先制医療の実現にむけたエクソーム解析による遺伝性心筋症のリスク層別化の検討

• Project/Area Number: 26461072
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Ehime University
• Principal Investigator: 大木元 明義 愛媛大学, 医学部附属病院, 准教授 (00403832)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Discontinued (Fiscal Year 2015)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2016: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 心筋症 / 遺伝子解析 / 次世代シーケンサー / 遺伝性循環器疾患 / リスク層別化 / ターゲットリシーケンス

Outline of Annual Research Achievements

遺伝性循環器疾患ではサルコア蛋白などの原因遺伝子変異だけでなく，病態修飾遺伝子多型がその病態に大きく影響していることを報告してきた．既存の原因遺伝子解析では遺伝子変異同定率は約60％であり，病因と予後を解析するうえで限界があった．本研究では，遺伝性循環器疾患に対して網羅的にターゲット・リシーケンスを行い，遺伝性循環器疾患をより正確な診断群として分類することを目的とした．対象は60例（96例を予定）の遺伝性循環器疾患を対象にした．イルミナ社製の次世代シーケンサーMiSeqとTruSight Cardioキットを用いて，17の遺伝性循環器疾患における174遺伝子に対してターゲット・リシーケンス（0.57 Mb）を行った．平均リード深度は230，カバレッジ（20x）が97％であった． 平均297個/症例の遺伝子多型・変異（96%が既報）が確認できた．VariantStudioを使用して，アジア人1％未満のrare variantsを解析すると原因遺伝子候補が平均6個抽出できた．特に，心臓再同期療法や心臓移植登録を行った重症肥大型心筋症の4例では，MYBPC3遺伝子変異（各々Arg820Gln，Glu386Ter，Glu258Lys）だけでなく，まれなTTN遺伝子等の変異も重積していた（平均8個）．拡張型心筋症と刺激伝導系障害を合併する家系で，新規のLMNA遺伝子変異（Gln258HisfsTer222）を確認した．この変異は1塩基欠失によりフレームシフトがおこり，本来のLMNA蛋白よりも短い蛋白が翻訳されることが推察された． RBM20遺伝子（Ser75Leu)の重積変異の影響や，男性では女性に比較して若年で発症し重症化する可能性が推察され，早期の心臓再同期療法等による治療介入で病状の進展を抑制できる可能性が示された．今後も，先制医療に向けた新たな治療標的を探求する予定である．

