Endotypes of Refractory Airway Diseases: A Comprehensive Genomic Exploration of Gene Networks

• Project/Area Number: 19H03663
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: University of Tsukuba
• Principal Investigator: Hizawa Nobuyuki 筑波大学, 医学医療系, 教授 (00301896)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2021: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2020: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2019: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 喘息 / COPD / エンドタイプ / ネットワーク / CDHR3 / ORMDL3 / ETV4 / 遺伝子交互作用 / 遺伝子リスクスコア / 精密医療 / 分子ネットワーク

Outline of Research at the Start

本研究では遺伝子相互作用によって構築される分子ネットワークを探索し、喘息やCOPDの発症や重症度を規定する難治性気道疾患のエンドタイプの解明を目指す。ライノウイルス易感染性CDHR3遺伝子，アレルギー性炎症TSLP遺伝子，さらには小胞体ストレス応答やオートファジー制御に関連したORMDL3/GSDMB遺伝子に着目し，これらの遺伝子と相互作用をする遺伝子群をゲノム網羅的に探索し，複数の分子ネットワークを同定する。個々の分子ネットワークを構成する遺伝子群から計算される遺伝的リスクスコアと疾患フェノタイプとの関連を検討し、Precision Medicineを可能とする基盤データの創出を目指す。

Outline of Final Research Achievements

Behind the diverse phenotypes of asthma and COPD, there are complex molecular networks (endotypes) driven by multiple genetic and environmental factors, and the elucidation of molecular networks established by gene-gene interactions is essential for understanding their pathogenesis. In this study, we specifically identified 1) the interaction between rhinovirus susceptibility CDHR3 gene and atopy-related genetic risk score in the development of asthma and COPD, 2) the interaction between CDHR3 gene and ORMDL3 gene, an ER stress response molecule, and 3) the significant associations between eQTLs at the ETS translocation variant (ETV4), which defines asthma-related gene expression network, and asthma development as well as serum IL-6 levels in healthy subjects.

Academic Significance and Societal Importance of the Research Achievements

CDHR3遺伝子の喘息発症に及ぼす影響は、Atopy-GRSやORMDL3遺伝子の影響を強く受けていることが判明した。また、IL-6やTh17と関連する転写因子ETV4が幅広く喘息と関連することが明らかとなった。本研究の成果は、好中球性炎症やライノウイルス感受性分子ネットワークに関連したバイオマーカーや新規治療ターゲットの同定、さらには病名ではなく患者ごとにエンドタイプに基づいたPrecision Medicine（精密医療）やPreemptive Medicine（先制医療）を可能とするための基盤データの創出につながる。

