Investigation on pathogenesis of pulmonary diseases due to nontuberculous mycobacteria using human genomic analysis

• Project/Area Number: 19H03704
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54030:Infectious disease medicine-related
• Research Institution: Keio University
• Principal Investigator: HASEGAWA Naoki 慶應義塾大学, 医学部(信濃町), 教授 (20198724)
• Co-Investigator(Kenkyū-buntansha): 石井 誠 慶應義塾大学, 医学部(信濃町), 准教授 (30317333) ; 西村 知泰 慶應義塾大学, 保健管理センター(日吉), 講師 (90348649)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2021: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2019: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: 肺非結核性抗酸菌症 / 肺NTM症 / 肺MAC症 / モデルマウス / 気道上皮細胞 / GWAS / CHP2 / 肺非結核性抗酸菌(NTM)症 / 気管支拡張症 / 疾患感受性遺伝子

Outline of Research at the Start

肺非結核性抗酸菌(NTM)症は主に中高年以降の女性や既存肺疾患のある患者に好発する難治性の慢性進行性呼吸器感染症であり、本邦で急激に増加している。NTMは弱毒菌であるにも関わらず治癒が困難であり、好発する人種・性別・家族集積性などから疾患感受性遺伝子の存在が示唆されている。今回、肺NTM症患者の遺伝子検体から判明した疾患感受性遺伝子の候補について細胞培養および遺伝子改変マウスを用いた感染実験によりその機能解析を行い、病態・臨床像を明らかにすることを目的とする。

Outline of Final Research Achievements

Nontuberculous mycobacteria (NTM) causes chronic respiratory infection. Although NTM, including MAC bacteria, is a low-virulent mycobacteria in the environment, such as water and soil, pulmonary NTM disease occures mainly in middle-aged/older slender women, suggesting the existence of disease susceptibility genes. In this study, we conducted a genome-wide association study to compare genotypes between patients with pulmonary MAC disease and controls, and confirmed that genetic variation in the Calcineurin B homologous protein 2 (CHP2) region, which plays an important role in regulating intracellular and extracellular ions and pH, is highly associated with the risk of disease onset.

Academic Significance and Societal Importance of the Research Achievements

世界で初めて肺 MAC 症患者と対照者との遺伝子型を網羅的に比較するゲノムワイド関連解析を実施し、細胞内外のイオンや pH の調整に重要な役割を担う Calcineurin B homologous protein2領域の遺伝的変異が発症リスクと高い関連性を示すことを確認しました。新たな治療戦略の開発および臨床現場においては疾患感受性遺伝子型に基づく個別化医療の実現に寄与する可能性が期待されます。

Research Products

• [Journal Article] Genome-wide association study in patients with pulmonary Mycobacterium avium complex disease (2021)
  • Author(s): Ho Namkoong, Yosuke Omae, Takanori Asakura, Makoto Ishii, Shoji Suzuki, Kozo Morimoto, Yosuke Kawai, Katsura Emoto, Andrew J. Oler, Eva P. Szymanski, Mitsunori Yoshida, et al.
  • Journal Title: European Respiratory Journal Volume: 57 Issue: 2 Pages: 1902269-1902269
  • DOI: 10.1183/13993003.02269-2019
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Host Genetic Analysis of Pulmonary NTM Disease and Non-CF Bronchietasis. (2020)
  • Author(s): Namkoong H, Omae Y, Asakura T, Ishii M, Suzuki S, Morimoto K, Yoshida M, Emoto K, Oler AJ, Szymanski EP, Matsuda S, Yagi K, Hase I, Nishimura T,他25名,Hasegawa N
  • Organizer: International Conference of American Thoracic Society.
  • Int'l Joint Research
• [Presentation] Genome-Wide Association Study in Patients with Pulmonary Mycobacterium Avium complex Disease. (2019)
  • Author(s): Namkoong H, Omae Y, Asakura T, Yoshida M, Suzuki S, Morimoto K, A J Oler, E P Szymanski, Matsuda S, Yagi K, Ishii M, Hase I, Nishimura T, Sasaki Y, Asami T, Shiomi T, Matsubara H, Shimada H, Ato M, Kosaki K, Betsuyaku T, Kurashima A, H Tettelin , K N Oliver, Hoshino Y, S M Holland, Tokunaga K, Hasegawa N
  • Organizer: International Conference of American Thoracic Society
  • Int'l Joint Research
• [Book] 非結核性抗酸菌症マネジメント (2020)
  • Author(s): 南宮湖, 長谷川直樹 (編集)菊池利明, 渡辺彰
  • Total Pages: 212
  • Publisher: 日本医事新報社