Identification and functional analysis of novel susceptibility genes for the development of pulmonary arterial hypertension

• Project/Area Number: 18K08154
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Kyorin University
• Principal Investigator: Inami Takumi 杏林大学, 医学部, 学内講師 (80580381)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肺動脈性肺高血圧症 / 全エクソーム解析 / 発症原因遺伝子 / 遺伝子解析 / 肺高血圧症

Outline of Final Research Achievements

BMPR2 has been reported as a causative gene for pulmonary arterial hypertension (PAH), but the pathogenic mechanism of PAH due to BMPR2 mutations has not been elucidated. We also identified RNF213 as a new susceptibility gene for PAH. In this study, we generated genetically modified mice with hot-spot mutations in BMPR2 and RNF213, respectively. Single-cell analysis using BMPR2 mutant mice has led to the elucidation of the pathogenic mechanism of PAH onset due to changes in gene expression levels of cells in lung tissue. In addition, verification using RNF213 mutant mice has led to the elucidation of the downstream signal pathway of RNF213 leading to the onset of angiopathy.

Academic Significance and Societal Importance of the Research Achievements

本研究では、難病疾患である肺動脈性肺高血圧症(PAH)の発症機序全容解明に繋がる研究成果を得ることができた。これらの成果はPAH患者の早期診断や早期治療介入による予後改善に繋がることが期待される。また、患者で認めるhot-spot変異を再現した遺伝子改変マウスを用いた本研究成果は、難病疾患領域における病態解明研究のモデルケースとして他難病疾患へも応用可能であり、学術的意義および社会的意義が高いものと考えられる。

Research Products

• [Journal Article] TET2 Variants in Japanese Patients With Pulmonary Arterial Hypertensio (2021)
  • Author(s): Hiraide T, Suzuki H, Shinya Y, Momoi M, Inami T, Katsumata Y, Fukuda K, Kosaki K, Kataoka M.
  • Journal Title: Cnadian Journal of Cardiology Volume: 4 Issue: 4 Pages: 416-419
  • DOI: 10.1016/j.cjco.2021.11.008
  • Peer Reviewed / Open Access
• [Journal Article] Pulmonary Arterial Hypertension Caused by AhR Signal Activation Protecting against Colitis. (2021)
  • Author(s): Hiraide T., Teratani T., Uemura S., Yoshimatsu Y., Naganuma M., Shinya Y., Momoi M., Kobayashi E., Hakamata Y., Fukuda K., Kanai T., Kataoka M.
  • Journal Title: Am J Respir Crit Care Med Volume: 203 Issue: 3 Pages: 385-388
  • DOI: 10.1164/rccm.202009-3385le
  • Peer Reviewed
• [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] 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] 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] 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