Genetic epidemiology in the ion channel disease

2016 Fiscal Year Annual Research Report

• Project/Area Number: 25460406
• Research Institution: Shiga University of Medical Science
• Principal Investigator: 伊藤 英樹 滋賀医科大学, 医学部, 講師 (30402738)
• Co-Investigator(Kenkyū-buntansha): 堀江 稔 滋賀医科大学, 医学部, 教授 (90183938)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Keywords: QT延長症候群 / KCNQ1 / 遺伝子

Outline of Annual Research Achievements

本研究は先天性QT延長症候群の遺伝形式がメンデル遺伝から乖離していることを示すものであり、心筋カリウムチャネル遺伝子のひとつでKCNQ1の遺伝子変異が原因となるQT延長症候群type1、いわゆるLQT1の家系調査を最終年度も引き続き実施した。2015年に本邦で頻度の高いAla341Val, Ala344splの臨床像を報告したが、本年度はS5膜貫通領域に位置するSer277LeuとGly269Ser、C末端領域に位置するArg591His変異症例の発症年齢を含めた臨床経過について検討した。QTc間隔はSer277LeuとArg591Hisで486±76ms、485±41msとGly269Serの447±30msより有意に延長していた。Ser277Leu保因者のうち有症候者は64%と、Gly269Serの15%あるいはArg591Hisの17%と比較して高率であった。S277L変異保因者は他のLQT1と異なり、思春期以降も致死性不整脈イベントの発症率が高く、β遮断薬の投与の判断を含め慎重に経過を診ていく必要があると考えられた。Ser277Leuの予後が悪い理由として、女性の占める率が高率であることが原因の一つと考えられた。Ser277Leuの保因者のうち女性は86%で、Gly269Serの65%、Arg591Hisの50%と比して女性の占める比率が高率であった。重症変異であるほど女性優位となることを裏付ける結果であり、昨年度までの報告内容と一致する見解であった。

