Comprehensive understanding for the relationship between HLA class II genes and chronic hepatitis B infection

• Project/Area Number: 16K09387
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Nishida Nao 国立研究開発法人国立国際医療研究センター, その他部局等, 上級研究員 (50456109)
• Research Collaborator: Sugiyama Masaya
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: B型肝炎 / HLA / GWAS / HBワクチン / HBV / ゲノム / 感染症 / 遺伝学 / がん / B型肝炎ウイルス

Outline of Final Research Achievements

By conducting GWAS, the following were identified: host factors concerning responsiveness of hepatitis B vaccine (HB vaccine) and HBV related liver cancer. Specific HLA class II genotypes were associated with the responsiveness to Bimmugen, which is one of the widely used hepatitis B vaccine (HB vaccine) in Japan. Moreover, we revealed that BTNL2 gene contributed to the high response to the vaccine. Genome analysis (i.e. pathway analysis, upstream regulator analysis) based on detailed clinical information on vaccine responsiveness showed that recognition of HBV-derived peptide antigens by HLA molecules and transmission of costimulatory signals from antigen-presenting cells via costimulatory molecules such as BTNL2 molecules on T cells play important roles in HB vaccine responsiveness.

Academic Significance and Societal Importance of the Research Achievements

ビームゲン接種者のうち約10%はその中和抗体であるHBs抗体を十分に獲得できないという問題がある。B型肝炎は血液汚染により引き起こされる疾患であるため、特に肝移植患者や医療従事者におけるHBs抗体陰性は早急な解決が求められる非常に重大な問題である。本研究で明らかとなったHBワクチン応答性に特異的に関連するHLA class II分子やワクチン高反応に関わるBTNL2分子を介したHBs抗体産生の機序を明らかにすることで、HBワクチンの適正かつ効率的な使用方法の確立が期待できる。

