Elucidation of genetic predispositions to cardiac sudden death in Brugada syndrome

• Project/Area Number: 18K15894
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: National Cardiovascular Center Research Institute (2019); Nagasaki University (2018)
• Principal Investigator: ISHIKAWA TAISUKE 国立研究開発法人国立循環器病研究センター, オープンイノベーションセンター, 室長 (60708692)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 心臓突然死 / ブルガダ症候群 / リスク層別化 / 次世代シーケンス / ブルガダ症候群患者 / ゲノム / SNP / 突然死 / プレシジョンメディスン / リスク予測 / 致死性不整脈 / ゲノムワイド関連解析 / 一次予防 / リスク階層化

Outline of Final Research Achievements

There is no definitive methods to estimate the risk of sudden cardiac death in Brugada syndrome (BrS), which is characterized by nocturnal fetal arrhythmia among middle-aged men. To identify the genetic variants for the sudden death, we performed a Genome-Wide Association Study on 752 Japanese BrS patients and 1146 Japanese controls, and found multiple risk variants for sudden death. Since it was not replicated in other races, we considered the variant to increase the risks of sudden death race-specifically. We next performed deep sequencing around the sudden death risk variant in Japanese BrS patients and found candidate variants associated with sudden death. We are now conducting experiments on the cellular system to elucidate the molecular mechanisms that link variants to the risk of sudden death.

Academic Significance and Societal Importance of the Research Achievements

ブルガダ症候群(BrS)は中年男性に好発する心臓突然死だが、誰にいつ起こるか予測する手法がない。BrSには家族歴が認められ遺伝する側面があることからゲノムに心臓突然死のリスクを予期するものがあると考え、BrSと対称群のゲノムワイド関連解析を行って突然死リスクに関連するSNPを複数同定した。この結果は他人種では再現されなかったため日本人特異的であると考えた。周辺配列をシーケンスすると、この日本人らしさに関与すると思われるバリアントを複数同定した。現在これらがどのようにして心臓突然死に関与するか明らかにする実験を進めており、これによって突然死予防法の確立につながると考えられる。

