Comprehensive analyses of IL28B genetic factor toward tailor-made therapy for chronic hepatitis C

• Project/Area Number: 22390151
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Nagoya City University
• Principal Investigator: TANAKA Yasuhito 名古屋市立大学, 大学院・医学研究科, 教授 (90336694)
• Co-Investigator(Kenkyū-buntansha): SUGAUCHI Fuminaka 名古屋市立大学, 大学院・医学研究科, 研究員 (20405161) ; KONDO Yutaka 愛知県がんセンター, 分子腫瘍学部, 室長 (00419897) ; MIYOSHI Ichiro 名古屋市立大学, 大学院・医学研究科, 教授 (10183972)
• Co-Investigator(Renkei-kenkyūsha): FUJITA Takashi 京都大学, ウイルス研究所, 教授 (10156870)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000); Fiscal Year 2012: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2011: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2010: ¥10,140,000 (Direct Cost: ¥7,800,000、Indirect Cost: ¥2,340,000)
• Keywords: HCV / テーラーメイド治療 / IL28B / SNP / IFN ラムダ / HLA-DQ / IFNラムダ / エピゲノム

Research Abstract

(Aim) Toward the tailor-made therapy for chronic hepatitis C, basic and clinical researches of IL28B were conducted. (Methods and Results) Clinical research:
(1) Detection of new candidate SNPs
(2) Successful tailor-made therapy based on IL28B and ITPA SNPs. Basic research:
(1) IL28B gene expression was controlled by SNPs and the epigenetic changes within promoter region
(2) Functional analyses of IL28B showed that the induction of IFN-λs followed by immune response might contribute to different viral kinetics and treatment outcome in HCV-infected patients.

Research Products

• [Journal Article] Hepatitis C virus kinetics by administration of pegylated interferon-α in human and chimeric mice carrying human hepatocytes with variants of the IL28B gene. (2013)
  • Author(s): Watanabe T,Sugauchi F,Tanaka Y.
  • Journal Title: Gut Volume: (印刷中)
  • URL: http://gut.bmj.com/content/early/2012/11/06/gutjnl-2012-302553.full.pdf+html.
  • Peer Reviewed
• [Journal Article] Novel cell culture-adapted genotype 2a hepatitis C virus infectious clone (2012)
  • Author(s): Date T,Tanaka Y.
  • Journal Title: J Virol. Volume: 86(19) Issue: 19 Pages: 10805-10820
  • DOI: 10.1128/jvi.07235-11
  • Peer Reviewed
• [Journal Article] Development of new IL28B genotyping method using invader plus assay. (2012)
  • Author(s): Kani S,Tanaka Y.
  • Journal Title: Microbiol Immunol. Volume: 56(5) Issue: 5 Pages: 318-323
  • DOI: 10.1111/j.1348-0421.2012.00439.x
  • NAID: 40019309986
  • Peer Reviewed
• [Journal Article] Genome-wide association study identified ITPA/DDRGK1 variants reflecting thrombocytopenia in pegylated interferon and ribavirin therapy for chronic hepatitis C (2011)
  • Author(s): Tanaka Y, Sakamoto N, et al.
  • Journal Title: Human Molecular Genetics Volume: 20(17) Issue: 17 Pages: 3507-3516
  • DOI: 10.1093/hmg/ddr249
  • Peer Reviewed
• [Journal Article] Hepatitis C pharmacogenetics:state of the art in 2010 (2011)
  • Author(s): Afdhal NH,Tanaka Y.
  • Journal Title: Hepatology Volume: 53(1) Issue: 1 Pages: 336-345
  • DOI: 10.1002/hep.24052
  • Peer Reviewed
• [Journal Article] Association of IL28B variants with response to pegylated-interferon alpha plus ribavirin combination therapy reveals intersubgenotypic differences between genotypes 2a and 2b (2011)
  • Author(s): Sakamoto N, Nakagawa M, Azuma S, Watanabe M, et al.
  • Journal Title: J Med Virol Volume: 83 Issue: 5 Pages: 871-878
  • DOI: 10.1002/jmv.22038
  • Peer Reviewed
• [Journal Article] Novel Findings for the Development of Drug Therapy for Various Liver Diseases:Genetic Variation in IL-28B Is Associated With Response to the Therapy for Chronic Hepatitis C. (2011)
  • Author(s): Sugiyama M,Tanaka Y.
  • Journal Title: JPharmacol Sci Volume: 115(3) Pages: 263-269
  • URL: https://www.jstage.jst.go.jp/article/jphs/115/3/115_10R15FM/_pdf.
