Interferon stimulated genes and its polymorphisms determining Hepatitis C virus replication and pathogenesis of hepatitis C

• Project/Area Number: 20590760
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: KATO Naoya The University of Tokyo, 医科学研究所, 特任准教授 (90313220)
• Co-Investigator(Kenkyū-buntansha): MUROYAMA Ryosuke 東京大学, 医科学研究所, 特任助教 (50549459)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2008: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: C型肝炎ウイルス / インターフェロン / PKR / OAS / コア蛋白 / 肝癌 / GWAS / SNP / MICA / 自然免疫 / MxA / TLR3 / 2-5AS / RNA干渉

Research Abstract

Hepatitis C virus (HCV) infection induces interferon (IFN). IFN induces antiviral molecules that suppress HCV replication. Although IFN stimulated genes, PKR, MxA, and OAS suppressed HCV replication, only MxA was essential in IFN treatment. In addition, chronic hepatitis C (CHC) patients having OAS polymorphism with weaker anti-HCV activity were easier to develop cirrhosis. There are individual differences for development of hepatocellular carcinoma (HCC) in patients with CHC. Genome wide association study (GWAS) identified HCC susceptible single nucleotide polymorphism (SNP) in MICA gene.

Research Products

• [Journal Article] Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. (2011)
  • Author(s): Kumar V, Kato N, Urabe Y, Takahashi A, Muroyama R, Hosono N, Otsuka M, Tateishi R, Omata M, Nakagawa H, Koike K, Kamatani N, Kubo M, Nakamura Y, Matsuda K
  • Journal Title: Nat Genet 43 Pages: 455-458
  • Peer Reviewed
• [Journal Article] MicroRNA122 is a key regulator of α-fetoprotein expression and biologically aggressive behavior of hepatocellular carcinoma. (2011)
  • Author(s): Kojima K, Takata A, Vadnais C, Otsuka M, Yoshikawa T, Akanuma M, Kondo Y, Kang YJ, Kishikawa T, Kato N, Xie Z, Zhang WJ, Yoshida H, Omata M, Nepveu A, Koike K
  • Journal Title: Nat Commun 2 Pages: 338-338
  • Peer Reviewed
• [Journal Article] Direct differentiation of hepatic cells from human induced pluripotentstem cells using a limited number of cytokines. (2011)
  • Author(s): Takata A, Kato N, et al.
  • Journal Title: Hepatol Int Volume: (in press)(掲載確定)
  • Peer Reviewed
• [Journal Article] Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. (2011)
  • Author(s): Kumar V, Kato N, et al.
  • Journal Title: Nat Genet Volume: (in press)(掲載確定)
  • Peer Reviewed
• [Journal Article] Double-stranded-RNA-activated protein kinase inhibits hepatitis C virus replication but may be not essential in interferon treatment. (2010)
  • Author(s): Chang J-H, Kato N, Muroyama R, Taniguchi H, Guleng B, Dharel N, Shao R-X, Tateishi K, Jazag A, Kawabe T, Omata M
  • Journal Title: Liver Int 30 Pages: 311-318
  • Peer Reviewed
• [Journal Article] Influence of anti-HBc seropositivity on the risk of hepatocellular carcinoma in HCV-infected patients after adjusting for confounding factors. (2010)
  • Author(s): Ohki T, Tateishi R, Goto E, Sato T, Masuzaki R, Imamura J, Goto T, Kanai F, Kato N, Shiina S, Yoshida H, Kawabe T, Omata M
  • Journal Title: J Viral Hepat 17 Pages: 91-97
  • Peer Reviewed
• [Journal Article] Double-stranded-RNA-activated protein kinase inhibits hepatitis C virus replication but may be not essential in interferon treatment. (2010)
  • Author(s): Chang J-H, Kato N, et al.
  • Journal Title: Liver Int Volume: 30 Pages: 311-318
  • Peer Reviewed
• [Journal Article] Influence of anti-HBc seropositivity on the risk of hepatocellular carci-noma in HCV-infected patients after adjusting for confounding factors. (2010)
  • Author(s): Ohki T, Kato N, et al.
  • Journal Title: J Viral Hepato Volume: 17 Pages: 91-97
  • Peer Reviewed
• [Journal Article] Double-stranded-RNA-activated protein kinase inhibits hepatitis C virus replication but maybe not essential in interferon treatment. (2010)
  • Author(s): Chang J-H, Kato N, et al.
  • Journal Title: Liver International 30 Pages: 311-318
  • Peer Reviewed
• [Journal Article] Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography. (2009)
  • Author(s): Masuzaki R, Tateishi R, Yoshida H, Yoshida H, Sato S, Kato N, Kanai F, Sugioka Y, Ikeda H, Shiina S, Kawabe T, Omata M
  • Journal Title: Hepatology 49 Pages: 1954-1961
  • Peer Reviewed
