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RESEARCH

肝炎研究
Research for hepatitis

Our aim is to identify genetic factors associated with various disease states caused by HBV. ・ We have collected thousands of samples through collaboration in Japan and outside Japan. We have conducted large scale Genome-wide Association Studies (GWAS) in order to identify novel variants that might associate with the divergence of HBV infection.

研究背景

肝炎は、B型肝炎ウイルス(HBV)およびC型肝炎ウイルス(HCV)によって引き起こされる感染症です。HBVは感染した時期等によって、一過性感染に終息する一過性感染と、ほぼ生涯にわたり感染が継続する持続感染に大別されます。B型慢性肝炎は主に垂直感染（母子感染）した持続感染者に起こりますが、出産後しばらくは発症しません。10-30代に一過性の肝炎を引き起こした後はそのまま安定してキャリアとなる人が80-90%にのぼります。そして残りの10-20%の人は慢性肝炎に移行し、さらに一部が肝硬変・肝癌へと移行しますが、これらの経過には遺伝要因の寄与が示唆されています。

研究アプローチ

私たちは、国内外の多施設共同研究施設で収集されたウイルス性肝炎由来の様々な病態に関わる検体を用いて、ゲノムワイドSNPタイピングを実施し、それらのSNP情報を用いたゲノムワイド関連解析(GWAS)を実施する事により、HBV・HCV感染に起因する様々な病態に関連する遺伝要因を同定することを目的としています。同定された疾患関連遺伝子領域について、次世代シークエンサーを用いた詳細な遺伝子構造解析を実施したり、機能的に重要な分子について、タンパク質機能解析を実施したりしています。

2019年度より国立研究開発法人 日本医療研究開発機構（AMED)の肝炎等克服緊急対策研究事業に採択され、B型肝炎ウイルスおよびヒトゲノムの解析に基づくクリニカルシークエンスに向けた研究を実施しています。

主な成果

HBV感染に伴う慢性化、および肝発癌にHLA-DP遺伝子が関与している事を明らかにし、HLA-DPアリルの詳細な解析を実施しました。また、HCVについては、IL28B遺伝子上のSNPがペグインターフェロン＋リバビリン(PEG-IFN/RBV)併用療法の治療効果に関連する事を同定し、このほかにもPEG-IFN/RBV併用療法の副作用の一つである貧血にITPA遺伝子が関連することを同定しました。

