整脈基盤・予後との関係

• Project Area: Establishment of Integrative Multi-level Systems Biology and its Applications
• Project/Area Number: 25136727
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: 相庭 武司 国立研究開発法人国立循環器病研究センター, 病院, 医長 (40574348)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000); Fiscal Year 2014: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
• Keywords: QT延長 / イオンチャネル / 突然死 / 心室性不整脈 / 遺伝子 / QT延長症候群 / 心室頻拍

Outline of Annual Research Achievements

QT延長症候群における遺伝子解析を次世代シーケンサー（NGS）を用いて集中的かつ網羅的に行い、得られた膨大なゲノム情報をデータベース化し臨床情報と家系情報も含めゲノム情報と患者情報を有機的に関連づけ、新たなLQTの疾患原因遺伝子の候補となる可能性のある遺伝子を同定した。
新たなLQTSの原因と考えられる遺伝子はRyR2やｶﾙﾓｼﾞｭﾘﾝなどのCa関連蛋白と関係する遺伝子であると考えられた。
NGSを用いた解析からLQTSの新たな原因遺伝子として3家系においてKチャネルに関係する遺伝子がQT延長あるいは心室性不整脈にも関係することを証明した。
LQT3あるいはBrugada症候群におけるSCN5Aのリスク評価を検討したところ、ポア領域の変異を有する患者はそれ以外の患者に比べて有意に突然死のリスクが高いことを証明した。
遺伝子検査にてLQT1~3の原因遺伝子は認められない遺伝子型未診断例（genotype-unknown)について、リスク評価を行った結果、遺伝子未診断でも必ずしもリスクが低い訳ではないことを証明した。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] St George's, University of London(United Kingdom)
• [Journal Article] The genetics underlying acquired long QT syndrome: impact for genetic screening. (2016)
  • Author(s): Itoh H, Crotti L, Aiba T, Spazzolini C, Denjoy I, Fressart V, Hayashi K, Nakajima T, Ohno S, Makiyama T, Wu J, Hasegawa K, Mastantuono E, Dagradi F, Pedrazzini M, Yamagishi M, Berthet M, Murakami Y, Shimizu W, Guicheney P, Schwartz PJ, Horie M.
  • Journal Title: European Heart Journal Volume: 37 (18) Issue: 18 Pages: 1456-1464
  • DOI: 10.1093/eurheartj/ehv695
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pronounced Shortening of QT Interval With Mexiletine Infusion Test in Patients With Type 3 Congenital Long QT Syndrome (2016)
  • Author(s): Funasako M, Aiba T, Ishibashi K, Nakajima I, Miyamoto K, Inoue Y, Okamura H, Noda T, Kamakura S, Anzai T, Noguchi T, Yasuda S, Miyamoto Y, Fukushima Kusano K, Ogawa H, Shimizu W.
  • Journal Title: Circulation Journal Volume: 80 Issue: 2 Pages: 340-345
  • DOI: 10.1253/circj.CJ-15-0984
  • NAID: 130005120922
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genetic defects in a His-Purkinje system transcription factor, IRX3, cause lethal cardiac arrhythmias. (2016)
  • Author(s): Koizumi A, Sasano T, Kimura W, Miyamoto Y, Aiba T, Ishikawa T, Nogami A, Fukamizu S, Sakurada H, Takahashi Y, Nakamura H, Ishikura T, Koseki H, Arimura T, Kimura A, Hirao K, Isobe M, Shimizu W, Miura N, Furukawa T.
  • Journal Title: European Heart Journal. Volume: 37 (18) Issue: 18 Pages: 1469-1475
  • DOI: 10.1093/eurheartj/ehv449
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Exome Analyses of Long QT Syndrome Reveal Candidate Pathogenic Mutations in Calmodulin-Interacting Genes. (2015)
  • Author(s): Shigemizu D, Aiba T, Nakagawa H, Ozaki K, Miya F, Satake W, Toda T, Miyamoto Y, Fujimoto A, Suzuki Y, Kubo M, Tsunoda T, Shimizu W, Tanaka T.
  • Journal Title: PLoS One. Volume: 10 (7) Issue: 7 Pages: e0130329-e0130329
  • DOI: 10.1371/journal.pone.0130329
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Prognostic significance of early repolarization in inferolateral leads in Brugada patients with documented ventricular fibrillation: a novel risk factor for Brugada syndrome with ventricular fibrillation. (2013)
  • Author(s): Kawata H, Morita H, Yamada Y, Noda T, Satomi K, Aiba T, Isobe M, Nagase S, Nakamura K, Fukushima Kusano K, Ito H, Kamakura S, Shimizu W.
  • Journal Title: Heart Rhythm. Volume: 10 Issue: 8 Pages: 1161-1168
  • DOI: 10.1016/j.hrthm.2013.04.009
  • Peer Reviewed / Open Access
• [Journal Article] A nonsynonymous polymorphism in semaphorin 3A as a risk factor for human unexplained cardiac arrest with documented ventricular fibrillation (2013)
