The Role of Allergic sensitization in Allergic Diseases

• Project/Area Number: 16K19441
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: University of Tsukuba
• Principal Investigator: Masuko Hironori 筑波大学, 医学医療系, 講師 (50758943)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: アレルギー性鼻炎 / 喘息 / IgE / GWAS / 抗原感作 / アトピー素因 / 気管支喘息 / 花粉症 / アレルギー・ぜんそく / 疾患遺伝子

Outline of Final Research Achievements

We reported the importance of TYRO3 functional polymorphism that alters gene expression in the pathogenesis of allergic sensitization and allergic rhinitis. Our meta-analysis of 3 independent Japanese populations showed the rs2297377 at TYRO3 is negatively associated with the development of allergic sensitization and allergic rhinitis. Our findings suggest that the mutated TYRO3 genotype that correlates with lower mRNA expression leads to an enhanced type 2 immunity which subsequently results in an increased susceptibility to allergic sensitization and allergic rhinitis.

We also calculated the atopy Genetic Risk Score using the genotype information of 19 SNPs that have been identified in 2 previous non- Japanese GWASs as being associated with atopy. However, despite the strong association of GRS with atopy, GRS was not associated with asthma. Given that these findings suggest that allergic sensitization in asthma may be an inconstant secondary effect of asthma instead of its cause.

Academic Significance and Societal Importance of the Research Achievements

TYRO3遺伝子の発現に関与する機能的遺伝子多型がアレルギー感作とアレルギー性鼻炎に関与する遺伝因子であることを示した。TYRO3がスギ花粉症などのアレルギー疾患に対する薬物治療の新たな標的分子となる可能性がある。
また、喘息発症の結果としてアトピー素因を獲得する可能性をメンデルランダム化法にて検証した。アレルギー性喘息の原因が一律にアレルゲン感作であるという特定の理論のみを強調しすぎると、ウイルス感染や肺の成長障害といった病態進展に関するアレルギー感作以外の重要な因子を過小評価してしまう危険があることが示された。

Research Products

• [Journal Article] Association analyses of eQTLs of the <i>TYRO3</i> gene and allergic diseases in Japanese populations (2019)
  • Author(s): Kanazawa J, Masuko H, Yatagai Y, Sakamoto T, Yamada H, Kitazawa H, Iijima H, Naito T, Saito T, Noguchi E, Hirota T, Tamari M, Hizawa N
  • Journal Title: Allergology International Volume: 68 Issue: 1 Pages: 77-81
  • DOI: 10.1016/j.alit.2018.07.004
  • NAID: 130007557962
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [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
• [Presentation] アレルギー感作感受性遺伝子群がCDHR3及びTYRO3遺伝子の効果に与える影響 (2019)
  • Author(s): 金澤潤、増子裕典、北沢晴奈、谷田貝洋平、飯島弘晃、内藤隆志、広田朝光、玉利真由美、坂本透、檜澤伸之
  • Organizer: 第59回日本呼吸器学会学術講演会
• [Presentation] アレルギー感作関連遺伝子が成人喘息に与える影響 (2018)
  • Author(s): 金澤潤、増子裕典、山田英恵、谷田貝洋平、北沢晴奈、飯島弘晃、内藤隆志、広田朝光、玉利真由美、坂本透、檜澤伸之
  • Organizer: 第67回日本アレルギー学会学術大会
• [Presentation] Genetic association of eQTLs of the TYRO3 gene and allergic diseases in a Japanese population (2018)
  • Author(s): J.Kanazawa, H.Masuko, H.Kitazawa, H.Yamada, Y.Yatagai, H.Iijima, T.Naito, T.Saito, E.Noguchi, T.Hirota, M.Tamari, T. Sakamoto, N.Hizawa
  • Organizer: ATS 2018
  • Int'l Joint Research
• [Presentation] シンポジウム4『遺伝子から解くアレルギーの謎』「遺伝子から解くウイルス感染による気道アレルギー」 (2017)
  • Author(s): 増子裕典
  • Organizer: 第66回日本アレルギー学会学術大会
  • Invited
• [Presentation] Role Of The Cdhr3 Variant (cys529tyr) In Early-Onset Adult Asthma In Japanese Populations (2017)
  • Author(s): J. Kanazawa, H. Masuko, H. Kitazawa, H. Yamada, Y. Yatagai, Y. Kaneko, H. Iijima, T. Naito, T. Saito, E. Noguchi, S.Konno, M. Nishimura, T. Hirota, M. Tamari, T. Sakamoto, N. Hizawa
  • Organizer: ATS2017
• [Funded Workshop] American Thoracic Society Conference 2016 (2016)
  • Place of Presentation: Moscone Center, San Francisco, CA, USA
  • Year and Date: 2016-05-13