Endotypes of severe airway diseases based on genomic information

• Project/Area Number: 15H04827
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: University of Tsukuba
• Principal Investigator: Hizawa Nobuyuki 筑波大学, 医学医療系, 教授 (00301896)
• Co-Investigator(Renkei-kenkyūsha): NOGUCHI Emiko 筑波大学, 医学医療系, 教授 (40344882) ; TAMARI Mayumi 東京慈恵会医科大学, 総合医科学研究センター, 教授 (00217184)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2017: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2016: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
• Keywords: Endotype / Phenotype / Asthma / COPD / Precision medicine / CDHR3 / YKL-40 / Tyro3 / 喘息 / TYRO3 / エンドタイプ / フェノタイプ / 遺伝因子 / 遺伝子

Outline of Final Research Achievements

Identification of genetic factors associated with severe airway diseases allows us to understand the pathogenesis of diseases and to implement precision medicine based on endotypes. We found that the CDHR3 gene, which is the receptor for rhinovirus C, is associated with a specific phenotype of adult asthma characterized by early-onset, atopic and decreased FEV1. We also found that the CHI3L1 gene encoding YKL-40, which is a negative regulator of inflammasome, is associated with adult-onset non-smoking asthma. Furthermore, we found that the TAM family receptor tyrosine kinase TYRO3, which is a negative regulator of type 2 immunity, is associated with allergic sensitization to common inhalant allergens or allergic rhinitis. These finding indicated the presence of endotypes each associated with increased susceptibility to viral infection, aberrant activation of inflammasome or increased susceptibility to allergic sensitization underlying asthma and COPD.

