Clarification of epigenetic pathological mechanisms in pulmonary hypertension through Japanese high-volume sample library

• Project/Area Number: 15H05665
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Cardiovascular medicine
• Research Institution: Keio University
• Principal Investigator: KATAOKA Masaharu 慶應義塾大学, 医学部(信濃町), 講師 (20445208)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥21,710,000 (Direct Cost: ¥16,700,000、Indirect Cost: ¥5,010,000); Fiscal Year 2018: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000); Fiscal Year 2015: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
• Keywords: 肺動脈性肺高血圧症 / 全エクソーム解析 / long non-coding RNA / 肺高血圧症 / ゲノム解析 / エピジェネティクス / 発症原因遺伝子 / 循環器病学 / 長鎖非コーディングRNA / 病態医学

Outline of Final Research Achievements

In this study, we aimed to search for novel causative genes of pulmonary arterial hypertension (PAH) and to elucidate the roles of long non-coding RNA in PAH by collecting large samples from Japanese PAH patients. SOX17 and RNF213 were identified as novel causative genes of PAH by whole exome sequencing. Furthermore, we succeeded in narrowing down long non-coding RNAs (lncRNAs), which are thought to have the important epigenetic roles for the pathogenesis of PAH through multidisciplinary analysis including lncRNA array.

Academic Significance and Societal Importance of the Research Achievements

欧米を中心として、患者サンプルを収集したドライビッグデータは既に存在しており、数々のエビデンスも報告されている。しかしながら、海外からのエビデンスをそのまま日本人患者へ応用することはリスクを伴う。多人種による異質性が高い海外の解析結果に比べ、統一プロトコールで収集した均質性の高い日本人患者の臨床検体から得られた本研究での知見は、日本人患者の病態に最適化した個別化医療の実現にとって非常に重要な基盤になると考える。海外の報告例は、必ずしも本邦の患者病態を反映していることは限らないことから、日本人患者に最適化された医療を提供することが極めて重要であり、我々の研究の意義は大きい。

Research Products

• [Journal Article] Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension (2020)
  • Author(s): Hiraide Takahiro、Kataoka Masaharu、Suzuki Hisato、Aimi Yuki、Chiba Tomohiro、Isobe Sarasa、Katsumata Yoshinori、Goto Shinichi、Kanekura Kohsuke et al.,
  • Journal Title: The Journal of Heart and Lung Transplantation Volume: 39 Issue: 2 Pages: 103-112
  • DOI: 10.1016/j.healun.2019.08.022
  • Peer Reviewed
• [Journal Article] Genetics in pulmonary arterial hypertension in a large homogeneous Japanese population (2018)
  • Author(s): Gamou S.、Kataoka M.、Aimi Y.、Chiba T.、Momose Y.、Isobe S.、Hirayama T.、Yoshino H.、Fukuda K.、Satoh T.
  • Journal Title: Clinical Genetics Volume: - Issue: 1 Pages: 70-80
  • DOI: 10.1111/cge.13154
  • Peer Reviewed / Open Access
• [Journal Article] SOX17 Mutations in Japanese Patients with Pulmonary Arterial Hypertension (2018)
  • Author(s): Hiraide Takahiro、Kataoka Masaharu、Suzuki Hisato、Aimi Yuki、Chiba Tomohiro、Kanekura Kohsuke、Satoh Toru、Fukuda Keiichi、Gamou Shinobu、Kosaki Kenjiro
  • Journal Title: American Journal of Respiratory and Critical Care Medicine Volume: 198 Issue: 9 Pages: 1231-1233
  • DOI: 10.1164/rccm.201804-0766le
  • Peer Reviewed
• [Journal Article] Genomic Comparison With Supercentenarians Identifies RNF213 as a Risk Gene for Pulmonary Arterial Hypertension (2018)
  • Author(s): Suzuki Hisato、Kataoka Masaharu、Hiraide Takahiro、Aimi Yuki、Yamada Yoshitake、Katsumata Yoshinori、Chiba Tomohiro、Kanekura Kohsuke、Isobe Sarasa、Sato Yasunori、Satoh Toru、Gamou Shinobu、Fukuda Keiichi、Kosaki Kenjiro
  • Journal Title: Circulation: Genomic and Precision Medicine Volume: 11 Issue: 12
  • DOI: 10.1161/circgen.118.002317
  • Peer Reviewed
• [Journal Article] Familial Chronic Thromboembolic Pulmonary Hypertension in a Pair of Japanese Brothers. (2016)
  • Author(s): Kataoka M, Momose Y, Aimi Y, Fukuda K, Gamou S, Satoh T.
  • Journal Title: Chest Volume: 150 Issue: 3 Pages: 748-749
  • DOI: 10.1016/j.chest.2016.06.021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Improved Survival of Patients with Pulmonary Arterial Hypertension with BMPR2 Mutations in the Last Decade. (2016)
  • Author(s): Isobe S, Kataoka M, Aimi Y, Gamou S, Satoh T, Fukuda K.
  • Journal Title: Am J Respir Crit Care Med Volume: 193 Issue: 11 Pages: 1310-1314
  • DOI: 10.1164/rccm.201601-0158le
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 発症分子病態から迫る肺動脈性肺高血圧症治療の展望 (2019)
  • Author(s): 片岡雅晴
  • Organizer: 第83回日本循環器学会学術集会
  • Invited
• [Book] 実験医学別冊: もっとよくわかる！循環器学と精密医療 (2020)
  • Author(s): 片岡雅晴
  • Total Pages: 13
  • Publisher: 羊土社
  • ISBN: 9784758122085