Research Products

• [Int'l Joint Research] linstitute du thorax(フランス)
• [Int'l Joint Research] Academic Medical Center(オランダ)
• [Journal Article] Transethnic genome-wide association study provides insights in the genetic architecture and heritability of long QT syndrome (2020)
  • Author(s): Lahrouchi N., Ishikawa T., Makita N., Bezzina C. R., et al.
  • Journal Title: Circulation Volume: -
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] TBX5 R264K acts as a modifier to develop dilated cardiomyopathy in mice independently of T-box pathway (2020)
  • Author(s): Miyao N., Hata Y., Izumi H., Nagaoka R., Oku Y., Takasaki I., Ishikawa T., Takarada S., Okabe M., Nakaoka H., Ibuki K., Ozawa S., Yoshida T., Hasegawa H., Makita N., Nishida N., Mori H., Ichida F., Hirono K.
  • Journal Title: PLOS ONE Volume: 15 Issue: 4 Pages: 0227393-0227393
  • DOI: 10.1371/journal.pone.0227393
  • Peer Reviewed / Open Access
• [Journal Article] Desmin‐related myopathy characterized by non‐compaction cardiomyopathy, cardiac conduction defect, and coronary artery dissection (2020)
  • Author(s): Tamiya R., Saito Y., Fukamachi D., Nagashima K., Aizawa Y., Ohkubo K., Hatta T., Sezai A., Tanaka M, Ishikawa T., Makita N., Sumitomo N., Okumura Y.
  • Journal Title: ESC Heart Failure Volume: - Issue: 3 Pages: 1338-1343
  • DOI: 10.1002/ehf2.12667
  • Peer Reviewed / Open Access
• [Journal Article] Identification of transmembrane protein 168 mutation in familial Brugada syndrome. (2020)
  • Author(s): Shimizu A, Zankov DP, Sato A, Komeno M, Toyoda F, Yamazaki S, Makita T, Noda T, Ikawa M, Asano Y, Miyashita Y, Takashima S, Morita H, Ishikawa T, Makita N, Hitosugi M, Matsuura H, Ohno S, Horie M, Ogita H.
  • Journal Title: FASEB Journal Volume: 34 Issue: 5 Pages: 6399-6417
  • DOI: 10.1096/fj.201902991r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pathological Features of Lamin Cardiomyopathy (2020)
  • Author(s): Kawano, H., Ishimatsu, T., Ishijima, I., Hayashi, T., Ishikawa, T., Makita, N., Maemura,K.
  • Journal Title: Circulation Journal Volume: -
  • NAID: 130007864268
  • Peer Reviewed / Open Access
• [Journal Article] 遺伝性不整脈のPrecision medicine (2020)
  • Author(s): 石川泰輔, 蒔田直昌
  • Journal Title: 週間 医学のあゆみ Volume: 272 Pages: 1279-1283
• [Journal Article] 遺伝性不整脈の遺伝子診断：有効性と限界 (2019)
  • Author(s): 石川泰輔, 蒔田 直昌
  • Journal Title: 循環器病研究の進歩 Volume: 40 Pages: 58-66
• [Journal Article] Clinical Manifestations and Long-Term Mortality in <i>Lamin A/C</i> Mutation Carriers From a Japanese Multicenter Registry (2018)
  • Author(s): 14.Nakajima K, Aiba T, Makiyama T, Nishiuchi S, Ohno S, Kato K, Yamamoto Y, Doi T, Shizuta S, Onoue K, Yagihara N, Ishikawa T, Watanabe I, Kawakami H, Oginosawa Y, Murakoshi N, Nogami A, Aonuma K, Saito Y, Kimura T, Yasuda S, Makita N, Shimizu W, Horie M, Kusano K.
  • Journal Title: Circulation Journal Volume: 82 Issue: 11 Pages: 2707-2714
  • DOI: 10.1253/circj.CJ-18-0339
  • NAID: 40021697176
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2018-10-25
  • Peer Reviewed / Open Access
• [Journal Article] HCN4 pacemaker channels attenuate the parasympathetic response and stabilize the spontaneous firing of the sinoatrial node (2018)
  • Author(s): Kozasa Yuko、Nakashima Noriyuki、Ito Masayuki、Ishikawa Taisuke、Kimoto Hiroki、Ushijima Kazuo、Makita Naomasa、Takano Makoto
