Comprehensive analysis of severe asthma pathogenesis

• Project/Area Number: 24390206
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• 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 独立行政法人理化学研究所, 呼吸器疾患研究チーム, チームリーダー (00217184)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000); Fiscal Year 2014: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2013: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2012: ¥9,620,000 (Direct Cost: ¥7,400,000、Indirect Cost: ¥2,220,000)
• Keywords: 喘息 / COPD / 呼吸機能 / GWAS / HAS2 / PBMUCL2 / DPB / Phenotype / ネットワーク / AhR / IL-17 / IL-12

Outline of Final Research Achievements

To identify additional genetic determinants of susceptibility to asthma or COPD, we conducted GWAS using a selected Japanese population with reduced tobacco smoking exposure or with late-onset-asthma.These GWASs identified HAS2 gene and PBMUCL2 gene as susceptibility genes for particular phenotypes of asthma.PBMUCL2 gene was also associated with COPD or DPB.
We have also conducted GWAS for FEV1/FVC, which failed to find any significant regions; however, this GWAS indicated that the heritability for FEV1/FVC were 41.6% in a Japanese population.Therefore, given many loci with individual weak effects may contribute to asthma risk, in this study, we created a quantitative score of genetic load based on 16 SNPs implicated in lower lung function both in Japanese and non-Japanese populations. This genetic risk score (GRS) for lower FEV1/FVC was consistently associated with the onset of asthma in two independent Japanese populations as well as with the onset of COPD.