  • Author(s): Nakano Y, Makita N, (32人中31番目) et al
  • Journal Title: PLOS Genet Volume: 9 Issue: 4 Pages: e1003364-e1003364
  • DOI: 10.1371/journal.pgen.1003364
  • NAID: 120006985866
  • Peer Reviewed / Open Access
• [Journal Article] Cardiac resynchronization therapy improves altered Na channel gating in canine model of dyssynchronous heart failure. (2013)
  • Author(s): Aiba T, Barth AS, Hesketh GG, Hashambhoy YL, Chakir K, Tunin RS, Greenstein JL, Winslow RL, Kass DA, Tomaselli GF.
  • Journal Title: Circulation Arrhythmia and Electrophysiology Volume: 6 Issue: 3 Pages: 546-54
  • DOI: 10.1161/circep.113.000400
  • Peer Reviewed / Open Access
• [Journal Article] Significance of non-type 1 anterior early repolarization in patients with inferolateral early repolarization syndrome. (2013)
  • Author(s): Kamakura T, Kawata H, Nakajima I, Yamada Y, Miyamoto K, Okamura H, Noda T, Satomi K, Aiba T, Takaki H, Aihara N, Kamakura S, Kimura T, Shimizu W.
  • Journal Title: Journal of American Collage of Cardiology Volume: 62 Issue: 17 Pages: 1610-1618
  • DOI: 10.1016/j.jacc.2013.05.081
  • Peer Reviewed / Open Access
• [Journal Article] Common variants at SCN5A-SCN10A and HEY2 are associated with Brugada syndrome, a rare disease with high risk of sudden cardiac death. (2013)
  • Author(s): Bezzina CR, Makita N(63人中31番目)et al
  • Journal Title: Nat Genet. Volume: 45 Issue: 9 Pages: 1044-1049
  • DOI: 10.1038/ng.2712
  • Peer Reviewed / Open Access
• [Journal Article] Congenital long QT syndrome with compound mutations in the KCNH2 gene (2013)
  • Author(s): Bando S, Soeki T, Matsuura T, Niki T, Ise T, Yamaguchi K, Taketani Y, Iwase T, Yamada H, Wakatsuki T, Akaike M, Aiba T, Shimizu W, Sata M.
  • Journal Title: Heart Vessels Volume: - Issue: 4 Pages: 554-559
  • DOI: 10.1007/s00380-013-0406-2
  • NAID: 130002130326
  • Peer Reviewed / Open Access
• [Presentation] Calmodulin interacting genes as a novel candidate for pathogenesis of long-QT syndrome (2015)
  • Author(s): 23. Aiba T, Shigemizu D, Ishibashi K, Wada M, Nakajima I, Miyamoto K, Okamura H, Noda T, Satake W, Toda T, Kusano K, Kamakura S, Sekine A, Miyamoto Y, Tanaka T, Ogawa H, Shimizu W
  • Organizer: AHA Scientific Session 2015
  • Place of Presentation: Orlando FL
  • Year and Date: 2015-11-07
  • Int'l Joint Research
• [Presentation] A novel KCNJ3 mutation as a susceptibility for ventricular arrhythmias in long-QT Syndrome (2015)
  • Author(s): T. Aiba1, M. Ono2, F. Toyoda2, K. Ishibashi1, Y. Miyamoto1, A. Sekine1, K. Kusano1, H. Matsuura2, T. Tanaka3, W. Shimizu4
  • Organizer: European Society of Cardiology 2015
  • Place of Presentation: Lonodon UK
  • Year and Date: 2015-08-29
  • Int'l Joint Research
• [Presentation] A novel KCNJ3 mutation as a susceptibility for ventricular arrhythmias in long-QT Syndrome (2015)
  • Author(s): 22. Aiba T, Toyoda F, Ono M, Ishibashi K, Wada M, Nakajima I, Miyamoto K, Okamura H, Noda T, Kamakura S, Kusano K, Sekine A, Tanaka T, Miyamoto Y, Matsuura H, Horie M, Shimizu W.
  • Organizer: 第30回日本不整脈学会・第32回日本心電学会合同学術集会
  • Place of Presentation: 京都
  • Year and Date: 2015-07-28
• [Presentation] Genetic-based Arrhythmic Risk in Patients with Congenital Long QT Syndrome from the Japanese LQTS Multicenter Registry (2015)
  • Author(s): 21. Aiba T, Makimoto H, Makiyama T, Watanabe H, Hayashi K, Morita H, Yoshinaga M, KusanoK, MiyamotoY, Kamakura S, Yasuda S, Ogawa H, Makita N, Horie M, Shimizu W.
  • Organizer: 第79 回日本循環器学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2015-04-24
• [Presentation] Brugada syndrome and Early repolarization syndrome (2013)
  • Author(s): Aiba Takeshi
  • Organizer: Europace
  • Place of Presentation: Athenes
  • Year and Date: 2013-06-23 – 2013-06-26
  • Invited