  • Peer Reviewed
• [Journal Article] Genome-wide association study identified ITPA/DDRGK1 variants reflecting thrombocytopenia in pegylated interferon and ribavirin therapy for chronic hepatitis C (2011)
  • Author(s): Tanaka Y
  • Journal Title: Hum Mol Genet Volume: 20(17) Pages: 3507-3516
  • Peer Reviewed
• [Journal Article] Pretreatment Prediction of Response to Pegylated-Interferon Plus Ribavirin for Chronic Hepatitis C using Genetic Polymorphism in IL28B and Viral Factors (2011)
  • Author(s): Kurosaki M, Tanaka Y, Sugauchi F.
  • Journal Title: J Hepatol. Volume: 54(3) Pages: 439-448
  • Peer Reviewed
• [Journal Article] Hepatitis C pharmacogenetics : state of the art in 2010. (2011)
  • Author(s): Afdhal NH, Tanaka Y.
  • Journal Title: Hepatology. Volume: 53(1) Pages: 336-345
  • Peer Reviewed
• [Journal Article] Association of IL28B variants with response to pegylated-interferon alpha plus ribavirin combination therapy reveals intersubgenotypic differences between genotypes 2a and 2b. (2011)
  • Author(s): Sakamoto N, Tanaka Y.
  • Journal Title: J Medical Virol. Volume: 83(5) Pages: 871-878
  • Peer Reviewed
• [Journal Article] Novel Findings for the Development of Drug Therapy for Various Liver Diseases : Genetic Variation in IL-28B Is Associated With Response to the Therapy for Chronic Hepatitis C. (2011)
  • Author(s): Sugiyama M, Tanaka Y.
  • Journal Title: J Pharmacol Sci. Volume: 115(3) Pages: 263-269
  • NAID: 10029892326
  • Peer Reviewed
• [Journal Article] lambda-Interferons and the single nucleotide polymorphisms:A milestone to tailor-made therapy for chronic hepatitis C. (2010)
  • Author(s): Tanaka Y.Nishida N,Sugiyama M.
  • Journal Title: Hepatol Res. Volume: 40(5) Issue: 5 Pages: 449-460
  • DOI: 10.1111/j.1872-034x.2010.00671.x
  • Peer Reviewed
• [Journal Article] Positive selection of core 70Q variant genotype 1b hepatitis Cvirus strains induced by pegylated interferon and ribavirin. (2010)
  • Author(s): Kurbanov F,Tanaka Y,Sugauchi F.
  • Journal Title: J Infect Dis. Volume: 201(11) Issue: 11 Pages: 1663-1671
  • DOI: 10.1086/652500
  • Peer Reviewed
• [Journal Article] ITPA gene variant protects against anemia induced by pegylated interferon-αand ribavirin therapy for Japanese patients with chronic hepatitis C (2010)
  • Author(s): Honda M, (他14名, 12番目)
  • Journal Title: Hepatol Res Volume: 40(11) Issue: 11 Pages: 1063-1071
  • DOI: 10.1111/j.1872-034x.2010.00741.x
  • Peer Reviewed
• [Journal Article] lambda-Interferons and the single nucleotide polymorphisms : A milestone to tailor-made therapy for chronic hepatitis C. (2010)
  • Author(s): Tanaka Y.
  • Journal Title: Hepatol Res. Volume: 40(5) Pages: 449-460
  • Peer Reviewed
• [Journal Article] Hepatic ISG expression is associated with genetic variation in IL28B and the outcome of IFN therapy for chronic hepatitis C. (2010)
  • Author(s): Honda M, Tanaka Y.
  • Journal Title: Gastroenterology. Volume: 139(2) Pages: 499-509
  • Peer Reviewed
• [Journal Article] Positive selection of core 70Q variant genotype 1b hepatitis C virus strains induced by pegylated interferon and ribavirin. (2010)
  • Author(s): Kurbanov F, Tanaka Y, Sugauchi F.
  • Journal Title: J Infect Dis. Volume: 201(11) Pages: 1663-1671
  • Peer Reviewed
• [Journal Article] High sensitivity assay using serum sample for IL28B genotyping to predict treatment response in chronic hepatitis C patients. (2010)
  • Author(s): Akkarathamrongsin S, Tanaka Y.
  • Journal Title: Hepatol Res. Volume: 40(10) Pages: 956-962
  • NAID: 10027821107
  • Peer Reviewed
• [Journal Article] Hepatitis C virus kinetics by administration of pegylated interferon-α in human and chimeric mice carrying human hepatocytes with variants of the IL28B gene
  • Author(s): Watanabe T.