Research Products

• [Journal Article] Characteristics of Left Atrial Deformation Parameters and Their Prognostic Impact in Patients with Pathological Left Ventricular Hypertrophy: Analysis by Speckle Tracking Echocardiography. (2015)
  • Author(s): Iio C, Inoue K, Nishimura K, Fujii A, Nagai T, Suzuki J, Okura T, Higaki J, Ogimoto A.
  • Journal Title: Echocardiography Volume: － Issue: 12 Pages: 1821-1830
  • DOI: 10.1111/echo.12961
  • Peer Reviewed
• [Journal Article] Takayasu arteritis and ulcerative colitis -high concurrence ratio and genetic overlap. (2015)
  • Author(s): Terao C, Matsumura T, Yoshifuji H, Kirino Y, Maejima Y, Kochi Y, Ogimoto A, Yamamoto M, Takahashi H, Nakayamada S, Saito K, Wada Y, Narita I, Kawaguchi Y, Yamanaka H, Ohmura K, Atsumi T, Tanemoto K, Miyata T, Kuwana M, Komuro I, Tabara Y, Ueda A, Isobe M, Mimori T, Matsuda F.
  • Journal Title: Arthritis Rheumatol. Volume: - Issue: 8 Pages: 2226-2232
  • DOI: 10.1002/art.39157
  • Peer Reviewed
• [Journal Article] Quantitative analysis of myocardial 18F-fluorodeoxyglucose uptake by PET/CT for detection of cardiac sarcoidosis. (2015)
  • Author(s): Yokoyama R, Miyagawa M, Okayama H, Inoue T, Miki H, Ogimoto A, Higaki J, Mochizuki T
  • Journal Title: J Cardiol Volume: 195 Pages: 180-7
  • DOI: 10.1016/j.ijcard.2015.05.075
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Impact of chronic use of cibenzoline on left ventricular pressure gradient and left ventricular remodeling in patients with hypertrophic obstructive cardiomyopathy. (2015)
  • Author(s): Hamada M, Ikeda S, Ohshima K, Nakamura M, Kubota N, Ogimoto A, Shigematsu Y.
  • Journal Title: J Cardiol Volume: － Issue: 3 Pages: 279-286
  • DOI: 10.1016/j.jjcc.2015.05.014
  • Peer Reviewed
• [Journal Article] Aortic prosthetic graft infection detected by 18F-fluorodeoxyglucose positron emission tomography/computed tomography. (2015)
  • Author(s): Kono T, Ogimoto A, Iio C, Fujimoto K, Fujii A, Uetani T, Nagai T, Nishimura K, Inoue K, Suzuki J, Hiasa G, Okayama H, Okura T, Miyagawa M, Mochizuki T
  • Journal Title: Int J Cardiol. Volume: 203 Pages: 972-974
  • DOI: 10.1016/j.ijcard.2015.11.069
  • Peer Reviewed / Open Access
• [Journal Article] Cardiac resynchronization therapy in a young patient with Duchenne muscular dystrophy. (2015)
  • Author(s): Kono T, Ogimoto A, Nishimura K, Yorozuya T, Okura T, Higaki J. Cardiac resynchronization therapy in a young patient with Duchenne muscular dystrophy.
  • Journal Title: Int Med Case Rep J Volume: 8 Pages: 173-5
  • DOI: 10.2147/imcrj.s87512
  • Peer Reviewed
• [Journal Article] Association between Genetic Variation in the SCN10A Gene and Cardiac Conduction Abnormalities in Patients With Hypertrophic Cardiomyopathy. (2015)
  • Author(s): Iio C, Ogimoto A, et al
  • Journal Title: Int Heart J Volume: 56
  • NAID: 130005087577
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Fusion image of coronary artery and myocardial perfusion using computed tomography. (2015)
  • Author(s): Kido T, Kuata A, Uetani T, Tanabe Y, Nishiyama H, Ogimoto A, Izutani H, Mochizuki T.
  • Journal Title: Ann Thorac Surg Volume: 99 Issue: 2 Pages: 715-715
  • DOI: 10.1016/j.athoracsur.2014.09.065
  • Peer Reviewed
• [Journal Article] Possible role of angiotensin-converting enzyme 2 and activation of angiotensin II type 2 receptor by angiotensin-(1-7) in improvement of vascular remodeling by angiotensin II type 1 receptor blockade (2014)
  • Author(s): Ohshima K, Mogi M(31人中②), et al
  • Journal Title: Hypertension Volume: 63 Issue: 3
  • DOI: 10.1161/hypertensionaha.113.02426
  • Peer Reviewed / Open Access
• [Journal Article] Positron emission tomography-computed tomography for imaging of inflammatory cardiovascular diseases. (2014)
  • Author(s): Miyagawa M, Yokoyama R, Nishiyama Y, Ogimoto A, Higaki J, Mochizuki T.
  • Journal Title: Circ J Volume: 78 Pages: 1302-10
  • Peer Reviewed / Open Access
• [Journal Article] Three-dimensional phase-sensitive inversion recovery sequencing in the evaluation of left ventricular myocardial scars in ischemic and non-ischemic cardiomyopathy: Comparison to three-dimensional inversion recovery sequencing. (2014)
  • Author(s): Kido T, Kido T, Nakamura M, Kawaguchi N, Nishiyama Y, Ogimoto A, Miyagawa M, Mochizuki T.
  • Journal Title: Eur J Radiol Volume: 83 Issue: 12 Pages: 2159-66
  • DOI: 10.1016/j.ejrad.2014.09.014
  • Peer Reviewed
• [Journal Article] Cardiac magnetic resonance imaging for assessment of steroid therapy in a patient with cardiac sarcoidosis and a magnetic resonance-conditional pacemaker (2014)
  • Author(s): Kono T, Ogimoto A, Saito M, Fujimoto K, Fujii A, Uetani T, Nagai T, Nishimura K, Inoue K, Suzuki J, Okura T, Kido T, Miyagawa M, Mochizuki T, Higaki J.
  • Journal Title: Int J Cardiol Volume: 176 Issue: 3 Pages: e89-e91
  • DOI: 10.1016/j.ijcard.2014.07.157
  • Peer Reviewed
• [Journal Article] Optimization of coronary attenuation in coronary computed tomography angiography using diluted contrast material. (2014)
  • Author(s): Kawaguchi N, Kurata A, Kido T, Nishiyama Y, Kido T, Miyagawa M, Ogimoto A, Mochizuki T.
  • Journal Title: Circ J Volume: 78 Pages: 662-70
  • NAID: 130003382244
  • Peer Reviewed / Open Access
• [Journal Article] Combined supine and prone myocardial perfusion SPECT with a cadmium-zinc telluride camera for detection of coronary artery disease. (2014)
  • Author(s): Nishiyama Y, Miyagawa M, Kawaguchi N, Nakamura M, Kido T, Kurata A, Kido T, Ogimoto A, Higaki J, Mochizuki T.
  • Journal Title: Circ J Volume: 78 Pages: 1169-75
  • Peer Reviewed / Open Access
• [Presentation] Genotype-Phenotype Correlations in Dilated-Phase Hypertrophic Cardiomyopathy Patients with Cardiac Resynchronization Therapy or Left Ventricular Assist Device by Next Generation Sequencing. (2016)
  • Author(s): Iio C, Ogimoto A, et al
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センターetc.（宮城県仙台市）
  • Year and Date: 2016-03-18
• [Presentation] Targeted Next Generation Sequencing of 174 Genes in Patients with Cardiomyopathy for Future Clinical Utility. (2016)
  • Author(s): Higashi H, Ogimoto A, et al
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センターetc.（宮城県仙台市）
  • Year and Date: 2016-03-18
• [Presentation] MYBPC3 Truncation Mutation Induces Heart Failure and Reduced Ca Transient Amplitude in Zebrafish. (2016)
  • Author(s): Ogimoto A, et al.
  • Organizer: 第80回日本循環器学会学術集会
  • Place of Presentation: 仙台国際センターetc.（宮城県仙台市）
  • Year and Date: 2016-03-18
  • Invited
• [Presentation] Myosin Binding Protein C Gene Mutation (S593Pfs*9) Induces Heart Failure and Reduced Ca Transient Amplitude in Zebrafish. (2015)
  • Author(s): Ogimoto A, et al
  • Organizer: American Heart Association Scientific Sessions 2015
  • Place of Presentation: Orlando FL（USA）
  • Year and Date: 2015-11-07
• [Presentation] Cumulative and Individual Effects of Single Nucleotide Polymorphisms for Atrial Fibrillation by Meta-Analysis of Genome-Wide Association Studies in Patients with Heart Failure. (2015)
  • Author(s): Fujii A, Ogimoto A, et al
  • Organizer: American College of Cardiology
  • Place of Presentation: San Diego, USA
  • Year and Date: 2015-03-14 – 2015-03-16