Research Products

• [Journal Article] Heritability of pulmonary function estimated from genome-wide SNPs in healthy Japanese adults. (2015)
  • Author(s): Yamada H, Yatagai Y, Masuko H, Sakamoto T, Iijima H, Naito T, Noguchi E, Hirota T, Tamari M, Hizawa N
  • Journal Title: Respir Investig Volume: 53 Issue: 2 Pages: 60-67
  • DOI: 10.1016/j.resinv.2014.10.004
  • Peer Reviewed
• [Journal Article] Genomewide association study identifies HAS2 as a novel susceptibility gene for adult asthma in a Japanese population (2014)
  • Author(s): Yatagai Y, Sakamoto T, Yamada H, Masuko H, Kaneko Y, Iijima H, Naito T, Noguchi E, Hirota T, Tamari M, Konno S, Nishimura M, Hizawa N
  • Journal Title: Clin Exp Allergy Volume: 44 Issue: 11 Pages: 1327-1334
  • DOI: 10.1111/cea.12415
  • Peer Reviewed
• [Journal Article] Influence of MILR1 promoter polymorphism on expression levels and the phenotype of atopy. (2014)
  • Author(s): Nanatsue K, Ninomiya T, Tsuchiya M, Tahara-Hanaoka S, Shibuya A, Masuko H, Sakamoto T, Hizawa N, Arinami T, Noguchi E.
  • Journal Title: J Hum Genet Volume: 59(9) Issue: 9 Pages: 480-483
  • DOI: 10.1038/jhg.2014.57
  • Peer Reviewed
• [Journal Article] Association of the CAT-262C>T polymorphism with asthma in smokers and the nonemphysematous phenotype of chronic obstructive pulmonary disease. (2014)
  • Author(s): Taniguchi N
  • Journal Title: Ann Allergy Asthma Immunol Volume: 113 Issue: 1 Pages: 31-36
  • DOI: 10.1016/j.anai.2014.04.012
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The effects of a Gly16Arg ADRB2 polymorphism on responses to salmeterol or montelukast in Japanese patients with mild persistent asthma (2014)
  • Author(s): Konno S, Hizawa N, Makita H, Shimizu K, Sakamoto T, Kokubu F, Saito T, Endo T, Ninomiya H, Iijima H, Kaneko N, Ito YM, Nishimura M
  • Journal Title: Pharmacogenet Genomics Volume: 24 Issue: 5 Pages: 246-255
  • DOI: 10.1097/fpc.0000000000000043
  • Peer Reviewed
• [Journal Article] 北海道上士幌町における成人喘息，アレルギー性鼻炎有病率の検討―2006年，2011年の比較― (2014)
  • Author(s): 清水薫子, 今野 哲, 木村孔一, 荻 喬博,谷口菜津子, 清水健一, 伊佐田朗, 服部健史,檜澤伸之, 谷口正実, 赤澤 晃, 西村正治
  • Journal Title: アレルギー Volume: 63 Pages: 928-937
  • NAID: 110009832675
  • Peer Reviewed
• [Journal Article] アレルゲン特異的IgE反応性から分類した喘息フェノタイプ―Thymic stromal lymphopoietin（TSLP）遺伝子と喫煙の役割― (2014)
  • Author(s): 飯島弘晃, 山田英恵, 谷田貝洋平, 金子美子, 内藤隆志, 坂本透, 増子裕典, 広田朝光, 玉利真由美, 今野哲, 西村正治, 檜澤伸之
  • Journal Title: アレルギー Volume: 63 Pages: 33-44
  • NAID: 110009798511
  • Peer Reviewed
• [Journal Article] Effects of thymic stromal lymphopoietin (TSLP) genotypes on asthma phenotypes defined by the atopy cluster -influence of smoking habits- (2014)
  • Author(s): Iijima H, Yamada H, Yatagai Y, Kaneko Y, Naito T, Sakamoto T, Masuko H, Hirota T, Tamari M, Konno S, Nishimura M, Hizawa N
  • Journal Title: アレルギー Volume: 63(1) Pages: 33-44
  • NAID: 110009798511
  • Peer Reviewed
• [Journal Article] Genome-wide association study for levels of total serum IgE identifies HLA-C in a Japanese population (2013)
  • Author(s): Yatagai Y, Sakamoto T, Masuko H, et al
  • Journal Title: PLoS One Volume: 8(12) Issue: 12 Pages: 1-9
  • DOI: 10.1371/journal.pone.0080941
  • Peer Reviewed
• [Journal Article] The CC16 A38G polymorphism is associated with asymptomatic airway hyper-responsiveness and development of late-onset asthma (2013)
  • Author(s): Taniguchi N
  • Journal Title: Annals of Allergy, Asthma & Immunology Volume: 111 Issue: 5 Pages: 376-381
  • DOI: 10.1016/j.anai.2013.08.005
  • Peer Reviewed
• [Journal Article] Pharmacogenetics of chronic obstructive pulmonary disease (2013)
  • Author(s): Hizawa N
  • Journal Title: Pharmacogenomics Volume: 14(10) Issue: 10 Pages: 1215-1225
  • DOI: 10.2217/pgs.13.107
  • Peer Reviewed
• [Journal Article] The search for common pathways underlying asthma and COPD (2013)
  • Author(s): Kaneko Y, Yatagai Y, Yamada H, Iijima H, Masuko H, Sakamoto T, Hizawa N
  • Journal Title: Int J Chron Obstruct Pulmon Dis Volume: 8 Pages: 65-78
  • DOI: 10.2147/copd.s39617
  • Peer Reviewed
• [Journal Article] Asthma Phenotypes in Japanese Adults . Their Associations with the CCL5 and ADRB2 Genotypes. Dec 25,2012 (2012)
  • Author(s): Kaneko Y, Hizawa N, 他
  • Journal Title: Allergol Int..[Epub ahead of print]
  • Peer Reviewed
• [Journal Article] Interleukin-33 induces interleukin-17F in bronchial epithelial cells (2012)
  • Author(s): Fujita J, Kawaguchi M, Kokubu F, Ohara G, Ota K, Huang SK, Morishima Y, IshiiY, Satoh H, Sakamoto T, Hizawa N
  • Journal Title: Allergy Volume: 67 Issue: 6 Pages: 744-750
  • DOI: 10.1111/j.1398-9995.2012.02825.x
  • Peer Reviewed
• [Journal Article] Associating serum biomarkers with genetic susceptibility to chronic obstructive pulmonary disease : a step towards improved diagnosis and therapy? (2012)
  • Author(s): Hizawa N
  • Journal Title: Am J Respir Crit Care Med Volume: 186 Issue: 12 Pages: 1201-1202
  • DOI: 10.1164/rccm.201210-1898ed
  • Peer Reviewed
• [Presentation] Genome-Wide Association Study Identifies Hyaluronan Synthase 2 (HAS2) As A Susceptibility Gene For Adult Asthma In A Japanese Population (2014)
  • Author(s): Yatagai Y
  • Organizer: アメリカ胸部疾患学会2014
  • Place of Presentation: サンディエゴ
  • Year and Date: 2014-05-17 – 2014-05-21
• [Presentation] The Role Of Lung Function Genes In The Development Of Asthma (2014)
  • Author(s): Yamada H
  • Organizer: アメリカ胸部疾患学会2014
  • Place of Presentation: サンディエゴ
  • Year and Date: 2014-05-17 – 2014-05-21
• [Presentation] 中高年発症喘息のフェノタイプ，エンドタイプ (2014)
  • Author(s): 檜澤伸之
  • Organizer: 第26回日本アレルギー学会春季臨床大会
  • Place of Presentation: 京都
  • Year and Date: 2014-05-11
• [Presentation] 今後の喘息・COPD治療～ICS/LABAの有用性～ (2014)
  • Author(s): 檜澤伸之
  • Organizer: 第26回日本アレルギー学会春季臨床大会
  • Place of Presentation: 京都
  • Year and Date: 2014-05-09
• [Presentation] Genetic Polymorphisms Associated With Total IgE Levels In The Japanese Population : A Replication Analysis By Genome-Wide Association Study (2012)
  • Author(s): Masuko H, Hizawa N, 他
  • Organizer: アメリカ胸部疾患学会
  • Place of Presentation: サンフランシスコ(USA)
• [Presentation] 気道炎症をターゲットとした喘息の治療戦略
  • Author(s): 檜澤伸之
  • Organizer: 第25回日本アレルギー学会春季臨床大会
  • Place of Presentation: 横浜
• [Presentation] 成人喘息のフェノタイプ : クラスター解析と遺伝因子
  • Author(s): 檜澤伸之
  • Organizer: 第25回日本アレルギー学会春季臨床大会
  • Place of Presentation: 横浜
• [Presentation] 気管支喘息・COPD治療へのアプローチ～ICS/LABA配合剤の可能性～
  • Author(s): 檜澤伸之
  • Organizer: 第53回日本呼吸器学会総会
  • Place of Presentation: 東京
• [Presentation] Asthma phenotypes in Japanese adults and their associations with the CCL5 and ADRB2 genotypes
  • Author(s): Hizawa N
  • Organizer: The 53rd Annual Meeting of the Japanese Respiratory Society International Symposium
  • Place of Presentation: 東京
• [Presentation] 喘息難治化における遺伝因子の役割
  • Author(s): 檜澤伸之
  • Organizer: 第23回国際喘息学会日本・北アジア部会
  • Place of Presentation: 東京