Research Products

• [Journal Article] Variants at HLA-A, HLA-C, and HLA-DQB1 confer risk of psoriasis vulgaris in Japanese. (2018)
  • Author(s): Hirata J, --- Saeki H, et al
  • Journal Title: J Invest Dermatol Volume: 138 Issue: 3 Pages: 542-548
  • DOI: 10.1016/j.jid.2017.10.001
  • NAID: 120007134453
  • Peer Reviewed / Open Access
• [Journal Article] The distribution of blood eosinophil levels in a Japanese COPD clinical trial database and in the rest of the world (2018)
  • Author(s): Barnes N, Ishii T, Hizawa N, Midwinter D, James M, Hilton E, Jones PW
  • Journal Title: Int J Chron Obstruct Pulmon Dis Volume: 13 Pages: 433-440
  • DOI: 10.2147/copd.s144108
  • NAID: 120007134336
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] How important is allergic sensitization as a cause of atopic asthma? (2018)
  • Author(s): Kanazawa J, Masuko H, Yamada H, Yatagai Y, Sakamoto T, Kitazawa H, Iijima H, Naito T, Hirota T, Tamari M, Hizawa N
  • Journal Title: Allergology International Volume: 67 Issue: 2 Pages: 292-294
  • DOI: 10.1016/j.alit.2017.10.005
  • NAID: 130006721768
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [Journal Article] Association study of childhood food allergy with genome-wide association studies-discovered loci of atopic dermatitis and eosinophilic esophagitis. (2017)
  • Author(s): Hirota T, et al
  • Journal Title: J Allergy Clin Immunol Volume: 140 Issue: 6 Pages: 1713-1716
  • DOI: 10.1016/j.jaci.2017.05.034
  • Peer Reviewed
• [Journal Article] Genetic association of the functional <i>CDHR3</i> genotype with early-onset adult asthma in Japanese populations (2017)
  • Author(s): Kanazawa J, Masuko H, Yatagai Y, Sakamoto T, Yamada H, Kaneko Y, Kitazawa H, Iijima H, Naito T, Saito T, Noguchi E, Konno S, Nishimura M, Hirota T, Tamari M, Hizawa N
  • Journal Title: Allergology International Volume: 66 Issue: 4 Pages: 563-567
  • DOI: 10.1016/j.alit.2017.02.012
  • NAID: 130006179446
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] IL-17F induces IL-6 via TAK1-NFκB pathway in airway smooth muscle cells (2017)
  • Author(s): Masayuki Nakajima, Mio Kawaguchi, Kyoko Ota, Junichi Fujita, Satoshi Matsukura, Shau-Ku Huang, Yuko Morishima, Yukio Ishii, Hiroaki Satoh, Tohru Sakamoto, Nobuyuki Hizawa.
  • Journal Title: Immunity, Inflammation and Disease Volume: 3 Issue: 2 Pages: 1-8
  • DOI: 10.1002/iid3.149
  • NAID: 120007129102
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Effects of the common polymorphism in the human aldehyde dehydrogenase 2 (ALDH2) gene on the lung (2017)
  • Author(s): Kuroda Aoi、Hegab Ahmed E.、Jingtao Gao、Yamashita Shuji、Hizawa Nobuyuki、Sakamoto Tohru、Yamada Hideyasu、Suzuki Satoshi、Ishii Makoto、Namkoong Ho、Asakura Takanori、Ozaki Mari、Yasuda Hiroyuki、Hamamoto Junko、Kagawa Shizuko、Soejima Kenzo、Betsuyaku Tomoko
  • Journal Title: Respir Res Volume: 18 Issue: 1 Pages: 69-69
  • DOI: 10.1186/s12931-017-0554-5
  • NAID: 120007129115
  • Peer Reviewed / Open Access
• [Journal Article] GENETIC STUDIES OF ALLERGIC DISEASES BASED ON PHENOTYPES (2017)
  • Author(s): 檜澤伸之
  • Journal Title: Japanese Journal of Allergology Volume: 66 Issue: 2 Pages: 71-75
  • DOI: 10.15036/arerugi.66.71
  • NAID: 130005466689
  • ISSN: 0021-4884, 1347-7935
  • Peer Reviewed
• [Journal Article] ENDOTYPES OF NEUTROPHILIC AIRWAY INFLAMMATION (2017)
  • Author(s): 檜澤伸之
  • Journal Title: Japanese Journal of Allergology Volume: 66 Issue: 8 Pages: 1007-1010
  • DOI: 10.15036/arerugi.66.1007
  • NAID: 130006077600
  • ISSN: 0021-4884, 1347-7935
  • Peer Reviewed
• [Journal Article] Variants near the HLA complex group 22 gene (HCG22) confer increased susceptibility to late-onset asthma in Japanese populations. (2016)
  • Author(s): Yatagai Y, Hirota T, Sakamoto T, Yamada H, Masuko H, Kaneko Y, Iijima H, Naito T, Noguchi E, Tamari M, Kubo M, Takahashi A, Konno S, Makita H, Nishimura M, Hijikata M, Keicho N, Homma S, Taguchi Y, Azuma A, Kudoh S, Hizawa N.
  • Journal Title: J Allergy Clin Immunol Volume: 印刷中 Issue: 1 Pages: 281-283
  • DOI: 10.1016/j.jaci.2015.11.023
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clinical approaches toward asthma and COPD based on the heterogeneity of disease pathogenesis (2016)
  • Author(s): Hizawa N
  • Journal Title: Clin Exp Allergy Volume: 46(5) Issue: 5 Pages: 678-687
  • DOI: 10.1111/cea.12731
  • Peer Reviewed
• [Journal Article] 喘息患者におけるサルメテロールとモンテルカストの有効性の差に影響するロイコトリエン関連遺伝因子の検討 (2016)
  • Author(s): 山田英恵, 増子裕典, 乾 年秀, 金澤 潤, 谷田貝洋平, 坂本 透, 飯島弘晃, 今野 哲, 清水薫子, 牧田比呂仁, 西村正治, 國分二三男, 斎藤武文, 遠藤健夫, 二宮浩樹, 金子教宏 , 檜澤伸之
  • Journal Title: アレルギー Volume: 65(9) Pages: 1201-1208
  • NAID: 130005285007
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Role of Lung Function Genes in the Development of Asthma (2015)
  • Author(s): Yamada H, Masuko H, Yatagai Y, Sakamoto T, Kaneko Y, Iijima H, Naito T, Noguchi E, Konno S, Nishimura M, Hirota T, Tamari M, Hizawa N
  • Journal Title: PLoS One Volume: － Issue: 1 Pages: e0145832-e0145832
  • DOI: 10.1371/journal.pone.0145832
  • NAID: 120007129828
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Developments in the field of allergy in 2014 through the eyes of Clinical and Experimental Allergy (2015)
  • Author(s): Hales BJ, Hizawa N, Jenmalm M, Sverremark-Ekstrom E, Wardlaw AJ
  • Journal Title: Clin Exp Allergy Volume: 45 Issue: 12 Pages: 1723-45
  • DOI: 10.1111/cea.12663
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] LAMA/LABA vs ICS/LABA in the treatment of COPD in Japan based on the disease phenotypes (2015)
  • Author(s): Hizawa N
  • Journal Title: Int J Chron Obstruct Pulmon Dis Volume: 10 Pages: 1093-102
  • DOI: 10.2147/copd.s72858
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Role of the CDHR3 Variant (Cys529→Tyr) in Early-Onset Adult Asthma in Japanese Populations (2017)
  • Author(s): Kanazawa J, Hizawa N
  • Organizer: The ATS International Conference
  • Int'l Joint Research
• [Presentation] Pathogenesis of Severe Asthma: A Clue from the Common Genes Underlying Asthma and COPD (2016)
  • Author(s): Nobuyuki Hizawa
  • Organizer: ATS International Conference 2016
  • Place of Presentation: Moscone Center, San Francisco, USA
  • Year and Date: 2016-05-15
  • Int'l Joint Research / Invited
• [Presentation] Pathogenesis of Severe Asthma: A Clue from the Common Genes Underlying Asthma and COPD (2016)
  • Author(s): N. Hizawa
  • Organizer: The American Thoracic Society international conference 2016
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2016-05-15
  • Int'l Joint Research
• [Presentation] 喘息とCOPDにおける遺伝子解析 -データの読み方から臨床的意義まで- (2016)
  • Author(s): 檜澤伸之
  • Organizer: 日本呼吸器学会総会2016
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2016-04-09
  • Invited
• [Presentation] The Role of Pulmonary Function Genes in the Pathogenesis of Asthma (2015)
  • Author(s): H. Yamada
  • Organizer: The American Thoracic Society international conference 2015
  • Place of Presentation: Denver, USA
  • Year and Date: 2015-05-17
  • Int'l Joint Research