本研究に関する文献

Nishida N, Ohashi J, Suda G, Chiyoda T, Tamaki N, Tomiyama T, Ogasawara S, Sugiyama M, Kawai Y, Khor SS, Nagasaki M, Fujimoto A, Tsuchiura T, Ishikawa M, Matsuda K, Yano H, Yoshizumi T, Izumi N, Hasegawa K, Sakamoto N, Mizokami M, and Tokunaga K: Prediction model with HLA-A*33:03 reveals number of days to develop liver cancer from blood test. Int. J. Mol. Sci. 24(5): 4761, 2023.
Ashouri S, Khor SS, Hitomi Y, Sawai H, Nishida N, Sugiyama M, Kawai Y, Posuwan N, Tangkijvanich P, Komolmit P, Tsuiji M, Shotelersuk V, Poovorawan Y, Mizokami M, and Tokunaga K: Genome-Wide Association Study for Chronic Hepatitis B Infection in the Thai Population. Front. Genet. 13: 887121, 2022.
Kikuchi M, Kobayashi K, Nishida N, Sawai H, Sugiyama M, Mizokami M, Tokunaga K, and Nakaya A: Genome-wide copy number variation analysis of hepatitis B infection in a Japanese population. Hum. Genome Var. 8(1): e22, 2021.
Nishida N, Sugiyama M, Ohashi J, Kawai Y, Khor SS, Nishina S, Yamasaki K, Yazaki H, Okudera K, Tamori A, Eguchi Y, Sakai A, Kakisaka K, Sawai H, Tsuchiura T, Ishikawa M, Hino K, Sumazaki R, Takikawa Y, Kanda T, Yokosuka O, Yatsuhashi H, Tokunaga K, and Mizokami M: Importance of HBsAg recognition by HLA molecules as revealed by responsiveness to different hepatitis B vaccines. Sci. Rep. 11(1): e3703, 2021.
Kikuchi M, Kobayashi K, Nishida N, Sawai H, Sugiyama M, Mizokami M, Tokunaga K, Nakaya A. Genome-wide copy number variation analysis of hepatitis B infection in a Japanese population. Hum Genome Var. 2021 Jun 8;8(1):22.
Cordell HJ, Fryett JJ, Ueno K, Darlay R, Aiba Y, Hitomi Y, Kawashima M, Nishida N, Khor SS, Gervais O, Kawai Y, Nagasaki M, Tokunaga K, Tang R, Shi Y, Li Z, Juran BD, Atkinson EJ, Gerussi A, Carbone M, Asselta R, Cheung A, de Andrade M, Baras A, Horowitz J, Ferreira MAR, Sun D, Jones DE, Flack S, Spicer A, Mulcahy VL, Byan J, Han Y, Sandford RN, Lazaridis KN, Amos CI, Hirschfield GM, Seldin MF, Invernizzi P, Siminovitch KA, Ma X, Nakamura M, Mells GF; PBC Consortia; Canadian PBC Consortium; Chinese PBC Consortium; Italian PBC Study Group; Japan-PBC-GWAS Consortium; US PBC Consortium; UK-PBC Consortium. An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs. J Hepatol. 2021 May 23:S0168-8278(21)00334-2.
Khor SS, Omae Y, Nishida N, Sugiyama M, Kinoshita N, Suzuki T, Suzuki M, Suzuki S, Izumi S, Hojo M, Ohmagari N, Mizokami M, Tokunaga K. HLA-A*11:01:01:01, HLA-C*12:02:02:01-HLA-B*52:01:02:02, Age and Sex Are Associated With Severity of Japanese COVID-19 With Respiratory Failure. Front Immunol. 2021 Apr 22;12:658570.
Nishida N, Sugiyama M, Ohashi J, Kawai Y, Khor SS, Nishina S, Yamasaki K, Yazaki H, Okudera K, Tamori A, Eguchi Y, Sakai A, Kakisaka K, Sawai H, Tsuchiura T, Ishikawa M, Hino K, Sumazaki R, Takikawa Y, Kanda T, Yokosuka O, Yatsuhashi H, Tokunaga K, Mizokami M. Importance of HBsAg recognition by HLA molecules as revealed by responsiveness to different hepatitis B vaccines. Sci Rep. 2021 Mar 2;11(1):3703.
Goto K, Nishitsuji H, Sugiyama M, Nishida N, Mizokami M, Shimotohno K. Orchestration of Intracellular Circuits by G Protein-Coupled Receptor 39 for Hepatitis B Virus Proliferation. Int J Mol Sci. 2020 Aug 7;21(16):5661.
Liu J, Hu HH, Chang CL, Jen CL, Lee MH, Lu SN, Wang LY, Yuan Q, Xia NS, Sugiyama M, Nishida N, Mizokami M, Chen CJ, Chen PJ, Yang HI. Association Between High Levels of Hepatitis B Core Antibody and Seroclearance of Hepatitis B e Antigen in Individuals With Chronic Hepatitis B Virus Infection. Clin Gastroenterol Hepatol. 2019 Jun;17(7):1413-1415.
