Molecular pathogenesis mechanism of idiopatic ventricular fibrillation related to Semapolin 3A gene

2016 Fiscal Year Annual Research Report

• Project/Area Number: 26461130
• Research Institution: Hiroshima University
• Principal Investigator: 中野 由紀子 広島大学, 病院(医), 講師 (10397911)
• Co-Investigator(Kenkyū-buntansha): 越智 秀典 広島大学, 医歯薬保健学研究院(医), 講師 (10415119)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: セマフォリン3A / 特発性心室細動 / 一塩基多型 / ブルガダ症候群

Outline of Annual Research Achievements

我々は特発性心室細動(IVF)症例で、セマフォリン3A遺伝子(SEMA3A)I334V一塩基多型(SNP)を有する症例が有意に多いことを発見した。SEMA3AI334Vを有する症例の中でも心室細動(VF)を発症している症例と発症していない症例があるため、SEMA3Aの他のSNPとの相互作用の有無をみる為、IVF症例83例と健常人2958人においてSEMA3A TagSNPのタイピングを行った。他のSEMA3A遺伝子内のSNPとの相互作用でVF発症の要因になるSNPは見つからなかった。同時に心房細動症例573例とIVFと類似した致死的不整脈疾患であるブルガダ症候群(BrS)についてもSEMA3A TagSNPのタイピングを行った。新たに、SEMA3ASNPrs17158533が心房細動と関連している事、rs3801593がBrSに関連する事を発見し、ホルター心電図を用いた自律神経解析との関連も明らかになった。今回、IVFのみならず、その他の不整脈疾患でも心臓交感神経に関与するSEMA3A遺伝子が関与することは大きな発見である。近年、BrSとの関連が報告されている、HEY2,SCN10A遺伝子についても検討し、BrSでも無症候の症例にHEY2遺伝子SNPが多いことを発見した。HEY2,SCN10A遺伝子とIVFとの関連、SEMA3Aとの相互作用についても検討したが、関連は見出せなかった。SEMA3A I334Vの有無で受容体との結合効率が違うかについてBinding assayを施行したがレセプター結合率に差を認めなかった。I334Vの存在により二量体を形成しにくくなっている可能性を考慮してBlue-Native PAGEでのダイマー形成も違いを検討したが、二量体形成に明らかな差を認めず、I334Vが心室細動を起こすメカニズムについては今後も引き続き検討が必要である。

Research Products

• [Journal Article] Genotype-Phenotype Correlation of SCN5A Mutation for the Clinical and Electrocardiographic Characteristics of Probands with Brugada Syndrome: A Japanese Multicenter Registry (2017)
  • Author(s): Yamagata K, Horie M, Aiba T, Ogawa S, Aizawa Y, Ohe T, Yamagishi M, Makita N, Sakurada H, Tanaka T, Shimizu A, Hagiwara N, Kishi R, Nakano Y. et al.
  • Journal Title: Circulation Volume: - Pages: -
  • DOI: 10.1161/CIRCULATIONAHA.117.027983
  • Peer Reviewed / Int'l Joint Research
• [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, Ohno S, Motomura H, Ogawa Y, Goto H, Minami T, Yagihara N, Watanabe H, Hasegawa K, Terasawa A, Mikami H, Ogino K, Nakano Y.et al.
  • Journal Title: Heart Volume: - Pages: -
  • DOI: 10.1136/heartjnl-2016-310617
  • Peer Reviewed
• [Journal Article] DNA damage in lymphocytes induced by cardiac CT and comparison with physical exposure parameters submitted to European Radiology (2017)
  • Author(s): Fukumoto K, Ishida M, Nakano Y, Ishida T, Tashiro S, Awai K
  • Journal Title: European Radiology Volume: 27(4） Pages: 1660-1666
  • DOI: 10.1007/s00330-016-4519-8
  • Peer Reviewed
• [Journal Article] Variants in the SCN5A Promoter Associated With Various Arrhythmia Phenotypes (2016)
  • Author(s): Yagihara N, Watanabe H, Barnett P, Duboscq-Bidot L, Thomas AC, Yang P, Ohno S, Hasegawa K, Kuwano R, Chatel S, Redon R, Schott JJ, Probst V, Koopmann TT, Bezzina CR, Wilde AA, Nakano Y, et al.