  • Journal Title: The Journal of Physiology Volume: 596 Issue: 5 Pages: 809-825
  • DOI: 10.1113/jp275303
  • Peer Reviewed / Open Access
• [Journal Article] Overexpression of heart-specific small subunit of myosin light chain phosphatase results in heart failure and conduction disturbance (2018)
  • Author(s): Arimura Takuro、Muchir Antoine、Kuwahara Masayoshi、Morimoto Sachio、Ishikawa Taisuke、Du Cheng-Kun、Zhan Dong-Yun、Nakao Shu、Machida Noboru、Tanaka Ryo、Yamane Yoshihisa、Hayashi Takeharu、Kimura Akinori
  • Journal Title: American Journal of Physiology-Heart and Circulatory Physiology Volume: epub Issue: 6 Pages: H1192-H1202
  • DOI: 10.1152/ajpheart.00696.2017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 患者由来iPS 細胞モデルを用いたCav 1.2イオン選択性を障害するCACNA1C-E1115K変異がQT 延長症候群、Brugada 症候群を発症するメカニズムの解析 (2020)
  • Author(s): 柏麻美, 牧山武, 糀谷泰, マウリッセン トーマス, ウリヤンハイ イミン, 山本雄大, ガオ ジンシャン, ファン ハイ, 今村知彦, 相澤卓範, 石川泰輔, 大野聖子, 豊田太, 佐藤誠一, 高橋一浩, ウォルツェン クヌート, 堀江稔, 蒔田直昌, 木村剛
  • Organizer: 第97回日本生理学会大会
• [Presentation] 進行性心臓伝導障害患者の網羅的遺伝子解析とin vitro 機能解析系を用いて明らかになった心臓コネキシン病の分子病態 (2020)
  • Author(s): 石川泰輔, 関明子, 蒔田直昌
  • Organizer: 第97回日本生理学会大会
• [Presentation] Brugada症候群の予後予測に対する分子生理学的アプローチ (2019)
  • Author(s): 石川泰輔, 蒔田直昌
  • Organizer: 第67回日本心臓病学会学術集会
• [Presentation] 発症前診断を行ったQT延長症候群の姉妹 (2019)
  • Author(s): 松下悠紀, 永田弾尺, 小川昌宣, 鹿田佐和子, 石川泰輔, 蒔田直昌
  • Organizer: 日本人類遺伝学会第64回大会
• [Presentation] 次世代シーケンス解析による特発性心室細動の遺伝背景の解明 (2019)
  • Author(s): 謝颯琴, 高橋篤, 大野聖子, 鎌倉令, 石川泰輔, 植田初江, 斯波真理子, 南野直人, 林研至, 八木原伸江, 中野由紀子, 伊藤英樹, 宮本恵宏, 田中敏博, 蒔田直昌, 堀江稔, 清水渉, 草野研吾, 安田聡, 相庭武司
  • Organizer: 日本人類遺伝学会第64回大会
• [Presentation] Comprehensive Analyses Using Functional Evaluation and Whole-exome Sequencings to Decipher the Genetic predispositions for Sudden Death in Brugada Syndrome (2019)
  • Author(s): Makita N., Ishikawa T., Japanese Brugada Exome Consortium Investigators
  • Organizer: 第83回日本循環器学会学術集会
• [Presentation] Novel common genetic predispositions to sudden death in Brugada syndrome distinct from those to diagnostic Brugada-ECG pattern (2019)
  • Author(s): Ishikawa T.
  • Organizer: 第3回日本循環器病学会基礎研究フォーラム
  • Invited
• [Presentation] Single Cell Electrophysiological Analysis of iPS Cell-Derived Cardiomyocytes Generated from Long-QT Syndrome Patients Carrying a CALM2 Mutation Using a Membrane Potential Imaging System (2019)
  • Author(s): Yamamoto Y., Makiyama T., Wuriyanghai Y., Kohjitani H., Hirose S., Gao J., Kashiwa A., Huang H., Ishikawa T., Ohno S., Chonabayashi K., Suda K., Yoshida Y., Horie M., Makita N., Kimura T.
  • Organizer: 第66回日本不整脈心電学会
• [Presentation] Modeling Overlapping Phenotypes of Long-QT and Brugada Syndrome with CACNA1C-E1115K that Alters Ion Selectivity of the Cardiac L-Type Calcium Channel Using Induced Pluripotent Stem Cells (2019)
  • Author(s): Kashiwa A., Makiyama T., Kohjitani H., Hirose S., Gao J., Kashiwa A., Huang H., Ishikawa T., Ohno S., Chonabayashi K., Suda K., Yoshida Y., Horie M., Makita N., Kimura T.
  • Organizer: 第66回日本不整脈心電学会
• [Presentation] Functional Reappraisal of SCN5A Mutations Reemphasize Their Predictive Value for Lethal Cardiac Events in Brugada Syndrome (2019)
  • Author(s): Ishikawa T., Makita N.
  • Organizer: 第66回日本不整脈心電学会
• [Presentation] Modeling Overlap Syndrome of Long QT and Brugada Syndrome Associated with Induced Pluripotent Stem Cells (2019)
  • Author(s): Kashiwa A., Makiyama T., Kohjitani H., Wuriyanghai Y., Yamamoto Y., Jungshan G., Huang H., Ishikawa T., Ohno S., Toyoda F., Sato S., Horie M., Makita N., Kimura T.