Lin YJ, Chang CL, Chen LC, Hu HH, Liu J, Korenaga M, Huang YH, Jen CL, Su CY, Nishida N, Sugiyama M, Lu SN, Wang LY, Yuan Y, L'Italien G, Yang HI, Mizokami M, Chen CJ, Lee MH. A Glycomarker for Short-term Prediction of Hepatocellular Carcinoma: A Longitudinal Study With Serial Measurements. Clin Transl Gastroenterol. 2018 Sep 20;9(9):183.
Sawai H, Nishida N, Khor SS, Honda M, Sugiyama M, Baba N, Yamada K, Sawada N, Tsugane S, Koike K, Kondo Y, Yatsuhashi H, Nagaoka S, Taketomi A, Fukai M, Kurosaki M, Izumi N, Kang JH, 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. Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B virus-related hepatocellular carcinoma. Sci Rep. 2018 May 21;8(1):7958.
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. Key HLA-DRB1-DQB1 haplotypes and role of the BTNL2 gene for response to a hepatitis B vaccine. Hepatology. 2018 Sep;68(3):848-858.
Lee MH, Huang YH, Chen HY, Khor SS, Chang YH, Lin YJ, Jen CL, Lu SN, Yang HI, Nishida N, Sugiyama M, Mizokami M, Yuan Y, L'Italien G, Tokunaga K, Chen CJ; REVEAL-HCV Cohort Study Group. Human leukocyte antigen variants and risk of hepatocellular carcinoma modified by hepatitis C virus genotypes: A genome-wide association study. Hepatology. 2018 Feb;67(2):651-661.
Trinks J, Nishida N, Hulaniuk ML, Caputo M, Tsuchiura T, Marciano S, Haddad L, Blejer J, Bartoli S, Ameigeiras B, Frias SE, Vistarini C, Heinrich F, Remondegui C, Ceballos S, Echenique G, Charre Samman M, D'Amico C, Rojas A, Martinez A, Ridruejo E, Fernandez RJ, Burgos Pratx L, Salamone H, Nunez F, Galdame O, Gadano A, Corach D, Sugiyama M, Flichman D, Tokunaga K, Mizokami M. Role of HLA-DP and HLA-DQ on the clearance of hepatitis B virus and the risk of chronic infection in a multiethnic population. Liver Int. 2017 Oct;37(10):1476-1487.
Nagao Y, Nakasone K, Maeshiro T, Nishida N, Kimura K, Kawahigashi Y, Tanaka Y, Sata M. Successful Treatment of Oral Lichen Planus with Direct-Acting Antiviral Agents after Liver Transplantation for Hepatitis C Virus-Associated Hepatocellular Carcinoma. Case Rep Gastroenterol. 2017 Nov 29;11(3):701-710.
Nagao Y, Nishida N, Toyo-Oka L, Kawaguchi A, Amoroso A, Carrozzo M, Sata M, Mizokami M, Tokunaga K, Tanaka Y. Genome-Wide Association Study Identifies Risk Variants for Lichen Planus in Patients With Hepatitis C Virus Infection. Clin Gastroenterol Hepatol. 2017 Jun;15(6):937-944.e5.
Murata K, Asano M, Matsumoto A, Sugiyama M, Nishida N, Tanaka E, Inoue T, Sakamoto M, Enomoto N, Shirasaki T, Honda M, Kaneko S, Gatanaga H, Oka S, Kawamura YI, Dohi T, Shuno Y, Yano H, Mizokami M. Induction of IFN-λ3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection. Gut. 2018 Feb;67(2):362-371.
Matsunami K, Nishida N, Kaneko N, Ikeo K, Toyo-Oka L, Takeuchi H, Matsuura K, Tamori A, Nomura H, Yoshiji H, Imamura M, Masaki N, Hayakawa T, Ide T, Shimada N, Ikeda F, Hino K, Nishiguchi S, Okuse C, Nojiri S, Sawamoto K, Tokunaga K, Joh T, Tanaka Y. Genome-Wide Association Study Identifies ZNF354C Variants Associated with Depression from Interferon-Based Therapy for Chronic Hepatitis C. PLoS One. 2016 Oct 10;11(10)
Nishida N, Ohashi J, Khor SS, Sugiyama M, Tsuchiura T, Sawai H, Hino K, Honda M, Kaneko S, Yatsuhashi H, Yokosuka O, Koike K, Kurosaki M, Izumi N, Korenaga M, Kang JH, Tanaka E, Taketomi A, Eguchi Y, Sakamoto N, Yamamoto K, Tamori A, Sakaida I, Hige S, Itoh Y, Mochida S, Mita E, Takikawa Y, Ide T, Hiasa Y, Kojima H, Yamamoto K, Nakamura M, Saji H, Sasazuki T, Kanto T, Tokunaga K, Mizokami M. Understanding of HLA-conferred susceptibility to chronic hepatitis B infection requires HLA genotyping-based association analysis. Sci Rep. 2016 Apr 19;6:24767.
