Identification of host genetic factors associated with response to a HB vaccination

• Project/Area Number: 15K08986
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: SAWAI Hiromi 東京大学, 大学院医学系研究科(医学部), 助教 (60377124)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2015: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
• Keywords: B型肝炎 / 疾患関連遺伝子

Outline of Final Research Achievements

The GWAS and HLA association tests were carried out using a total of 1,193 Japanese individuals including low responders, intermediate responders, and high responders. Classical HLA class II alleles were statistically imputed using the genome-wide SNP typing data. The GWAS identified independent associations of HLA-DRB1-DQB1, HLA-DPB1 and BTNL2 genes. Five HLA DRB1-DQB1 haplotypes and two DPB1 alleles showed significant associations with response to the HB vaccine in a comparison of three groups of 1,193 HB vaccinated individuals. When frequencies of DRB1-DQB1 haplotypes and DPB1 alleles were compared between low immune responders and HBV patients, significant associations were identified for three DRB1-DQB1 haplotypes, and no association was identified for any of the DPB1 alleles. In contrast, no association was identified for DRB1-DQB1 haplotypes and DPB1 alleles in a comparison between high immune responders and healthy individuals.

Academic Significance and Societal Importance of the Research Achievements

世界180カ国以上でHBワクチン接種は行われており、日本ではGenotype Cに対応するHBワクチン（ビームゲン）が使用されてきた。しかし、ビームゲン接種者のうち約10％はHBs抗体を獲得できず、その原因は不明であった。本研究により、特定のHLA-DR-DQ分子によるHBs抗原の認識（ワクチン低反応）、およびBTNL2分子によるT細胞やB細胞の活性制御（ワクチン高反応）がHBワクチンの効果に重要な役割を果たすことが明らかとなり、今後国際共同等を進めることで、ユニバーサルワクチネーションが行われている日本やその他の国において、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