• [Journal Article] Polymorphism of OAS-1 determines liver fibrosis progression in hepatitis C by reduced ability to inhibit viral replication. (2009)
  • Author(s): Li C-Z, Kato N, Chang J-H, Muroyama R, Shao R-X, Dharel N, Sermsathanasawadi R, Kawabe T, Omata M
  • Journal Title: Liver Int 29 Pages: 1413-1421
  • Peer Reviewed
• [Journal Article] Serum IL-6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients ; An analysis based on gender differences. (2009)
  • Author(s): Nakagawa H, Maeda S, Yoshida H, Tateishi R, Masuzaki R, Ohki T, Hayakawa Y, Kinoshita H, Yamakado M, Kato N, Shiina S, Omata M
  • Journal Title: Int J Cancer 125 Pages: 2264-2269
  • Peer Reviewed
• [Journal Article] Ultrasound surveillance for early detection of hepatocellular carcinoma among patients with chronic hepatitis C. (2009)
  • Author(s): Sato T, Tateishi R, Yoshida H, Ohki T, Masuzaki R, Imamura J, Goto T, Kanai F, Obi S, Kato N, Shiina S, Kawabe T, Omata M
  • Journal Title: Hepatol Int 3 Pages: 544-550
  • Peer Reviewed
• [Journal Article] Characteristic mutations in hepatitis C virus core gene related to the occurrence of hepatocellular carcinoma. (2009)
  • Author(s): Hu Z, Muroyama R, Kowatari N, Chang J, Omata M, Kato N
  • Journal Title: Cancer Sci 100 Pages: 2465-2468
  • NAID: 10027198911
  • Peer Reviewed
• [Journal Article] Polymorphism of OAS-1 determines liver fibrosis progression in hepatitis C by reduced ability to inhibit viral replication. (2009)
  • Author(s): Li CZ, Kato N, et al.
  • Journal Title: Liver International 29 Pages: 1413-1421
  • Peer Reviewed
• [Journal Article] Characteristic mutations in hepatitis C virus core gene related to the occurrence of hepatocellular carcinoma. (2009)
  • Author(s): Hu Z, Kato N, et al.
  • Journal Title: Cancer Science 100 Pages: 2465-2468
  • NAID: 10027198911
  • Peer Reviewed
• [Journal Article] (2009)
  • Author(s): Omata M, Kato N, et al.
  • Journal Title: Hepatocellular carcinoma"epidemics"in Japan. In : Hepatitis C virus.(International Medical Press Ltd.)
• [Journal Article] Obesity is an independent risk factor for hepatocellular carcinoma development in chronic hepatitis C patients. (2008)
  • Author(s): Ohki T, Tateishi R, Sato T, Masuzaki R, Imamura J, Goto T, Yamashiki N, Yoshida H, Kanai F, Kato N, Shiina S, Yoshida H, Kawabe T, Omata M
  • Journal Title: Clin Gastroenterol Hepatol 6 Pages: 459-464
  • Peer Reviewed
• [Journal Article] Association of IRF-7 gene polymorphism with liver cirrhosis in chronic hepatitis C patients. (2008)
  • Author(s): Sermasathanasawadi R, Kato N, Muroyama R, Dharel N, Shao R-X, Chang J-H, Li C-Z, Kawabe T, Omata M
  • Journal Title: Liver Int 28 Pages: 798-806
  • Peer Reviewed
• [Journal Article] Risk Assessment of hepatocellular carcinoma in chronic hepatitis C patients by transient elastography. (2008)
  • Author(s): Masuzaki R, Tateishi R, Yoshida H, Yoshida H, Sato S, Kato N, Kanai F, Sugioka Y, Ikeda H, Shiina S, Kawabe T, Omata M
  • Journal Title: J Clin Gastroenterol 42 Pages: 839-843
  • Peer Reviewed
• [Journal Article] Association of interferon regulatory factor-7 gene polymorphism with liver cirrhosis in chronic hepatitis C patients. (2008)
  • Author(s): Sermasathanasawadi R, et al.
  • Journal Title: Liver Int 28 Pages: 798-806
  • Peer Reviewed
• [Journal Article] Obesity is an independent risk factor for hepatocellular carcinoma development in chronic hepatitis C patients. (2008)
  • Author(s): Ohki T,et al
  • Journal Title: Clin Gastroenterol Hepatol 6 Pages: 459-464
  • Peer Reviewed
• [Journal Article] Risk Assesment of hepatocellular carcinoma in chronic Hepatitis C patients by transient elastography. (2008)
  • Author(s): Masuzaki R, et al.
  • Journal Title: J Clin Gastroenterol 42 Pages: 839-843
  • Peer Reviewed
• [Journal Article] Direct differentiation of hepatic cells from human induced pluripotent stem cells using a limited number of cytokines.
  • Author(s): Takata A, Otsuka M, Kogiso T, Kojima K, Yoshikawa T, Tateishi R, Kato N, Shiina S, Yoshida H, Omata M, Koike K
  • Journal Title: Hepatol Int (in press)
  • Peer Reviewed
• [Presentation] A genome-wide study identifies susceptibility loci for hepatitis C virus induced hepatocellular carcinoma. (2011)