  • Journal Title: Gut. Volume: -
  • Peer Reviewed
• [Presentation] Role of IFN-λ on Antiviral Therapy for Hepatitis C (2012)
  • Author(s): Tanaka Y
  • Organizer: The 10th JSH Single Topic Conference
  • Place of Presentation: 京王プラザホテル
• [Presentation] IL28B genetic variants and serum IP-10 level associated with virological response to PEG-IFN/RBVand PEGIFN/RBV/Telaprevir therapy (2012)
  • Author(s): Matsuura K.
  • Organizer: The 63rd Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Hynes Convention Center(アメリカ).
• [Presentation] Host Factors Determining the Efficacy of Hepatitis C Treatment in Japan (2012)
  • Author(s): Tanaka Y.
  • Organizer: The 3rd International Forum of the 98th General Meeting of the Japanese Society of Gastroenterology
  • Place of Presentation: 京王プラザホテル
• [Presentation] Genetic variation in IL28B in response to interferon/ribavirin therapy (2012)
  • Author(s): Tanaka Y.
  • Organizer: The 22nd Conference of the Asian PacificAssociation for the Study of the Liver.
  • Place of Presentation: Taipei International Convention Center(台湾)
• [Presentation] Host genetic factors onthe treatment of chronic hepatitis C. (2012)
  • Author(s): Tanaka Y.
  • Organizer: The 22nd Conference of the AsianPacificAssociation for the Study of the Liver
  • Place of Presentation: Taipei International Convention Center (台湾)
• [Presentation] Host Factors Determining the Efficacy of Hepatitis C Treatment in Japan (2012)
  • Author(s): Tanaka Y.
  • Organizer: The 3rd International Forum of the 98th General Meeting of the Japanese Society of Gastroenterology
  • Place of Presentation: 京王プラザホテル（東京都）
  • Invited
• [Presentation] Pharmacogenomics for Hepatitis C (2012)
  • Author(s): Tanaka Y.
  • Organizer: 14th International Symposium on Viral Hepatitis and Liver Disease
  • Place of Presentation: Shanghai International Convention Center（中国 上海）
  • Invited
• [Presentation] IL28B genetic variants and serum IP-10 level associated with virological response to PEG-IFN/RBV and PEGIFN/RBV/Telaprevir therapy (2012)
  • Author(s): Matsuura K.
  • Organizer: The 63rd Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Hynes Convention Center(アメリカ ボストン）
  • Invited
• [Presentation] Role of IFN-λ on Antiviral Therapy for Hepatitis C (2012)
  • Author(s): Tanaka Y.
  • Organizer: The 10th JSH Single Topic Conference
  • Place of Presentation: 京王プラザホテル（東京都）
  • Invited
• [Presentation] Ｃ型慢性肝炎患者におけるインターフェロン投与直後の遺伝子発現変動 (2012)
  • Author(s): 飯島沙幸
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: グランキューブ大阪（大阪府）
• [Presentation] Host genetic factors on the treatment of chronic hepatitis C (2012)
  • Author(s): Yasuhito Tanaka
  • Organizer: The 22nd Conference of the Asian Pacific Association for the Study of the Liver (APASL 2012)
  • Place of Presentation: Taipei International Convention Center(台湾)(招待講演)
• [Presentation] Genetic variation in IL28B in response to interferon/ribavirin therapy (2012)
  • Author(s): Yasuhito Tanaka
  • Organizer: The 22nd Conference of the Asian Pacific Association for the Study of the Liver (APASL 2012)
  • Place of Presentation: Taipei International Convention Center(台湾)(招待講演)
• [Presentation] Influence of genetic variation in IL-28B promoter on the gene expression levels (2011)
  • Author(s): Masaya Sugiyama, Yasuhito Tanaka
  • Organizer: 第59回日本ウイルス学会学術集会、International Congress of Virology合同開催
  • Place of Presentation: 札幌コンベンションセンター(札幌)
  • Year and Date: 2011-09-13
• [Presentation] Genome-wide searches personalize hepatitis C treatment (2011)
  • Author(s): Yasuhito Tanaka
  • Organizer: 第8回日韓肝疾患シンポジウム
  • Place of Presentation: 神戸大学医学部(神戸)
  • Year and Date: 2011-07-17
• [Presentation] Host Genetic Factors and Treatment Response of Chronic Hepatitis C (2011)
  • Author(s): Tanaka Y.
  • Organizer: The 21st Conference of the Asian Pacific Association for The Study of the Liver
  • Place of Presentation: Queen Sirikit NationalConvention Center(タイ).
