Personalized prediction of susceptibility to asthma by genetic risk score

• Project/Area Number: 17K09603
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: University of Tsukuba
• Principal Investigator: Sakamoto Tohru 筑波大学, 医学医療系, 准教授 (50282356)
• Co-Investigator(Kenkyū-buntansha): 檜澤 伸之 筑波大学, 医学医療系, 教授 (00301896)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 喘息 / 一塩基多型 / リスクスコア / ゲノムワイド関連解析 / 遺伝的リスクスコア / アレルギー・ぜんそく / ゲノム

Outline of Final Research Achievements

We selected 15 eSNPs which meet a condition of P < 0.05 in asthma GWAS of our Cohort 1 (958 healthy volunteers and 242 patients with asthma). Genetic risk score (GRS) of susceptibility to asthma was calculated by summing up the number of risk alleles. Significant difference of GRS was confirmed between the controls and asthma patients (P = 9.54E-15).
Then, the same analysis was performed for independent Cohort 2 (565 healthy volunteers and 541 patients with asthma). Significant difference of GRS was validated between the controls and asthma patients also in Cohort 2 (P = 0.023). ROC analysis showed the AUC of 0.539, suggesting that prediction capability of susceptibility to asthma by using the 15 eSNPs was slightly low.
We are planning reevaluation of the prediction capability by increasing the number of eSNP candidates.

Academic Significance and Societal Importance of the Research Achievements

喘息に関連するSNPは多数報告されているが、個々のSNPから喘息発症を予測することは困難である。本研究では、十～数十個の喘息関連SNPsのリスクアリル数を合算して個人の喘息遺伝的リスクスコア（GRS）として解析を行った。その結果、GRSにより喘息発症を予測することができる可能性が示された。GRSは喫煙歴などの危険因子とは異なり、生涯を通して変わることはなく、また疾患の状態によっても変化しない。喘息発症が予測できれば、環境改善や禁煙などの早期介入により発症を予防できる可能性がある。また関連SNPsを用いた遺伝子・分子ネットワーク解析により、喘息の病態解明に大きく貢献できることが期待される。