  • Journal Title: J Am Heart Assoc Volume: - Pages: -
  • DOI: 10.1161/JAHA.116.003644
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genetic variations of aldehyde dehydrogenase 2 and alcohol dehydrogenase 1B are associated with the etiology of atrial fibrillation in Japanese (2016)
  • Author(s): Nakano Y, Ochi H, Onohara Y, Sairaku A, Tokuyama T, Matsumura H, Tomomori S, Amioka M, Hironomobe N, Motoda C, Oda N, Chayama K, Chen CH, Gross ER, Mochly-Rosen D, Kihara Y
  • Journal Title: J Biomed Sci Volume: - Pages: -
  • DOI: 10.1186/s12929-016-0304-x
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Risk Stratification of Ventricular Fibrillation in Brugada Syndrome Using Noninvasive Scoring Methods (2016)
  • Author(s): Kawazoe H, Nakano Y, Ochi H, Takagi M, Hayashi Y, Uchimura Y, Tokuyama T, Watanabe Y, Matsumura H, Tomomori S, Sairaku A, Suenari K, Awazu A, Miwa Y, Soejima K, Chayama K, Kihara Y
  • Journal Title: Heart Rhythm Volume: 13(10） Pages: 1947-54
  • DOI: 10.1016/j.hrthm.2016.07.009
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Common Variant Near HEY2 Has a Protective Effect on Ventricular Fibrillation Occurrence in Brugada Syndrome by Regulating the Repolarization Current (2016)
  • Author(s): Nakano Y, Ochi H, Onohara Y, Toshishige M, Tokuyama T, Matsumura H, Kawazoe H, Tomomori, S, Sairaku A, Watanabe Y, Ikenaga H, Motoda C, Suenari K, Hayashida Y, Miki D, Oda N, Kishimoto S, Oda N,Yoshida Y, Tashiro S, Chayama K, Kihara Y
  • Journal Title: Circ Arrhythm Electrophysiol Volume: - Pages: -
  • DOI: 10.1161/CIRCEP.115.003436
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Genetics of long-QT syndrome (2016)
  • Author(s): Nakano Y, Shimizu W
  • Journal Title: J Hum Genet Volume: 61(1) Pages: 51-55
  • DOI: 10.1038/jhg.2015.74
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Who is the operator, that is the question: a multicentre study of catheter ablation of atrial fibrillation (2016)
  • Author(s): Sairaku A, Yoshida Y, Nakano Y, Maeda M, Hirayama H, Hashimoto H, Kihara Y
  • Journal Title: Europace Volume: 18(9) Pages: 1352-6
  • DOI: 10.1093/europace/euv424
  • Peer Reviewed
• [Journal Article] Increased left atrial pressure in non-heart failure patients with subclinical hypothyroidism and atrial fibrillation (2016)
  • Author(s): Sairaku A, Nakano Y, Uchimura Y, Tokuyama T, Kawazoe H, Watanabe Y, Matsumura H, Kihara Y
  • Journal Title: Endocr Connect Volume: 5(3) Pages: 101-106
  • DOI: 10.1530/EC-16-0012
  • Peer Reviewed
• [Journal Article] Electrical remodeling of the atrioventricular node caused by persistent atrial fibrillation in humans (2016)
  • Author(s): Sairaku A, Nakano Y, Suenari K, Tokuyama T, Kawazoe H, Matsumura H, Tomomori S, Amioka M, Kihara Y
  • Journal Title: J Cardiovasc Electrophysiol Volume: 27(8) Pages: 918-22
  • DOI: 10.1093/ehjci/jew039
  • Peer Reviewed
• [Journal Article] Don't expect left ventricular reverse remodeling after cardiac resynchronization therapy in patients with systolic heart failure and atrioventricular block: A multicenter study (2016)
  • Author(s): Sairaku A, Yoshida Y, Nakano Y, Hirayama H, Maeda M, Hashimoto H, Kihara Y
  • Journal Title: Int J Cardiol Volume: 221 Pages: 597-600
  • DOI: 10.1016/j.ijcard.2016.06.338
  • Peer Reviewed
• [Journal Article] Dexmedetomidine depresses sinoatrial and atrioventricular nodal function without any change in atrial fibrillation inducibility (2016)
  • Author(s): Sairaku A, Nakano Y, Suenari K, Tokuyama T, Kawazoe H, Matsumura H, Tomomori S, Amioka M, Kihara Y.