• [Presentation] Polymorphism of IL-28B promoter region could improve the prediction value of response to CHC treatment following RS8099917 genotyping (2011)
  • Author(s): Masaya Sugiyama, Yasuhito Tanaka
  • Organizer: The 62th Ananual Meeting of The American Association for the Study of Liver Diseases
  • Place of Presentation: Moscone West Convention Center(サンフランシスコ)
• [Presentation] Prediction model of ribavirin-induced anemia incorporating ITPA genotype could identify chronic hepatitis C patients at high risk of relapse amnog virological responders to pegylated-interferon and ribavirin (2011)
  • Author(s): Masayuki Kurosaki, Yasuhito Tanaka
  • Organizer: The 62th Ananual Meeting of The American Association for the Study of Liver Diseases
  • Place of Presentation: Moscone West Convention Center(サンフランシスコ)
• [Presentation] IL28B And ITPA gene variants correlate with treatment efficacy in pegylated-interferon plus ribavirin therapy for chronic hepatitis C (2011)
  • Author(s): Kentaro Matsuura, Yasuhito Tanaka
  • Organizer: The 62th Ananual Meeting of The American Association for the Study of Liver Diseases
  • Place of Presentation: Moscone West Convention Center(サンフランシスコ)
• [Presentation] ITPA gene variant protects against treatment-induced anemia and improves viral clearance by pegylated interferon-alfa and ribavirin therapy in chronic hepatitis C patients (2011)
  • Author(s): Naoya Sakamoto, Yasuhito Tanaka
  • Organizer: The 62th Ananual Meeting of The American Association for the Study of Liver Diseases
  • Place of Presentation: Moscone West Convention Center(サンフランシスコ)
• [Presentation] Interferon-β treatment is effective for chronic hepatitis C patients with anti-interferon-α neutralizing antibodies (2011)
  • Author(s): Chisa Kuga, Yasuhito Tanaka
  • Organizer: The 62th Ananual Meeting of The American Association for the Study of Liver Diseases
  • Place of Presentation: Moscone West Convention Center(サンフランシスコ)
• [Presentation] ペグインターフェロン・リバビリン療法に伴う血球減少関連遺伝子の検討 (2011)
  • Author(s): 田中靖人
  • Organizer: 第47回日本肝臓学会総会
  • Place of Presentation: グランパシフィックLE DAIBA(東京)
• [Presentation] C型慢性肝疾患に対するペグインターフェロン・リバビリン療法とITPA遺伝子の検討 (2011)
  • Author(s): 松浦健太郎、田中靖人
  • Organizer: 第47回日本肝臓学会総会
  • Place of Presentation: グランパシフィックLE DAIBA(東京)
• [Presentation] C型慢性肝炎患者におけるIL28B関連SNPsに関する検討～どのSNPをどの測定法で検査すべきか～ (2011)
  • Author(s): 伊藤清顕、田中靖人
  • Organizer: 第47回日本肝臓学会総会
  • Place of Presentation: グランパシフィックLE DAIBA(東京)
• [Presentation] 肝炎ウイルスによるエピジェネティック異常の誘発機構 (2011)
  • Author(s): 近藤豊、田中靖人
  • Organizer: 第15回日本肝臓学会大会
  • Place of Presentation: 福岡国際センター他(福岡)
• [Presentation] IL28B遺伝子周囲に存在するSNPsの機能解析と臨床的意義 (2011)
  • Author(s): 杉山真也、田中靖人
  • Organizer: 第15回日本肝臓学会大会
  • Place of Presentation: 福岡国際センター他(福岡)
• [Presentation] IL28B・ITPA遺伝子検査に基づいたペグインターフェロン・リバビリン治療効果予測 (2011)
  • Author(s): 松浦健太郎、田中靖人
  • Organizer: 第15回日本肝臓学会大会
  • Place of Presentation: 福岡国際センター他(福岡)
• [Presentation] IL28BおよびITPA SNPs解析によるペグインターフェロン・リハビリン併用療法の効果予測 (2011)
  • Author(s): 可児里美、田中靖人
  • Organizer: 第58回日本臨床検査医学会学術集会
  • Place of Presentation: 岡山コンベンションセンター(岡山)
• [Presentation] C型慢性肝炎治療に対するIL28B遺伝子多型解析の日常臨床検査への導入 (2011)
  • Author(s): 柏木有美、田中靖人
  • Organizer: 第58回日本臨床検査医学会学術集会
  • Place of Presentation: 岡山コンベンションセンター(岡山)
• [Presentation] Host Genetic Factors and Treatment Response of Chronic Hepatitis C (2011)
  • Author(s): Tanaka Y.