  • Organizer: The 40th Heart Rhythm Society Scientific Sessions
  • Int'l Joint Research
• [Presentation] Cardiac Emerinopathy, Novel Nonsyndromic Xlinked Left Ventricular Noncompaction Associated With Progressive Atrial Conduction Disturbance (2019)
  • Author(s): Ishikawa T., Barc J., Mishima H., Hirono K., Terada S., Kowase S., Sato T., Mukai Y., Yui Y., Ohkubo K., Kimoto H., Hata Y., Aiba T., Ohno S., Chishaki A., Shimizu W., Horie M., Ichida F., Nogami A., Yoshiura K., Schott JJ., Makita N.
  • Organizer: The 40th Heart Rhythm Society Scientific Sessions
  • Int'l Joint Research
• [Presentation] Attempts to identify the genetic risk loci for the lethal arrhythmia in Japanese Brugada syndrome population. (2018)
  • Author(s): Ishikawa T
  • Organizer: 第一回日本循環器学会基礎研究フォーラム
• [Presentation] Rare Coding Variants in Genes Other Than SCN5A Are Minimal Genetic Burden on the Prognosis of Brugada Syndrome (2018)
  • Author(s): Ishikawa T, Mishima H, Ohno S, T. A, Nakano Y, Aizawa Y, Nakajima T, Hayashi K, Murakoshi N, Yagihara N, Kimoto H, Makiyama T, Watanabe H, Morita H, Yoshiura K, Nogami A, Shimizu W, Horie M, Tanaka T and Makita N.
  • Organizer: The 65th Annual Meeting of the Japan Heart Rhythm Society
• [Presentation] Cardiac Connexin Syndrome: A New Inherited Cardiac Conduction Disease Entity with Distinct Electrophysiological and Extracardiac Manifestations. (2018)
  • Author(s): Ishikawa T, Seki A, Hagiwara N and Makita N.
  • Organizer: 第82回日本循環器学会学術大会
• [Presentation] Clinical Manifestations and Long-term Mortality in Lamin A/C Mutation Carriers from the Japanese Multicenter Registry (2018)
  • Author(s): Nakajima K, Aiba T, Makiyama T, Nishiuchi S, Ohno S, Doi T, Shizuta S, Onoue K, Yagihara N, Ishikawa T, Watanabe I, Oginosawa Y, Nogami A, Aonuma K, Saitoh Y, Kimura T, Makita N, Shimizu W, Horie M and Kusano K.
  • Organizer: The 65th Annual Meeting of the Japan Heart Rhythm Society
• [Presentation] The inactivation of L-type Ca2+ Channel was impaired in Human iPS Cell Model of Long-QT Syndrome with CALM2-D134H Mutation. (2018)
  • Author(s): Yamamoto Y, Makiyama T, Harita T, Hayano M, Nishiuchi S, Wuriyanghai Y, Kohjitani H, Hirose S, Yokoi F, Ishikawa T, Ohno S, Chonabayashi K, Suda K, Yoshida Y, Horie M, Makita N and Kimura T.
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Single Cell Electrophysiological Analysis of Human iPS Cell-Derived Cardiomyocytes Generated from Long-QT Syndrome Patients Carrying a CALM2 Mutation Using a Membrane Voltage Imaging System (2018)
  • Author(s): Yamamoto Y, Makiyama T, Wuriyanghai Y, Kohjitani H, Hirose S, Gao J, Kashiwa A, Kimura T, Ishikawa T, Motomura H, Makita N, Ohno S, Chonabayashi K, Yoshida Y, Suda K and Horie M.
  • Organizer: The 11th Asia Pacific Heart Rhythm Society Scientific Session
• [Presentation] Naチャネルβ1サブユニット SCN1Bは致死性不整脈の原因遺伝子か？ (2018)
  • Author(s): 石川泰輔, 佐藤誠一, 髙橋一浩 and 蒔田直昌
  • Organizer: 第16回特発性心室細動研究会
  • Invited
• [Book] ゼロから学ぶブルガダ症候群 (2020)
  • Author(s): 石川泰輔, 蒔田直昌
  • Total Pages: 133
  • Publisher: 大道学館出版部
  • ISBN: 9784924391840
• [Book] 循環器科の心電図 (2018)
  • Author(s): 村川 裕二
  • Total Pages: 224
  • Publisher: 南江堂
  • ISBN: 9784524237913
• [Remarks] 国立循環器病研究センター 創薬オミックス解析センター ホームページ
  • URL: http://www.ncvc.go.jp/omics/research/project02.html