• [Journal Article] Identification of a two-SNP PLA2R1 Haplotype and HLA-DRB1 Alleles as Primary Risk Associations in Idiopathic Membranous Nephropathy (2018)
  • Author(s): Latt Khun Zaw、Honda Kenjiro、Thiri Myo、Hitomi Yuki、Omae Yosuke、Sawai Hiromi、Kawai Yosuke、Teraguchi Shunsuke、Ueno Kazuko、Nagasaki Masao、Mabuchi Akihiko、Kaga Hajime、Komatsuda Atsushi、Tokunaga Katsushi、Noiri Eisei
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 15576-15576
  • DOI: 10.1038/s41598-018-33612-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Discerning the Origins of the Negritos, First Sundaland People: Deep Divergence and Archaic Admixture (2017)
  • Author(s): Jinam Timothy A.、Phipps Maude E.、Aghakhanian Farhang、Majumder Partha P.、Datar Francisco、Stoneking Mark、Sawai Hiromi、Nishida Nao、Tokunaga Katsushi、Kawamura Shoji、Omoto Keiichi、Saitou Naruya
  • Journal Title: Genome Biology and Evolution Volume: 9 Issue: 8 Pages: 2013-2022
  • DOI: 10.1093/gbe/evx118
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The first genome-wide association study identifying new susceptibility loci for obstetric antiphospholipid syndrome (2017)
  • Author(s): Sugiura-Ogasawara Mayumi、Omae Yosuke、Kawashima Minae、Toyo-Oka Licht、Khor Seik-Soon、Sawai Hiromi、Horita Tetsuya、Atsumi Tatsuya、Murashima Atsuko、Fujita Daisuke、Fujita Tomio、Morimoto Shinji、Morishita Eriko、Katsuragi Shinji、Kitaori Tamao、Katano Kinue、Ozaki Yasuhiko、Tokunaga Katsushi
  • Journal Title: Journal of Human Genetics Volume: 62 Issue: 9 Pages: 831-838
  • DOI: 10.1038/jhg.2017.46
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genome-wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection. (2017)
  • Author(s): Matsuura K, Honda M, et al.
  • Journal Title: Gastroenterology. Volume: - Issue: 6 Pages: 1383-1394
  • DOI: 10.1053/j.gastro.2017.01.041
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genome-wide association study using the ethnicity-specific Japonica array: identification of new susceptibility loci for cold medicine-related Stevens-Johnson syndrome with severe ocular complications (2017)
  • Author(s): Mayumi Ueta , Hiromi Sawai*, Ryosei Shingaki, Yusuke Kawai, Chie Sotozono, Kaname Kojima, Kyung-Chul Yoon, Mee Kum Kim, Kyoung Yul Seo, Choun-Ki Joo, et al. *Contributed equally with the first author
  • Journal Title: Journal of Human Genetics Volume: 62 Issue: 4 Pages: 485-489
  • DOI: 10.1038/jhg.2016.160
  • NAID: 40021158280
  • Peer Reviewed / Open Access / 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] 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] 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] 全ゲノムシーケンスデータによる本土日本人の集団史に関する解析 (2018)
  • Author(s): 渡部裕介、中伊津美、人見祐基、澤井裕美、Khor Soon、徳永勝士、大橋順
  • Organizer: 日本人類遺伝学会第63回大会
• [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] 日本人集団におけるB型肝炎の全ゲノムコピー数多型解析 (2017)
  • Author(s): 菊地 正隆、小林 香織、澤井 裕美、西田 奈央、杉山 真也、溝上 雅史、徳永 勝士、中谷 明弘
  • 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: American Society of Human Genetics 2017
  • Int'l Joint Research
• [Presentation] Association of TLL1 variant with hepatocellular carcinoma developed after eradication of hepatitis C virus (2017)
  • Author(s): Tokunaga K, Matsuura K, Sawai H, Kawai Y, Kojima K, Nagasaki M, and Tanaka Y
  • Organizer: American Society of Human Genetics 2017
  • Int'l Joint Research
• [Presentation] Trial to make the combined genotyping to detect high-risk individuals for cold medicine related Stevens-Johnson syndrome (CM-SJS) (2017)
  • Author(s): Mayumi Ueta, Katsushi Tokunaga, Chikara Inoue, Hiromi Sawai, Chie Sotozono, Shigeru Kinoshita
  • Organizer: American Society of Human Genetics 2017
  • 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] New susceptibility loci for cold medicine-related Stevens-Johnson syndrome with severe ocular complications identified by GWAS using an ethnicity-specific SNP array (2017)
  • Author(s): Katsushi Tokunaga, Mayumi Ueta, Hiromi Sawai, Yusuke Kawai, Chie Sotozono, Kaname Kojima, Kyung-Chul Yoon, Mee Kum Kim, Kyoung Yul Seo, Choun-Ki Joo, Masao Nagasaki, Shigeru Kinoshita
  • Organizer: European Society of Human Genetics 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年会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-12-02
• [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 (2016)
  • Author(s): 馬場奈津美、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25回日本組織適合性学会
  • Place of Presentation: 北海道大学 学術交流会館 （北海道札幌市）
  • Year and Date: 2016-10-23
• [Presentation] Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B virus-related hepatocellular carcinoma (2016)
  • Author(s): Hiromi Sawai, Nao Nishida, Masaya Sugiyama, Seik-Soon Khor, Masashi Mizokami and Katsushi Tokunaga
  • Organizer: ASHG2016
  • Place of Presentation: Vancouver Convention Centre (Vancouver, Canada)
  • Year and Date: 2016-10-19
  • Int'l Joint Research
• [Presentation] Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B virus-related hepatocellular carcinoma (2016)
  • Author(s): Hiromi Sawai, Nao Nishida, Masaya Sugiyama, Seik-Soon Khor, Masashi Mizokami and Katsushi Tokunaga
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: Kyoto International Conference Center (Kyoto, Japan)
  • Year and Date: 2016-04-05
  • Int'l Joint Research
• [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 (2015)
  • Author(s): 澤井裕美、西田奈央、田中靖人、溝上雅史、徳永勝士
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 熊本ホテルキャッスル （熊本県熊本市）
  • Year and Date: 2015-05-21