Research Products

• [Int'l Joint Research] THE UNIVERSITY OF OXFORD(英国)
• [Journal Article] Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B virus-related hepatocellular carcinoma (2018)
  • Author(s): awai H, Nishida N, Sugiyama M, Murata K, Hino K, Nishina S, Matsumoto A, Tanaka E, Sakamoto N, Ogawa K, Yamamoto K, Tamori A, Yokosuka O, Kanda T, Sakaida I, Itoh Y, Eguchi Y, Oeda S, Mochida S, Yuen MF, Seto WK, Poovorawan Y, Posuwan N, Mizokami M, Tokunaga K
  • Journal Title: Ｓｃｉ Ｒｅｐ Volume: 8 Issue: 1 Pages: 7958-7958
  • DOI: 10.1038/s41598-018-26217-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Key HLA-DRB1-DQB1 haplotypes and role of the BTNL2 gene for response to a hepatitis B vaccine. (2018)
  • Author(s): Nishida N, Sugiyama M, Sawai H, Nishina S, Sakai A, Ohashi J, Khor SS, Kakisaka K, Tsuchiura T, Hino K, Sumazaki R, Takikawa Y, Murata K, Kanda T, Yokosuka O, Tokunaga K, Mizokami M
  • Journal Title: Hepatology Volume: 印刷中 Issue: 3 Pages: 848-858
  • DOI: 10.1002/hep.29876
  • Peer Reviewed / Open Access
• [Journal Article] Role of HLA-DP and HLA-DQ on the clearance of hepatitis B virus and the risk of chronic infection in a multiethnic population. (2017)
  • Author(s): Trinks J, Nishida N, et al.
  • Journal Title: Liver Int Volume: 37 (10) Issue: 10 Pages: 1476-1487
  • DOI: 10.1111/liv.13405
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Understanding of HLA-conferred susceptibility to chronic hepatitis B infection requires HLA genotyping-based association analysis. (2016)
  • Author(s): N. Nishida (他37名, 山本31番目)
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 24767-24767
  • DOI: 10.1038/srep24767
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] B型肝炎ワクチンの効果に対するHLA class II遺伝子型の影響 (2018)
  • Author(s): 西田奈央、杉山真也、澤井裕美、大橋順、Seik-Soon Khor、土浦貴代、徳永勝士、溝上雅史
  • Organizer: 日本人類遺伝学会 第６３回大会
• [Presentation] B型肝炎ワクチンの応答性に関わるHLA-DRB1-DQB1ハプロタイプとBTNL2遺伝子 (2018)
  • Author(s): 西田奈央、杉山真也、澤井裕美、大橋順、Seik-Soon Khor、土浦貴代、徳永勝士、溝上雅史
  • Organizer: 第27回日本組織適合性学会大会
• [Presentation] Effects of HLA class II genotypes on a response to HB vaccine in Japanese population (2018)
  • Author(s): Nao Nishida, Masaya Sugiyama, Hiromi Sawai, Jun Ohashi, Seik-Soon Khor, Takayo Tsuchiura, Katsushi Tokunaga, Masashi Mizokami
  • Organizer: ASHG2018
  • Int'l Joint Research
• [Presentation] B型肝炎の癌化に関連するHLAクラスI領域における新規遺伝要因の同定 (2018)
  • Author(s): 澤井裕美、西田奈央、杉山真也、Seik-Soon Khor、溝上雅史、徳永勝士
  • Organizer: 第27回日本組織適合性学会大会
• [Presentation] ゲノムワイド関連解析によるB型肝炎の癌化に関連する新規遺伝要因の同定 (2018)
  • Author(s): 澤井裕美、西田奈央、杉山真也、Seik-Soon Khor、溝上雅史、徳永勝士
  • Organizer: 日本人類遺伝学会 第６３回大会
• [Presentation] 遺伝子解析が肝疾患の理解を深める (2018)
  • Author(s): 西田奈央
  • Organizer: 平成29年度肝炎等克服実用化研究事業 公開報告会 最新研究からみえてくる肝炎克服
  • Invited
• [Presentation] 肝発がん抵抗性HLA遺伝子型を有する症例におけるHBV-DNA変異解析 (2017)
  • Author(s): 西田奈央、杉山真也、土浦貴代、徳永勝士、溝上雅史
  • Organizer: 第26回 日本組織適合性学会大会
• [Presentation] B型肝炎ワクチンの効果に関連する宿主因子の同定 (2017)
  • Author(s): 西田奈央、杉山真也、澤井裕美、Seik-Soon Khor、土浦貴代、徳永勝士、溝上雅史
  • Organizer: 日本人類遺伝学会 第62回大会
• [Presentation] GWAS identified associations of HLA-DRB1-DQB1 haplotypes and BTNL2 gene with response to a hepatitis B vaccine (2017)
  • Author(s): Nao Nishida, Masaya Sugiyama, Hiromi Sawai, Jun Ohashi, Seik-Soon Khor, Takayo Tsuchiura, Katsushi Tokunaga, Masashi Mizokami
  • Organizer: ASHG 2017 Annual Meeting
  • Int'l Joint Research
• [Presentation] HLA-DRB1-DQB1 haplotypes and BTNL2 gene associate with response to a hepatitis B vaccine (2017)
  • Author(s): Nao Nishida, Masaya Sugiyama, Hiromi Sawai, Sohji Nishina, Aiko Sakai, Keisuke Kakisaka, Keisuke Hino, Ryo Sumazaki, Yasuhiro Takikawa, Kazumoto Murata, Tatsuo Kanda, Osamu Yokosuka, Katsushi Tokunaga, and Masashi Mizokami
  • Organizer: American Association for the study of Liver Diseases The Liver Meeting 2017
  • Int'l Joint Research
• [Presentation] 日本人におけるB型肝炎関連疾患とHLA遺伝子の関連 (2016)
  • Author(s): 西田奈央、澤井裕美、大橋順、Seik-Soon Khor、杉山真也、土浦貴代、石井真由美、徳永勝士、溝上雅史
  • Organizer: 第39回日本分子生物学会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] Comprehensive understanding of associations between HLA class II genes and chronic hepatitis B infection in the Japanese population (2016)
  • Author(s): Nao Nishida, et al.
  • Organizer: American Association for the study of Liver Diseases The Liver Meeting 2016
  • Place of Presentation: Boston
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Comprehensive understanding of associations between HLA class II genes and chronic hepatitis B infection in Japanese individuals (2016)
  • Author(s): Nao Nishida, Jun Ohashi, Seik-Soon Khor, Masaya Sugiyama, Hiromi Sawai, Katsushi Tokunaga, Masashi Mizokami
  • Organizer: 66th Annual ASHG Meeting
  • Place of Presentation: Vancouver
  • Year and Date: 2016-10-18
  • Int'l Joint Research
• [Presentation] Associations between HLA class II genes and chronic hepatitis B infection in the Japanese population (2016)
  • Author(s): Masashi Mizokami, Nao Nishida, Katsushi Tokunaga
  • Organizer: 2016 International HBV Meeting
  • Place of Presentation: Seoul
  • Year and Date: 2016-09-21
  • Int'l Joint Research
• [Presentation] HBV関連疾患とHLAの関連 (2016)
  • Author(s): 西田奈央、杉山真也、澤井裕美、考藤達哉、徳永勝士、溝上雅史
  • Organizer: 第52回 日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張、東京ベイ幕張ホール
  • Year and Date: 2016-05-19
• [Presentation] Effects of HLA-DPB1 genotypes on HBV-related diseases in Japanese population (2016)
  • Author(s): Nao Nishida, Jun Ohashi, Masaya Sugiyama, Takayo Tsuchiura, Mayumi Ishii, Katsushi Tokunaga, and Masashi Mizokami
  • Organizer: 第13回国際人類遺伝学会
  • Place of Presentation: 国立京都国際会館
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] 肝疾患研究におけるゲノム解析 (2016)
  • Author(s): 西田奈央
  • Organizer: 2016年度 大学共同利用機関法人 情報・システム研究機構 国立遺伝学研究所 研究会
  • Place of Presentation: 国立遺伝学研究所
  • Invited
• [Remarks] 肝炎データストレージ
  • URL: http://tokyogw.bits.cc/hep-smpl-mng_public/public/
• [Remarks] B型肝炎ワクチンの効果に影響を与えるHLA-DRB1-DQB1ハプロタイプとBTNL2遺伝子
  • URL: https://www.amed.go.jp/news/release_20180323.html
• [Patent(Industrial Property Rights)] B型肝炎の慢性化の素因の検出方法 (2016)
  • Inventor(s): 徳永勝士、澤井裕美、溝上雅史、西田奈央、杉山真也
  • Industrial Property Rights Holder: 徳永勝士、澤井裕美、溝上雅史、西田奈央、杉山真也
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-204735
  • Filing Date: 2016-10-17