Research Products

• [Journal Article] Common exacerbation-prone phenotypes across asthma and chronic obstructive pulmonary disease (COPD). (2022)
  • Author(s): Hyodo K, Masuko H, Oshima H, Shigemasa R, Kitazawa H, Kanazawa J, Iijima H, Ishikawa H, Kodama T, Nomura A, Kagohashi K, Satoh H, Saito T, Sakamoto T, Hizawa N.
  • Journal Title: PLoS One Volume: 17 Issue: 3 Pages: e0264397-e0264397
  • DOI: 10.1371/journal.pone.0264397
  • Peer Reviewed / Open Access
• [Journal Article] Expression quantitative trait loci for ETV4 and MEOX1 are associated with adult asthma in Japanese populations. (2021)
  • Author(s): Yatagai Y, Oshima H, Sakamoto T, Shigemasa R, Kitazawa H, Hyodo K, Masuko H, Iijima H, Naito T, Saito T, Hirota T, Tamari M, Hizawa N.
  • Journal Title: Sci Reports Volume: 11 Issue: 1 Pages: 18791-18791
  • DOI: 10.1038/s41598-021-98348-3
  • Peer Reviewed / Open Access
• [Journal Article] <i>ORMDL3/GSDMB</i> genotype as a risk factor for early-onset adult asthma is linked to total serum IgE levels but not to allergic sensitization (2021)
  • Author(s): Kitazawa H, Masuko H, Kanazawa J, Shigemasa R, Hyodo K, Yamada H, Yatagai Y, Kaneko Y, Iijima H, Naito T, Saito T, Noguchi E, Konno S, Hirota T, Tamari M, Sakamoto T, Hizawa N
  • Journal Title: Allergology International Volume: 70 Issue: 1 Pages: 55-60
  • DOI: 10.1016/j.alit.2020.04.009
  • NAID: 130007966769
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed
• [Journal Article] <i>ORMDL3/GSDMB</i> genotype is associated with distinct phenotypes of adult asthma (2021)
  • Author(s): Kitazawa H, Masuko H, Kanazawa J, Shigemasa R, Hyodo K, Yamada H, Yatagai Y, Kaneko Y, Iijima H, Naito T, Saito T, Noguchi E, Konno S, Hirota T, Tamari M, Sakamoto T, Hizawa N.
  • Journal Title: Allergology International Volume: 70 Issue: 4 Pages: 495-497
  • DOI: 10.1016/j.alit.2021.04.004
  • NAID: 130008103675
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed
• [Journal Article] Transcriptome genetic differences between responders and non-responders before bronchial thermoplasty (2021)
  • Author(s): Ano Satoshi、Kikuchi Norihiro、Matsuyama Masashi、Nakajima Masayuki、Kondo Yuzuru、Masuda Michiko、Osawa Hajime、Ishii Yukio、Hizawa Nobuyuki
  • Journal Title: Journal of Asthma Volume: - Issue: 8 Pages: 1-11
  • DOI: 10.1080/02770903.2021.1945088
  • Peer Reviewed
• [Journal Article] Dust mite-dominant sensitization pattern as a causal factor for adult-onset asthma (2021)
  • Author(s): Shigemasa R, Masuko H, Oshima H, Hyodo K, Kitazawa H, Kanazawa J, Iijima H, Naito T, Saito T, Sakamoto T, Hizawa N
  • Journal Title: Allergology International Volume: 70 Issue: 3 Pages: 368-369
  • DOI: 10.1016/j.alit.2021.02.004
  • NAID: 130008064029
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Genetic impact of CDHR3 on the adult onset of asthma and COPD (2020)
  • Author(s): Shigemasa R, Masuko H, Hyodo K, Kitazawa H, Kanazawa J, Yatagai Y, Iijima H, Naito T, Saito T, Hirota T, Tamari M, Sakamoto T, Hizawa N
  • Journal Title: Clin Exp Allergy Volume: 50 Issue: 11 Pages: 1223-1229
  • DOI: 10.1111/cea.13699
  • Peer Reviewed / Open Access
• [Journal Article] Effects of Lung Function-Related Genes and TSLP on COPD Phenotypes (2020)
  • Author(s): Yamada H, Hida N, Masuko H, Sakamoto T, Hizawa N
  • Journal Title: COPD Volume: 17 Issue: 1 Pages: 59-64
  • DOI: 10.1080/15412555.2019.1708296
  • NAID: 120007127638
  • Peer Reviewed
• [Journal Article] A genetic variant near <i>TSLP</i> is associated with chronic rhinosinusitis with nasal polyps and aspirin-exacerbated respiratory disease in Japanese populations (2020)
  • Author(s): Nakayama T, Hirota T, Asaka D, Sakashita M, Ninomiya T, Morikawa T, Okano M, Haruna S, Yoshida N, Takeno S, Tanaka Y, Yoshikawa M, Ishitoya J, Hizawa N, Isogai S, Mitsui C, Taniguchi M, Kojima H, Fujieda S, Tamari M
  • Journal Title: Allergology International Volume: 69 Issue: 1 Pages: 138-140
  • DOI: 10.1016/j.alit.2019.06.007
  • NAID: 130007788675
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] A cis-eQTL allele regulating reduced expression of CHI3L1 is associated with late-onset adult asthma in Japanese cohorts. (2019)
  • Author(s): Kanazawa J, Kitazawa H, Masuko H, Yatagai Y, Sakamoto T, Kaneko Y, Iijima H, Naito T, Saito T, Noguchi E, Konno S, Nishimura M, Hirota T, Tamari M, Hizawa N
  • Journal Title: BMC Med Genet Volume: 20 Issue: 1 Pages: 58-68
  • DOI: 10.1186/s12881-019-0786-y
  • NAID: 120007127949
  • Peer Reviewed / Open Access
• [Presentation] 成人喘息における増悪関連フェノタイプの検討―多施設共同による観察研究― (2021)
  • Author(s): 檜澤伸之
  • Organizer: 第70回日本アレルギー学会学術大会
• [Presentation] 閉塞性肺疾患におけるTreatable trait approach (2021)
  • Author(s): 檜澤伸之
  • Organizer: 第70回日本アレルギー学会学術大会
• [Presentation] 経皮感作と喘息 (2021)
  • Author(s): 檜澤伸之
  • Organizer: 第70回日本アレルギー学会学術大会
• [Presentation] 成人喘息発症におけるORMDL3/GSDMC遺伝子とCDHR3遺伝子との相互作用 (2021)
  • Author(s): 北澤晴奈
  • Organizer: 第70回日本アレルギー学会学術大会
• [Presentation] ETV4遺伝子の発現量的形質遺伝子座（eQTL）と日本人喘息との関連 (2021)
  • Author(s): 大島央之
  • Organizer: 第70回日本アレルギー学会学術大会
• [Presentation] 喘息のフェノタイプとエンドタイプーPrecision medicineに向けて (2020)
  • Author(s): 檜澤伸之
  • Organizer: 第69回日本アレルギー学会学術大会
• [Presentation] ORMDL3/GSDMB genotype as a risk factor for early-onset adult asthma is linked to total serum IgE levels but not to atopy (2020)
  • Author(s): Kitazawa H
  • Organizer: ATS 2020 International Conference
  • Int'l Joint Research
• [Presentation] ORMDL3/GSDMB遺伝子多型が成人喘息に与える影響 (2020)
  • Author(s): 北澤春奈
  • Organizer: 第60回日本呼吸器学会学術講演会
• [Presentation] Genetic Impact Of CDHR3 On The Adult Onset Of Chronic Inflammatory Airway Diseases (2020)
  • Author(s): Shigemasa R
  • Organizer: ATS 2020 International Conference
  • Int'l Joint Research
• [Presentation] Genetic Impact of CDHR3 on the Adult Onset of Chronic Inflammatory Airway Diseases (2020)
  • Author(s): Rie Shigemasa and Nobuyuki Hizawa
  • Organizer: the 2020 ATS International Conference
  • Int'l Joint Research
• [Presentation] ORMDL3/GSDMB Genotype As A Risk Factor For Early-onset Adult Asthma Is Linked To Total Serum IgE Levels But Not To Atopy (2020)
  • Author(s): Haruna Kitazawa and Nobuyuki Hizawa
  • Organizer: the 2020 ATS International Conference
  • Int'l Joint Research