Research Products

• [Journal Article] A type 2 ryanodine receptor variant associated with reduced Ca2+ release and short-coupled torsades de pointes ventricular arrhythmia. (2017)
  • Author(s): Fujii Y, Itoh H, Ohno S, Murayama T, Kurebayashi N, Aoki H, Blancard M, Nakagawa Y, Yamamoto S, Matsui Y, Ichikawa M, Sonoda K, Ozawa T, Ohkubo K, Watanabe I, Guicheney P, Horie M.
  • Journal Title: Heart Rhythm Volume: 14 Pages: 2435-1442
  • DOI: 10.1016/j.hrthm.2016.10.015.
  • Peer Reviewed
• [Journal Article] Contribution of a KCNH2 variant in genotyped long QT syndrome: Romano-Ward syndrome under double mutations and acquired long QT syndrome under heterozygote. (2017)
  • Author(s): Fujii Y, Matsumoto Y, Hayashi K, Ding WG, Tomita Y, Fukumoto D, Wada Y, Ichikawa M, Sonoda K, Ozawa J, Makiyama T, Ohno S, Yamagishi M, Matsuura H, Horie M, Itoh H.
  • Journal Title: J Cardiol Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1016/j.hrthm.2016.10.015
  • Peer Reviewed
• [Journal Article] Arrhythmia risk and β-blocker therapy in pregnant women with long QT syndrome. (2017)
  • Author(s): Ishibashi K, Aiba T, Kamiya C, Miyazaki A, Sakaguchi H, Wada M, Nakajima I, Miyamoto K, Okamura H, Noda T, Yamauchi T, Itoh H, et al.
  • Journal Title: Heart Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1136/heartjnl-2016-310617
  • Peer Reviewed
• [Journal Article] 疾患・病態別にみた医薬品の禁忌 循環器疾患 (2017)
  • Author(s): 伊藤英樹
  • Journal Title: 月刊薬事 Volume: 印刷中 Pages: 印刷中
• [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: Eur Heart J Volume: 37 Pages: 1456-64
  • DOI: 10.1093/eurheartj/ehv695
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy. (2016)
  • Author(s): Freyermuth F, Rau F, Kokunai Y, Horie M, Imoto K, Lee KY, Swanson MS, Lopez de Munain A, Inada S, Itoh H, Nakazawa K, Ashihara T, Wang E, Zimmer T, Furling D, Takahashi MP, Charlet-Berguerand N, et al
  • Journal Title: Nature Communications Volume: 7 Pages: 11067
  • DOI: 10.1038/ncomms11067
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction. (2016)
  • Author(s): Itoh H, Berthet M, Fressart V, Denjoy I, Maugenre S, Klug D, Mizusawa Y, Makiyama T, Hofman N, Stallmeyer B, Zumhagen S, Shimizu W, Wilde AA, Schulze-Bahr E, Horie M, Tezenas du Montcel S, Guicheney P.
  • Journal Title: Eur J Hum Genet Volume: 24 Pages: 1160-6
  • DOI: 10.1038/ejhg.2015.257
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Pediatric Cohort With Long QT Syndrome - KCNH2 Mutation Carriers Present Late Onset But Severe Symptoms. (2016)
  • Author(s): Ozawa J, Ohno S, Hisamatsu T, Itoh H, Makiyama T, Suzuki H, Saitoh A, Horie M.
  • Journal Title: Circ J Volume: 80 Pages: 696-702
  • DOI: 10.1253/circj.CJ-15-0933
  • Peer Reviewed
• [Journal Article] Multigenerational Inheritance of Long QT Syndrome Type 2 in a Japanese Family. (2016)
  • Author(s): Ichikawa M, Ohno S, Fujii Y, Ozawa J, Sonoda K, Fukuyama M, Kato K, Kimura H, Itoh H, Hayashi H, Horie M.
  • Journal Title: Intern Med Volume: 55 Pages: 259-62
  • DOI: 10.2169/internalmedicine.55.6014
  • Peer Reviewed
• [Journal Article] Practical applicability of landiolol, an ultra-short-acting β1-selective blocker, for rapid atrial and ventricular tachyarrhythmias with left ventricular dysfunction. (2016)
  • Author(s): Wada Y, Aiba T, Tsujita Y, Itoh H, Wada M, Nakajima I, Ishibashi K, Okamura H, Miyamoto K, Noda T, Sugano Y, Kanzaki H, Anzai T, Kusano K, Yasuda S, Horie M, Ogawa H.
  • Journal Title: J Arrhythm Volume: 32 Pages: 82-8
  • DOI: 10.1016/j.joa.2015.09.002
  • Peer Reviewed
• [Journal Article] Impact of Updated Diagnostic Criteria for Long QT Syndrome on Clinical Detection of Diseased Patients: Results from Study of Patients Carrying Gene Mutations. (2016)
  • Author(s): Hayashi K, Konno T, Fujino N, Itoh H, Fujii Y, Imi-Hashida Y, Tada H, Tsuda T, Tanaka Y, Saito T, Ino H, Kawashiri M, Ohta K, Horie M, Yamagishi.M.
  • Journal Title: JACC Clin Electrophysiol Volume: 2 Pages: 279-287
  • DOI: 10.1016/j.jacep.2016.01.003
  • Peer Reviewed
• [Journal Article] Early repolarization and risk of arrhythmia events in long QT syndrome. (2016)
  • Author(s): Hasegawa K, Watanabe H, Hisamatsu T, Ohno S, Itoh H, Ashihara T, Hayashi H, Makiyama T, Minamino T, Horie M.
  • Journal Title: Int J Cardiol Volume: 223 Pages: 540-542
  • DOI: 10.1016/j.ijcard.2016.08.215
  • Peer Reviewed
• [Journal Article] A novel SCN5A mutation associated with drug Induced Brugada type ECG. (2016)
  • Author(s): Turker I, Makiyama T, Vatta M, Itoh H, Ueyama T, Shimizu A, Ai T, Horie M.
  • Journal Title: PLoS One Volume: 11 Pages: e0161872
  • DOI: 10.1371/journal.pone.0161872
  • Peer Reviewed / Open Access
• [Journal Article] Patient-specific human induced pluripotent stem cell model assessed with electrical pacing validates S107 as a potential therapeutic agent for catecholaminergic polymorphic ventricular tachycardia. (2016)
  • Author(s): Sasaki K, Makiyama T, Yoshida Y, Wuriyanghai Y, Kamakura T, Nishiuchi S, Hayano M, Harita T, Yamamoto Y, Kohjitani H, Hirose S, Chen J, Kawamura M, Ohno S, Itoh H, Takeuchi A, Matsuoka S, Miura M, Sumitomo N, Horie M, Yamanaka S, Kimura T.
  • Journal Title: PLoS One Volume: 11 Pages: e0164795
  • DOI: 10.1371/journal.pone.0164795
  • Peer Reviewed / Open Access
• [Journal Article] Pediatric cohort with phenotypic variability of ANK2 mutations in patients with inherited primary arrhythmia syndromes. (2016)
  • Author(s): Ichikawa M, Aiba T, Ohno S, Shigemizu D, Ozawa J, Sonoda K, Fukuyama M, Itoh H, Miyamoto Y, Tsunoda T, Makiyama T, Tanaka T, Shimizu W, Horie M.
  • Journal Title: Circ J Volume: 80 Pages: 2435-2442
  • DOI: 10.1253/circj.CJ-16-0486
  • Peer Reviewed
• [Presentation] Acquired prolongation of QT interval is really “acquired” or genetic disease? (2016)
  • Author(s): Itoh H
  • Organizer: 第63回日本不整脈心電学会学術集会 遺伝性不整脈国際研究シンポジウム
  • Place of Presentation: 札幌
  • Year and Date: 2016-07-14 – 2016-07-17
  • Invited