Research Products

• [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: Journal of Chronic Obstructive Pulmonary Disease Volume: 17 Pages: 59-64
  • DOI: 10.1080/15412555.2019.1708296
  • NAID: 120007127638
  • Peer Reviewed
• [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: Allergol. Int. 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] 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 Medical Genetics Volume: 20 Pages: 58-58
  • DOI: 10.1186/s12881-019-0786-y
  • NAID: 120007127949
  • Peer Reviewed / Open Access
• [Journal Article] The Concavity of the Maximal Expiratory Flow?Volume Curve Reflects the Extent of Emphysema in Obstructive Lung Diseases (2019)
  • Author(s): Mochizuki Fumi、Iijima Hiroaki、Watanabe Azusa、Tanabe Naoya、Sato Susumu、Shiigai Masanari、Fujiwara Keiji、Shimada Takafumi、Ishikawa Hiroichi、Kanazawa Jun、Yatagai Yohei、Masuko Hironori、Sakamoto Tohru、Muro Shigeo、Hizawa Nobuyuki
  • Journal Title: Scientific Reports Volume: 9
  • DOI: 10.1038/s41598-019-49591-2
  • NAID: 120007132919
  • 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: Allergol. Int. Volume: - 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] Transcription elongation factor P-TEFb is involved in IL-17F signaling in airway smooth muscle cells. (2018)
  • Author(s): Nakajima Masayuki, Kawaguchi Mio, Matsuyama Masashi, Ota Kyoko, Fujita Jun, Matsukura Satoshi, Huang Shau-Ku, Morishima Yuko, Ishii Yukio, Satoh Hiroaki, Sakamoto Tohru, Hizawa Nobuyuki.
  • Journal Title: International Archives of Allergy and Immunology Volume: 印刷中 Pages: 83-90
  • DOI: 10.1159/000488154
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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: Allergol. Int. Volume: in press 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] 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: Respiratory Research Volume: 18 Pages: 69-69
  • DOI: 10.1186/s12931-017-0554-5
  • NAID: 120007129115
  • Peer Reviewed / Open Access
• [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: Immun Inflamm Dis. Volume: 3 Pages: 124-131
  • DOI: 10.1002/iid3.149
  • NAID: 120007129102
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] アレルギー感作感受性遺伝子群がCDHR3および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] BMI、IL6、高感度CRPに関する遺伝要因と喘息との関連 (2019)
  • Author(s): 北沢晴奈、増子裕典、金澤 潤、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] 閉塞性肺疾患におけるflow-volume曲線の視覚的評価と胸部CTの定量評価に関する検討 (2019)
  • Author(s): 望月芙美、飯島弘晃、嶋田貴文、藤原啓司、石川博一、増子裕典、坂本 透、田辺直也、佐藤 晋、室 繁郎、檜澤伸之
  • Organizer: 第59回日本呼吸器学会学術講演会
• [Presentation] Genetic effects of ORMDL3/GSDMB on asthma are modified by the GSDMC genotype at chromosome 8. (2019)
  • Author(s): Kitazawa H, Masuko H, Kanazawa J, Shigemasa R, Hyodo K, Yatagai Y, Iijima H, Naito T, Saito T, Hirota T, Tamari M, Sakamoto T, Hizawa N.
  • Organizer: American Thoracic Society Conference 2019
  • Int'l Joint Research
• [Presentation] A cis-eQTL allele lowering gene expression of CHL3L1 is associated with late-onset adult asthma in Japanese. (2019)
  • Author(s): Shigemasa R, Kanazawa J, Kitazawa H, Masuko H, Hyodo K, Yatagai Y, Sakamoto T, Kaneko Y, Iijima H, Naito T, Saito T, Noguchi E, Konno S, Nishimura M, Hirota T, Tamari M, Hizawa N.
  • Organizer: American Thoracic Society Conference 2019
  • Int'l Joint Research
• [Presentation] 呼吸機能関連遺伝子及びTSLP遺伝子がCOPDフェノタイプに与える影響 (2019)
  • Author(s): 山田英恵、肥田憲人、増子裕典、坂本 透、檜澤伸之
  • Organizer: 第68回日本アレルギー学会学術大会
• [Presentation] 中高年喫煙者における呼気一酸化窒素濃度に影響を与える因子について (2019)
  • Author(s): 金澤 潤、増子裕典、重政理恵、兵頭健太郎、北沢晴奈、谷田貝洋平、飯島弘晃、坂本 透、家城隆次、檜澤伸之
  • Organizer: 第68回日本アレルギー学会学術大会
• [Presentation] 原発性繊毛機能不全症に関連する遺伝子群が喘息に与える影響について (2019)
  • Author(s): 重政理恵、増子裕典、金澤 潤、北沢晴奈、兵頭健太郎、谷田貝洋平、飯島弘晃、内藤隆志、坂本 透、広田朝光、玉利真由美、檜澤伸之
  • Organizer: 第68回日本アレルギー学会学術大会
• [Presentation] 重症喘息に対するペンラリズマブ治療早期の有効性の検討 (2019)
