Exploration of disease associated pathway and lncRNA in connective tissue diseases by a comprehensive expression analysis

• Project/Area Number: 16K09886
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: University of Tsukuba
• Principal Investigator: Kawasaki Aya 筑波大学, 医学医療系, 助教 (30532816)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ANCA関連血管炎 / long non-coding RNA / 疾患感受性遺伝子 / non-coding RNA / SLE / 疾患感受性 / lncRNA / 発現解析 / 膠原病 / 多型

Outline of Final Research Achievements

It is likely that multiple genetic factors contribute to the pathogenesis of ANCA-associated vasculitis (AAV) and systemic lupus erythematosus (SLE). However, actual genetic variants that play a role in the pathogenesis have not fully determined. In this study, we tried to find new susceptibility genes by focusing on single nucleotide variant (SNV) which may potentially affect gene expression. Initially, we searched for disease-associated pathway genes and long non-coding RNA (lncRNA) by a comprehensive expression analysis. This analysis suggested that interferon pathway and lncRNA are substantially involved in the pathogenesis of AAV and SLE. Subsequent association study targeted to SNVs of the differentially expressed lncRNAs in the diseases identified ATP6V0E2-AS1 as a potential susceptibility gene to AAV.

Academic Significance and Societal Importance of the Research Achievements

難治性疾患であるANCA関連血管炎(AAV)は、罹患率の低さから他の膠原病と比較しても疾患発症に寄与する遺伝要因の解明は遅れている。本研究で見出されたlong non-coding RNAであるATP6V0E2-AS1は、AAVにおいて発現が減少しており、さらに転写調節領域に位置するバリアントがAAVの疾患感受性と関連することから、疾患発症や病態形成に寄与する可能性が高く、ATP6V0E2-AS1をターゲットとした治療薬の開発が期待できる。

Research Products

• [Journal Article] Association of ETS1 polymorphism with granulomatosis with polyangiitis and proteinase 3-anti-neutrophil cytoplasmic antibody positive vasculitis in a Japanese population (2018)
  • Author(s): A Kawasaki, K Yamashita, F Hirano, KE Sada, D Tsukui, Y Kondo, Y Kimura, K Asako, S Kobayashi, H Yamada, H Furukawa, K Nagasaka, T Sugihara, K Yamagata, T Sumida, S Tohma, H Kono, S Ozaki, S Matsuo, H Hashimoto, H Makino, Y Arimura, M Harigai, N Tsuchiya
  • Journal Title: Journal of Human Genetics Volume: 63 Issue: 1 Pages: 55
  • DOI: 10.1038/s10038-017-0362-2
  • URL: https://pure.teikyo.jp/en/publications/c184d55b-1ecc-4987-991d-fd64c36d75b6
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Detection of Association of Long Noncoding RNA ATP6V0E2-AS1 Single Nucleotide Polymorphism with Susceptibility to Myeloperoxidase-ANCA Associated Vasculitis Based on Transcriptome Analysis (2018)
  • Author(s): Y Iwahashi, A Kawasaki, T Tsuchiura, KE Sada, F Hirano, D Tsukui, S Kobayashi, H Yamada, H Furukawa, K Nagasaka, T Sugihara, N Nishida, K Yamagata, T Sumida, S Tohma, S Ozaki, H Hashimoto, H Makino, Y Arimura, H Kono, M Harigai, N Tsuchiya
  • Organizer: 2018 ACR/ARHP Annual Meeting
  • Int'l Joint Research
• [Presentation] IFN signature遺伝子発現における顕微鏡的多発血管炎と全身性エリテマトーデスの相違 (2017)
  • Author(s): 川崎 綾、津久井 大輔、近藤 裕也、木村 佳貴、浅子 来美、古川 宏、河野 肇、住田 孝之、土屋 尚之
  • Organizer: 第61回 日本リウマチ学会総会・学術集会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2017-04-20
• [Presentation] Association of ETS1 Polymorphism in 3’ Untranslated Region with Granulomatosis with Polyangiitis and PR3-ANCA-Positive Vasculitis in a Japanese Population (2017)
  • Author(s): Aya Kawasaki, Keita Yamashita, Fumio Hirano, Ken-ei Sada, Shigeto Kobayashi, Hidehiro Yamada, Hiroshi Furukawa, Kunihiro Yamagata, Takayuki Sumida, Nobuyuki Miyasaka, Shigeto Tohma, Shoichi Ozaki, Seiichi Matsuo, Hiroshi Hashimoto, Hirofumi Makino, Yoshihiro Arimura, Masayoshi Harigai, Naoyuki Tsuchiya
  • Organizer: The 18th International Vasculitis & ANCA Workshop 2017
  • Place of Presentation: 東京大学伊藤国際学術研究センター（東京都文京区）
  • Year and Date: 2017-03-27
  • Int'l Joint Research
• [Presentation] ETS1多型とANCA関連血管炎の関連 (2017)
  • Author(s): 川崎 綾、山下 計太、平野 史生、佐田 憲映、津久井 大輔、近藤 裕也、木村 佳貴、浅子 来美、小林 茂人、山田 秀裕、古川 宏、長坂 憲治、杉原 毅彦、山縣 邦弘、住田 孝之、當間 重人、河野 肇、尾崎 承一、松尾 清一、橋本 博史、槇野 博史、有村 義宏、針谷 正祥、土屋 尚之
  • Organizer: 日本人類遺伝学会第62回大会
• [Presentation] Association of ETS1 Polymorphism in 3’ Untranslated Region with Susceptibility to Granulomatosis with Polyangiitis and Proteinase 3-ANCA Positive Vasculitis in a Japanese Population. (2017)
  • Author(s): A Kawasaki, K Yamashita, F Hirano, KE Sada, D Tsukui, Y Kondo, Y Kimura, K Asako, S Kobayashi, H Yamada, H Furukawa, K Nagasaka, T Sugihara, K Yamagata, T Sumida, S Tohma, H Kono, S Ozaki, S Matsuo, H Hashimoto, H Makino, Y Arimura, M Harigai, N Tsuchiya
  • Organizer: 2017 ACR/ARHP Annual Meeting
  • Int'l Joint Research
• [Presentation] Interferon Signature Genes Are Differentially Expressed Between Microscopic Polyangiitis and Systemic Lupus Erythematosus Peripheral Blood Transcriptomes (2016)
  • Author(s): Aya Kawasaki, Daisuke Tsukui, Yuya Kondo, Yoshitaka Kimura, Kurumi Asako, Hiroshi Furukawa, Hajime Kono, Takayuki Sumida, Naoyuki Tsuchiya
  • Organizer: 2016 ACR/ARHP Annual Meeting
  • Place of Presentation: Walter E. Washington Convention Center(Washington, DC, USA)
  • Year and Date: 2016-11-14
  • Int'l Joint Research
• [Remarks] 筑波大学分子遺伝疫学研究室
  • URL: http://www.md.tsukuba.ac.jp/community-med/publicmd/GE/
• [Remarks] 筑波大学医学医療系分子遺伝疫学研究室
  • URL: http://www.md.tsukuba.ac.jp/community-med/publicmd/GE/