1-2.B型肝炎・C型肝炎に関連する遺伝要因の探索
The identification of genetic factors associated with hepatitis B and hepatitis C

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.

<研究目的>

B型肝炎・C型肝炎は、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。一方、HCVは一旦感染すると70-80%が慢性肝炎に移行し、自然治癒する事は殆どなく、多くは肝硬変・肝癌へと進展します。そのため、C型慢性肝炎に対する抗ウイルス療法は重要であり、薬剤への応答性や副作用とSNPとの関連を調べる事は、治療上有効であると考えられます。

<研究のアプローチ>

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。

<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>

  • 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, and Mano S. The SNP x age interaction on response to interferon-α and ribavirin therapy in hepatitis C woman patients. J Med Virol doi: 10.1002/jmv.23939. (in press)
  • 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.

(文責:澤井 裕美)

研究内容・設備

1.疾患関連研究
(Genetics and complex human diseases)

2.ヒトゲノムDNA解析システム
(Human Genome DNA analysis system)

3.データベース・解析ツール
(Database and analysis tool)

4.日本人健常者の全ゲノム多型・配列解析データの提供方針
(Data sharing policy of whole-genome polymorphism/sequence data of Japanese healthy individuals)