  • Author(s): Kato N, Kumar V, Muroyama R, Kowatari N, Li W, Otsuka M, Tateishi R, Yoshida H, Omata M, Koike K, Nakamura Y, Matsuda K
  • Organizer: 46th Annual Meeting of the European Association for the Study of the Liver.
  • Place of Presentation: Berlin, Germany
• [Presentation] Core mutant ratio is associated with response to PEG-IFN/RBV treatment in HCV genotype 1b patients. (2011)
  • Author(s): Li W, Muroyama R, Hu Z, Kowatari N, Goto T, Yoshida H, Li Q, Omata M, Koike K, Kato N
  • Organizer: The 21st Conference of the Asian Pacific Association for the Study of the Liver.
• [Presentation] Core mutant ratio is associated with response to PEG-IFN/RBV treatment in HCV genotype 1b patients. (2011)
  • Author(s): Li W, Kato N, et al.
  • Organizer: The 21st Conference of the Asian Pacific Association for the Study of the Liver
  • Place of Presentation: Bangkok, Thailand
• [Presentation] A genome-wide study identifies susceptibility loci for hepatitis C virus-induced hepatocellular carcinoma. (2011)
  • Author(s): Kato N, et al.
  • Organizer: 46th Annual Meeting of the European Association for the Study of the Liver
  • Place of Presentation: Berlin, Germany
• [Presentation] Mutant ratio of amino acid 70 in genotype 1b HCV core protein is associated with response to PEG-IFN/RBV treatment. (2010)
  • Author(s): Li W, Kato N
  • Organizer: The APASL 7th Single Topic Conference "Hepatitis C Virus"
  • Place of Presentation: Chiba, Japan
• [Presentation] Quantification of hepatitis C virus genotype 1b codon 70 wild and mutant types and their response to PEG-IFN/RBV treatment. (2010)
  • Author(s): 加藤直也
  • Organizer: BIT's 1st World Congress of Virus and Infections 2010.
  • Place of Presentation: Busan, Republic of Korea
• [Presentation] Quantification of hepatitis C virus genotype 1b codon 70 wild and mutant types and their response to PEG-IFN/RBV treatment. (2010)
  • Author(s): Kato N.
  • Organizer: BIT's 1st World Congress of Virus and Infections-2010
  • Place of Presentation: Busan, Republic of Korea
• [Presentation] Amino acid substitutions in genotype 1b HCV core protein and response to PEG-IFN/RBV treatment. (2010)
  • Author(s): Li W, Kato N, et al.
  • Organizer: 17th International Meeting on Hepatitis C Virus and Related Viruses
  • Place of Presentation: パシフィコ横浜
• [Presentation] Mutant ratio of amino acid 70 in genotype lb HCV core protein is associated with response to PEG-IFN/RBV treatment. (2010)
  • Author(s): Li W, Kato N, et al.
  • Organizer: The APASL 7th Single Topic Conference "Hepatitis C Virus"
  • Place of Presentation: 千葉幕張メッセ
• [Presentation] Amino acid substitutions at position 70 of HCV genotype 1b core region is related to the increased HCC risk and non-virological response to PEG-IFN plus RBV combination therapy. (2009)
  • Author(s): Kato N, Hu Z, Muroyama R, Goto T, Kowatari N, Chang J, Omata M
  • Organizer: 16th International Symposium on Hepatitis C Virus and Related Viruses.
  • Place of Presentation: Nice, France
• [Presentation] Amino acid substitutions at position 70 of HCV genotype 1b core region is related to the increased HCC risk and non-virological response to PEG-IFN plus RBV combination therapy. (2009)
  • Author(s): Kato N, et al.
  • Organizer: 16^<th> International Symposium on Hepatitis C Virus and Related Viruses
  • Place of Presentation: Nice, France
• [Presentation] C型肝炎ウイルス増殖と病態を規定するインターフェロン関連分子とその多型 (2008)
  • Author(s): 加藤直也、常金海、小俣政男
  • Organizer: 第94回日本消化器病学会総会
  • Place of Presentation: 福岡
  • Year and Date: 2008-05-08
• [Book] Hepatitis C virus.(Karayiannis P, Main J, Thomas H eds.)(Hepatocellular carcinoma "epidemics" in Japan.) (2009)
  • Author(s): Omata M, Yoshida H, Shiina S, Kato N
  • Publisher: International Medical Press Ltd.
• [Book] 肝胆膵診療エキスパートマニュアル (2008)
  • Author(s): 加藤直也
  • Publisher: 羊土社
• [Book] 肝胆膵診療エキスパートマニュアル (2008)
  • Author(s): 加藤直也,他
  • Total Pages: 436
  • Publisher: 羊土社
• [Remarks] 東京大学医科学研究所 発表論文解説:ゲノムワイド関連解析によりHCV陽性肝細胞癌の感受性遺伝子を同定
  • URL: http://www.ims.u-tokyo.ac.jp/imsut/jp/research/papers/hcv.php
• [Remarks] MTPro記事:【寄稿】遺伝子検査で慢性C型肝炎患者の発がんリスクが予測可能に
  • URL: http://mtpro.medical-tribune.co.jp/mtpronews/1104/1104072.html
• [Remarks]
  • URL: http://www.ims.u-tokyo.ac.jp/imsut/jp/research/papers/hcv.php