  • Journal Title: J Cardiovasc Pharmacol Volume: 68(6) Pages: 473-478
  • DOI: 10.1097/FJC.0000000000000434
  • Peer Reviewed
• [Presentation] Risk Stratification of Ventricular Fibrillation in Brugada Syndrome Using Clinical and Molecular Biological Parameters is useful for Deciding an Optimal Therapeutic Strategy (2017)
  • Author(s): Nakano Y, Kawazoe H, Ochi H, Sairaku A, Tokuyama T, Matsumura H, Tomomori S, Amioka M, Hironobe N, Motoda C, Onohara Y, Chayama K, Kihara Y
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17 – 2017-03-19
• [Presentation] Variants of Aldehyde Dehydrogenase 2 and Alcohol Dehydrogenase Genes are Associated with Atrial Fibrillation (2017)
  • Author(s): Nakano Y, Ochi H, Onohara Y, Sairaku A, Tokuyama T, Matsumura H, Tomomori S, Amioka M, Hironobe N, Motoda C, Oda N, Chayama K, Kihara Y
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17 – 2017-03-19
• [Presentation] Sinus Node Recovery Time and ZFHX3 SNP Minor Allele were Independent Predictors of Atrial Fibrillation Recurrence after Pulmonary Vein Isolation (2017)
  • Author(s): Tomomori S, Nakano Y, Tokuyama T, Sairaku A, Matsumura H, Amioka M, Hironobe N, Kihara Y
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17 – 2017-03-19
• [Presentation] Can NT-pro BNP predict left atrial pressure in patients with persistent atrial fibrillation: Lame duck or smart apple? (2017)
  • Author(s): Amioka M, Sairaku A, Hironobe N, Tomomori S, Matsumura H, Tokuyama T, Nakano Y, Kihara Y
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17 – 2017-03-19
• [Presentation] A common SCN5A polymorphism H558R modifies cis-allelic expression level of SCN5A by modulating DNA methylation of SCN5A promoters (2017)
  • Author(s): Matumura H, Nakano Y, Sairaku A, Tokuyama T, Tomomori S, Amioka M, Hironobe N, Kihara Y
  • Organizer: 第81回日本循環器学会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2017-03-17 – 2017-03-19
• [Presentation] Variants Of Aldehyde Dehydrogenase 2 And Alcohol Dehydrogenase Genes Are Associated With Atrial Fibrillation (2016)
  • Author(s): Nakano Y, Ochi H, Tomomori S, Matsumura H, Tokuyama T, Sairaku A, Motoda C, Chayama K, Chen C, Mochly-Rosen D, Kihara Y
  • Organizer: American Heart Association 2016
  • Place of Presentation: New Orleans,USA
  • Year and Date: 2016-11-12 – 2016-11-16
  • Int'l Joint Research
• [Presentation] A common SCN5A polymorphism H558R modifies clinical phenotype of Brugada syndrome by modulating DNA methylation of SCN5A promoters (2016)
  • Author(s): Matsumura H, Nakano Y, Sairaku A, Tokuyama T, Tomomori S, Amioka M, Hironobe N, Kihara Y
  • Organizer: American Heart Association 2016
  • Place of Presentation: New Orleans,USA
  • Year and Date: 2016-11-12 – 2016-11-16
  • Int'l Joint Research
• [Presentation] A common genetic variant within SCN10A modulates DNA methylation of SCN5A Promoters (2016)