Ueyama M, Nishida N, Korenaga M, Korenaga K, Kumagai E, Yanai H, Adachi H, Katsuyama H, Moriyama S, Hamasaki H, Sako A, Sugiyama M, Aoki Y, Imamura M, Murata K, Masaki N, Kawaguchi T, Torimura T, Hyogo H, Aikata H, Ito K, Sumida Y, Kanazawa A, Watada H, Okamoto K, Honda K, Kon K, Kanto T, Mizokami M, Watanabe S. The impact of PNPLA3 and JAZF1 on hepatocellular carcinoma in non-viral hepatitis patients with type 2 diabetes mellitus. J Gastroenterol. 2016 Apr;51(4):370-9. doi: 10.1007/s00535-015-1116-6. Epub 2015
Nishida N, Ohashi J, Sugiyama M, Tsuchiura T, Yamamoto K, Hino K, Honda M, Kaneko S, Yatsuhashi H, Koike K, Yokosuka O, Tanaka E, Taketomi A, Kurosaki M, Izumi N, Sakamoto N, Eguchi Y, Sasazuki T, Tokunaga K, Mizokami M. Effects of HLA-DPB1 genotypes on chronic hepatitis B infection in Japanese individuals. Tissue Antigens. 2015 Dec;86(6):406-12. doi: 10.1111/tan.12684. Epub 2015
Iio E, Matsuura K, Nishida N, Maekawa S, Enomoto N, Nakagawa M, Sakamoto N, Yatsuhashi H, Kurosaki M, Izumi N, Hiasa Y, Masaki N, Ide T, Hino K, Tamori A, Honda M, Kaneko S, Mochida S, Nomura H, Nishiguchi S, Okuse C, Itoh Y, Yoshiji H, Sakaida I, Yamamoto K, Watanabe H, Hige S, Matsumoto A, Tanaka E, Tokunaga K, and Tanaka Y: Genome-wide association study identifies a PSMD3 variant associated with neutropenia in interferon-based therapy for chronic hepatitis C. Hum Genet 134(3):279-89, 2015.
Oda K, Uto H, Kumagai K, Ido A, Kusumoto K, Shimoda K, Hayashi K, Stuver SO, Tanaka Y, Nishida N, Tokunaga K, and Tsubouchi H. Impact of a single nucleotide polymorphism upstream of the IL28B gene in patients positive for anti-HCV antibody in an HCV hyperendemic area in Japan. J Med Virol 86(11): 1877-1885, 2014.
Nishino J, Sugiyama M, Nishida N, Tokunaga K, Mizokami M, Mano S. The interaction of a single-nucleotide polymorphism with age on response to interferon-α and ribavirin therapy in female patients with hepatitis C infection. J Med Virol. 2014 Jul;86(7):1130-3.
Nishida N, Sawai H, Kashiwase K, Minami M, Sugiyama M, Seto WK, Yuen MF, Posuwan N, Poovorawan Y, Ahn SH, Han KH, Matsuura K, Tanaka Y, Kurosaki M, Asahina Y, Izumi N, Kang JH, Hige S, Ide T, Yamamoto K, Sakaida I, Murawaki Y, Itoh Y, Tamori A, Orito E, Hiasa Y, Honda M, Kaneko S, Mita E, Suzuki K, Hino K, Tanaka E, Mochida S, Watanabe M, Eguchi Y, Masaki N, Murata K, Korenaga M, Mawatari Y, Ohashi J, Kawashima M, Tokunaga K, Mizokami M: New Susceptibility and Resistance HLA-DP Alleles to HBV-Related Diseases Identified by a Trans-Ethnic Association Study in Asia. PLoS One 9(2):e86449, 2014.
Kurosaki M, Tanaka Y, Nishida N, Sakamoto N, Enomoto N, Matsuura K, Asahina Y, Nakagawa M, Watanabe M, Sakamoto M, Maekawa S, Tokunaga K, Mizokami M, Izumi N: Model incorporating the ITPA genotype identifies patients at high risk of anemia and treatment failure with pegylated-interferon plus ribavirin therapy for chronic hepatitis C. J Med Virol 85(3):449-58, 2013.
Kumar V, Yi Lo PH, Sawai H, Kato N, Takahashi A, Deng Z, Urabe Y, Tokunaga K, Tanaka Y, Sugiyama M, Mizokami M, Muroyama R, Tateishi R, Omata M, Koike K, Tanikawa C, Kamatani N, Kubo M, Nakamura Y, and Matsuda K: Soluble MICA and a MICA variation as possibl prognostic biomarkers for HBV-induced hepatocellular carcinoma. PLoS ONE 7(9): e44743, 2012.
Sawai H, Nishida N, Mbarek H, Matsuda K, Mawatari Y, Yamaoka M, Hige S, Kang J H, Abe K, Mochida S, Watanabe M, Kurosaki M, Asahina Y, Izumi N, Honda M, Kaneko S, Tanaka E, Matsuura K, Itoh Y, Mita E, Korenaga M, Hino K, Murawaki Y, Hiasa Y, Ide T, Ito K, Sugiyama M, Sang Ahn S H, Han K H, Park J Y, Yuen M F, Nakamura Y, Tanaka Y, Mizokami M and Tokunaga K: No association for Chinese HBV-related hepatocellular carcinoma susceptibility SNP in other East Asian populations. BMC Med Genet 13(1): 47, 2012.