  • Author(s): 中嶋真之、松山政史、川口未央、荒井直樹、北沢晴奈、吉田和史、兵頭健太郎、金澤 潤、山田英恵、増子裕典、際本拓未、森島祐子、石井幸雄、坂本 透、齋藤武文、檜澤伸之
  • Organizer: 第68回日本アレルギー学会学術大会
• [Presentation] 慢性炎症性肺疾患における増悪関連フェノタイプの検討 (2019)
  • Author(s): 兵頭健太郎、増子裕典、重政理恵、北沢晴奈、金澤 潤、谷田貝洋平、飯島弘晃、児玉孝秀、野村明広、籠橋克紀、佐藤浩昭、坂本 透、齋藤武文、檜澤伸之
  • Organizer: 第68回日本アレルギー学会学術大会
• [Presentation] ORMDL3/GSDMB遺伝子が喘息に与える影響はGSDMC遺伝子多型によって異なる (2019)
  • Author(s): 北沢晴奈、増子裕典、金澤 潤、重政理恵、兵頭健太郎、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68回日本アレルギー学会学術大会
• [Presentation] CHI3L1遺伝子eQTLが喘息に与える影響 (2018)
  • Author(s): 金澤 潤、増子裕典、谷田貝洋平、飯島弘晃、内藤隆志、齋藤武文、野口恵美子、今野 哲、西村正治、広田朝光、玉利真由美、坂本 透、檜澤伸之
  • Organizer: 第58回日本呼吸器学会学術講演会
• [Presentation] IL-17FによるIL-6、IL-8産生に対するステロイドとLABAの効果 (2018)
  • Author(s): 中嶋真之、川口未央、太田恭子、藤田純一、松山政史、松倉 聡、塩澤利博、中澤健介、増子裕典、際本拓未、松野洋輔、森島祐子、佐藤浩昭、坂本 透、檜澤伸之
  • Organizer: 第58回日本呼吸器学会学術講演会
• [Presentation] TYRO3: A Gene for Allergic Rhinitis? (2018)
  • Author(s): Kanazawa J, Masuko H, Yatagai Y, Yamada H, Sakamoto T, Kitazawa H, Iijima H, Naito T, HIrota M, Tamari M, Hizawa N.
  • Organizer: American Thoracic Society Conference 2018
  • Int'l Joint Research
• [Presentation] How important is allergic sensitization as a cause of atopic asthma? (2018)
  • Author(s): Yatagai Y, Kanazawa J, Masuko H, Yamada H, Sakamoto T, Kitazawa H, Iijima H, Naito T, Hirota T, Tamari M, Hizawa N.
  • Organizer: American Thoracic Society Conference 2018
  • Int'l Joint Research
• [Presentation] Effect of steroids and long-acting-beta agonist on IL-17F induced IL-6 and IL-8 expression (2018)
  • Author(s): Nakajima M, Kawaguchi M, Mastuyama M, Yoshida K, Ota K, Fujita J, Matsukura S, Huang S-K, Morishima Y, Ishii Y, Satoh H, Sakamoto T, Hizawa N.
  • Organizer: American Thoracic Society Conference 2018
  • Int'l Joint Research
• [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] 気道平滑筋細胞におけるIL-6、IL-8産生に対するIL17FとLABAの増強効果 (2018)
  • Author(s): 中嶋真之、川口未央、太田恭子、藤田純一、松山政史、松倉 聡、塩澤利博、中澤健介、増子裕典、際本拓未、松野洋輔、森島祐子、佐藤浩昭、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] 日本人集団におけるCDHR3遺伝子多型が若年発症瑞息に与える影響 (2017)
  • Author(s): 金澤 潤、増子裕典、北沢晴奈、山田英恵、谷田貝洋平、金子美子、飯島弘晃、内藤隆志、齋藤武文、今野 哲、西村正治、広田朝光、玉利真由美、坂本 透、檜澤伸之
  • Organizer: 第57回日本呼吸器学会学術講演会
• [Presentation] IL-17Fによる気道平滑筋細胞からのIL-6発現とその分子機構 (2017)
  • Author(s): 中嶋真之、太田恭子、藤田純一、川口未央、松倉 聡、塩澤利博、中澤健介、増子裕典、際本拓未、松野洋輔、森島祐子、佐藤浩昭、坂本 透、檜澤伸之
  • Organizer: 第57回日本呼吸器学会学術講演会
• [Presentation] Role of the CDHR3 Variant (Cys529→Tyr) in Early-Onset Adult Asthma in Japanese Populations. (2017)
  • Author(s): Kanazawa J, Masuko H, Kitazawa H, Yamada Y, Yatagai Y, Kaneko Y, Iijima H, Naito T, Saito T, Noguchi E, Konno S, Nishimura M, Hirota T, Tamari M, Sakamoto T, Hizawa N.
  • Organizer: American Thoracic Society Conference 2017
  • Int'l Joint Research
• [Presentation] IL-17F Induces IL-6 Via TAK1-NFbkB Pathway in Airway Smooth Muscle Cells. (2017)
  • Author(s): Nakajima M, Kawaguchi M, Ota K, Fujita J, Matsukura S, Huang SK, Masuko H, Kiwamoto T, Matsuno Y, Morishima Y, Ishii Y, Satoh H, Sakamoto T, Hizawa N.
  • Organizer: American Thoracic Society Conference 2017
  • Int'l Joint Research
• [Presentation] 喘息患者における血清高感度CRPの検討 (2017)
  • Author(s): 北沢晴奈、増子裕典、金澤 潤、谷田貝洋平、金子美子、飯島弘晃、内藤隆志、坂本 透、檜澤伸之
  • Organizer: 第66回日本アレルギー学会学術大会
• [Presentation] 日本人集団におけるTYRO3遺伝子多型がアレルギー疾患に与える影響 (2017)
  • 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、野口佳子、広田朝光、玉利真由美、坂本 透、檜澤伸之
  • Organizer: 第66回日本アレルギー学会学術大会
• [Presentation] 気道平滑筋細胞におけるIL-17FからのIL-6発現と分子機構 (2017)
  • Author(s): 中嶋真之、太田恭子、藤田純一、川口未央、松倉 聡、増子裕典、際本拓未、松野洋輔、森島祐子、佐藤浩昭、坂本 透、檜澤伸之
  • Organizer: 第66回日本アレルギー学会学術大会
• [Book] COPD (2019)
  • Author(s): 坂本 透、檜澤伸之
  • Total Pages: 360
  • Publisher: 中山書店
  • ISBN: 9784521745299
• [Book] Advances in Asthma (2019)
  • Author(s): Tohru Sakamoto, Nobuyuki Hizawa
  • Total Pages: 12
  • Publisher: Springer
  • ISBN: 9789811327896