  • Organizer: The 21^<st> Conference Of the Asian Pacific Association for The Study of the Liver
  • Place of Presentation: Queen Sirikit National Convention Center (Bangkok, Thailand)
• [Presentation] Genetic Variation in IL28B is Associated with Response to Interferon Therapy for Chronic Hepatitis C (2010)
  • Author(s): Tanaka Y.
  • Organizer: The 7th APASL Single Topic Conference.
  • Place of Presentation: 幕張メッセ.
• [Presentation] ITPA Gene Variants Protect Against Anemia Induced By Pegylated Interferon-Alfa andRibavirin Therapy for Japanese Patients with Chronic Hepatitis C. (2010)
  • Author(s): Tanaka Y.
  • Organizer: 61th Annual Meeting of theAmerican Association for the Study of Liver Diseases
  • Place of Presentation: TheHynes Convention Center(アメリカ).
• [Presentation] Genome-Wide AssociationStudy Identifies IL28B Associated With Response to PegylatedInterferon-Alfa and RibavirinTherapy for Japanese Patients withChronic Hepatitis C. (2010)
  • Author(s): Tanaka Y.
  • Organizer: 45th Annual Meeting of The European Association for The Study of The Liver.
  • Place of Presentation: Reed Messe Wien Exhibition & Congress Center(オーストリア).
• [Presentation] IL28B遺伝子多型に基ついたC型肝炎に対するテーラーメイド治療の確立. (2010)
  • Author(s): 田中靖人
  • Organizer: 第46回日本肝臓学会総会
  • Place of Presentation: ホテルメトロポリタン山形.
• [Presentation] IL28B遺伝子多型に基ついたC型肝炎に対するテーラーメイド治療の確立 (2010)
  • Author(s): 田中靖人
  • Organizer: 第46回日本肝臓学会総会
  • Place of Presentation: ホテルメトロポリタン山形 (山形市)
• [Presentation] IL28B遺伝子多型はC型肝炎ウイルス自然排除に関与する (2010)
  • Author(s): 松浦健太郎、田中靖人、菅内文中
  • Organizer: 第46回日本肝臓学会総会
  • Place of Presentation: ホテルメトロポリタン山形 (山形市)
• [Presentation] HCV遺伝子変異およびIL28B遺伝子多型の統合的データマイニング解析:C型慢性肝炎に対するPeg-interferon・RBV治療効果予測モデルの構築 (2010)
  • Author(s): 黒崎雅之、田中靖人
  • Organizer: 第46回日本肝臓学会総会
  • Place of Presentation: ホテルメトロポリタン山形 (山形市)
• [Presentation] IL28B遺伝子型の違いによるインターフェロンの抗ウイルス効果～キメラマウスを用いて～ (2010)
  • Author(s): 田中靖人
  • Organizer: 日本肝臓学会東部会
  • Place of Presentation: 京王プラザホテル (東京都新宿区)
• [Presentation] GENOME-WIDE ASSOCIATION STUDY IDENTIFIES IL28B ASSOCIATED WITH RESPONSE TO PEGYLATED INTERFERON-ALFA AND RIBAVIRIN THERAPY FOR JAPANESE PATIENTS WITH CHRONIC HEPATITIS C (2010)
  • Author(s): Tanaka Y, Sugauchi F.
  • Organizer: 45^<th> Annual Meeting Of The European Association For The Study Of The Liver
  • Place of Presentation: Reed Messe Wien Exhibition & Congress Center (Vienna, Austria)
• [Presentation] ITPA GENE VARIANTS PROTECT AGAINST ANEMIA INDUCED BY PEGYLATED INTERFERON-ALFA AND RIBAVIRIN THERAPY FOR JAPANESE PATIENTS WITH CHRONIC HEPATITIS C (2010)
  • Author(s): Tanaka Y.
  • Organizer: 61th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: The Hynes Convention Center (Boston, USA)
• [Presentation] IDENTIFICATION OF GENETIC VARIANTS OF IL28B GENE ASSOCIATED WITH CLINICAL COURSE OF HEPATITIS C VIRUS INFECTION IN JAPANESE POPULATION (2010)
  • Author(s): Matsuura K, Tanaka Y, Sugauchi F.
  • Organizer: 61th Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: The Hynes Convention Center (Boston, USA)
• [Presentation] Genetic Variation in IL28B is Associated with Response to Interferon Therapy for Chronic Hepatitis C (2010)
  • Author(s): Tanaka Y.
  • Organizer: The 7^<th> APASL Single Topic Conference
  • Place of Presentation: Makuhari Messe (Chiba, Japan)