Nishida N, Sawai H, Matsuura K, Sugiyama M, Ahn SH, Park JY, Hige S, Kang JH, Suzuki K, Kurosaki M, Asahina Y, Mochida S, Watanabe M, Tanaka E, Honda M, Kaneko S, Orito E, Itoh Y, Mita E, Tamori A, Murawaki Y, Hiasa Y, Sakaida I, Korenaga M, Hino K, Ide T, Kawashima M, Mawatari Y, Sageshima M, Ogasawara Y, Koike A, Izumi N, Han K, Tanaka Y, Tokunaga K, and Mizokami M: Genome-wide association study confirming association of HLA-DP with protection against chronic hepatitis B and viral clearance in Japanese and Korean. PLoS ONE 7(6): e39175, 2012.
Tanaka Y, Kurosaki M, Nishida N, Sugiyama M, Matsuura N, Sakamoto N, Enomoto N, Yatsuhashi H, NIshiguchi S, Hino K, Hige S, Itoh Y, Tanaka E, Mochida S, Honda M, Hiasa Y, Koike A, Sugauchi F, Kaneko S, Izumi N, Tokunaga K, and Mizokami M: Genome-wide association study identified ITPA/DDRGK1 variants reflecting thrombocytopenia in pegylated interferon and ribavirin therapy for chronic hepatitis C. Hum Mol Genet 20(17): 3507-3516, 2011.
Kurosaki M, Tanaka Y, Tanaka K, Suzuki Y, Hoshioka Y, Tamaki N, Kato T, Yasui Y, Hosokawa T, Ueda K, Tsuchiya K, Kuzuya T, Nakanishi H, Itakura J, Takahashi Y, Asahina Y, Matsuura K, Sugauchi F, Enomoto N, Nishida N, Tokunaga K, Mizokami M, and Izumi N: Relationship between polymorphisms of the inosine triphosphatase gene and anaemia or outcome after treatment with pegylated interferon and ribavirin. Antivir Ther 16(5): 685-694, 2011.
Sakamoto N, Nakagawa M, Tanaka Y, Sekine-Osajima Y, Ueyama M, Kurosaki M, Nishida N, Tamori A, Nishimura-Sakurai Y, Itsui Y, Azuma S, Kakinuma S, Hige S, Ito Y, Tanaka E, Hiasa Y, Izumi N, Tokunaga K, Mizokami M, and Watanabe M: Association of IL28B polymorphism with response pegylated-interferon alpha plus ribavirin combination therapy in patients with chronic genotype 2 hepatitis C. J Med Virol 83(5): 871-878, 2011.
Kurosaki M, Tanaka Y, Nishida N, Sakamoto N, Enomoto N, Honda M, Sugiyama M, Matsuura K, Sugauchi F, Asahina Y, Nakagawa M, Watanabe M, Sakamoto M, Maekawa S, Sakai A, Kaneko S, Ito K, Masaki N, Tokunaga K, Izumi N, Mizokami M: Pre-treatment prediction of response to pegylated-interferon plus ribavirin for chronic hepatitis C using genetic polymorphism in IL28B and viral factors. J Hepatol 54(3): 439-448, 2011.
Sakamoto N, Tanaka Y, Nakagawa M, Yatsuhashi H, Nishiguchi S, Enomoto N, Azuma S, Nishimura-Sakurai Y, Kakinuma S, Nishida N, Tokunaga K, Honda M, Ito K, Mizokami M, and Watanabe M: ITPA gene variant protects against anemia induced by pegylated interferon-α andribavirin therapy for Japanese patients with chronic hepatitis C. Hepatol Res 40(11):1063-1071, 2010.
Tanaka Y*, Nishida N, Sugiyama M, Tokunaga K, and Mizokami M: λ- Interferons and the single nucleotide polymorphisms: A mikestone to tailor-made therapy for chronic hepatitis C. Hepatol Res 40(5): 449-460, 2010.
Honda M*, Sakai A, Yamashita T, Nakamoto Y, Mizukoshi E, Sakai Y, Yamashita T, Nakamura M, Shirasaki T, Horimoto K, Tanaka Y, Tokunaga K, Mizokami M, Kaneko S, Hokuriku Liver Study Group: Hepatic ISG expression is associated with genetic variation in IL28B and the outcome of IFN therapy for chronic hepatitis C. Gastroenterology 139(2): 499-509, 2010.
Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, Korenaga M, Hino K, Hige S, Ito Y, Mita E, Tanaka E, Mochida S, Murawaki Y, Honda M, Sakai A, Hiasa Y, Nishiguchi S, Koike A, Sakaida I, Imamura M, Ito K, Yano K, Masaki N, Sugauchi F, Izumi N, Tokunaga K, and Mizokami M*: Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 41(10): 1105-1109, 2009.