  • Author(s): Hironobe N, Nakano Y, Tokuyama T, Sairaku A, Matsumura H, Tomomori S, Amioka M, Kihara Y
  • Organizer: American Heart Association 2016
  • Place of Presentation: New Orleans,USA
  • Year and Date: 2016-11-12 – 2016-11-16
  • Int'l Joint Research
• [Presentation] Risk Stratification of Ventricular Fibrillation in Brugada Syndrome Using Logistic Models of Noninvasive Parameters (2016)
  • Author(s): Nakano Y, Kawazoe H, Ochi H, Takagi M, Tokuyama T, Sairaku A, Matsumura H, Tomomori S, Amioka M, Kihara Y
  • Organizer: American Heart Association 2016
  • Place of Presentation: New Orleans,USA
  • Year and Date: 2016-11-12 – 2016-11-16
  • Int'l Joint Research
• [Presentation] A novel approach to tailor heparin dosage during ablation of atrial fibrillation: an assessment of sensitivity to unfractionated heparin (2016)
  • Author(s): Sairaku A, Nakano Y, Kihara Y
  • Organizer: American Heart Association 2016
  • Place of Presentation: New Orleans,USA
  • Year and Date: 2016-11-12 – 2016-11-16
  • Int'l Joint Research
• [Presentation] Common variant in PITX2 contributes to the pathogenesis of paroxysmal atrial fibrillation by impairing sinus node function and progression of atrial remodeling (2016)
  • Author(s): Tomomori S, Nakano Y, Tokuyama T, Sairaku A, Matsumura H, Amioka M, Hironobe N, Kihara Y
  • Organizer: American Heart Association 2016
  • Place of Presentation: New Orleans,USA
  • Year and Date: 2016-11-12 – 2016-11-16
  • Int'l Joint Research
• [Presentation] Sinus node recovery time and minor allele of ZFHX3 SNP were independent predictors of atrial fibrillation recurrence after pulmonary vein isolation (2016)
  • Author(s): Tomomori S, Nakano Y, Tokuyama T, Sairaku A, Matsumura H, Amioka M, Hironobe N, Kihara Y
  • Organizer: American Heart Association 2016
  • Place of Presentation: New Orleans,USA
  • Year and Date: 2016-11-12 – 2016-11-16
  • Int'l Joint Research
• [Presentation] Newly Developed Atrial Fibrillation Is an Unfavorable Sign of Anthracycline-induced Cardiomyopathy (2016)
  • Author(s): Amioka M, Sairaku A, Ochi T, Okada T, Asaoku H, Nakano Y, Kihara Y
  • Organizer: European Society of Cardiology 2016
  • Place of Presentation: Roma,Italy
  • Year and Date: 2016-08-27 – 2016-08-30
  • Int'l Joint Research
• [Presentation] Predictors of the pulmonary vein isolation responders in terms of left atrial deformation and hemodynamics in patients with atrial fibrillation (2016)
  • Author(s): Suenari K, Tomomori S, Matsumura H, Kawazoe H, Tokuyama T, Sairaku A, Nakano Y, Kihara Y
  • Organizer: European Society of Cardiology 2016
  • Place of Presentation: Roma,Italy
  • Year and Date: 2016-08-27 – 2016-08-30
  • Int'l Joint Research
• [Remarks] 不整脈により突然死を起こすブルガダ症候群（ポックリ病）の発症リスクが低減する遺伝子を発見
  • URL: https://www.hiroshima-u.ac.jp/med/news/14582