Identification of novel genetic factors and genetic risk assessment models for non-viral HCC

• Project/Area Number: 17K09446
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Hiroshima University (2018-2019); Institute of Physical and Chemical Research (2017)
• Principal Investigator: Daiki Miki 広島大学, 医系科学研究科(医), 講師 (10584592)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: SNP / 肝癌 / NASH / NAFLD / SVR / HCV / 非ウイルス性肝癌 / 肝臓学

Outline of Final Research Achievements

Recently, it was reported that a single nucleotide polymorphism (SNP) rs17047200 located within the intron of TLL1 gene was associated with development of hepatocellular carcinoma (HCC) after eradication of hepatitis C virus (HCV). As a result of our study, we observed protective tendencies of rs17047200 T allele for the risk of HCC development in SVR patients as well as chronic HCV patients and chronic HBV patients. We also observed a similar tendency for the risk of fibrosis severity in SVR patients.
The SNP in PLPNA3 is the most famous genetic factor which confers susceptibility to nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Our findings revealed that SNPs of PNPLA3 and neighbor genes were associated not only to NAFLD/NASH susceptibility, but also to HCC development with stronger effects than those for NAFLD/NASH susceptibility. In addition, a novel candidate SNP which causes T94A substitution in FABP1 might affect NASH/NAFLD-related HCC.

Academic Significance and Societal Importance of the Research Achievements

現在、肝炎ウイルス非存在下における肝癌が増加傾向であるが、そのリスク因子は十分に解明されていない。より効率的なスクリーニングを行うためにも、リスク因子のさらなる解明が急務である。遺伝的要因について解析を行った本研究の結果、これまでの報告とは異なる結果や、これまでに報告の無かった結果が得られた。これらの結果については、さらなる検証が必要ではあるものの、今後、肝発癌リスクの予測に役立つことが期待できる。

Research Products

• [Journal Article] Risk factors for histological progression of non-alcoholic steatohepatitis analyzed from repeated biopsy cases. (2020)
  • Author(s): Daijo K, Nakahara T, Inagaki Y, Nanba M, Nishida Y, Uchikawa S, Kodama K, Oya K, Morio K, Fujino H, Ono A, Murakami E, Yamauchi M, Kawaoka T, Miki D, Tsuge M, Hiramatsu A, Hayes CN, Imamura M, Aikata H, Ochi H, Chayama K.
  • Journal Title: J Gastroenterol Hepatol. Volume: - Issue: 8 Pages: 1412-1419
  • DOI: 10.1111/jgh.14968
  • Peer Reviewed / Open Access
• [Journal Article] Comparative study on the replication of HCV1b genome between wild-type and cell culture-adaptive mutant in regard to sensitivities against anti-HCV drugs. (2019)
  • Author(s): Miyayama Y, Lee H, Song H, Abe-Chayama H, Miki D, Imamura M, Chayama K, Hijikata M.
  • Journal Title: Microbiol Immunol. Volume: - Issue: 4 Pages: 296-303
  • DOI: 10.1111/1348-0421.12768
  • Peer Reviewed / Open Access
• [Journal Article] Pruritus in patients with chronic liver disease and serum autotaxin levels in patients with primary biliary cholangitis. (2019)
  • Author(s): Fujino H, Tanaka M, Imamura M, Morio K, Ono A, Nakahara T, Murakami E, Kawaoka T, Takahashi S, Miki D, Tsuge M, Hiramatsu A, Aikata H, Hayes CN, Chayama K.
  • Journal Title: BMC Gastroenterol. Volume: 19 Issue: 1 Pages: 169-169
  • DOI: 10.1186/s12876-019-1092-z
  • Peer Reviewed / Open Access
• [Journal Article] Ribavirin induces hepatitis C virus genome mutations in chronic hepatitis patients who failed to respond to prior daclatasvir plus asunaprevir therapy. (2019)
  • Author(s): Saito Y, Imamura M, Uchida T, Osawa M, Teraoka Y, Fujino H, Nakahara T, Ono A, Murakami E, Kawaoka T, Miki D, Tsuge M, Serikawa M, Aikata H, Abe-Chayama H, Hayes CN, Chayama K.
  • Journal Title: J Med Virol. Volume: 92 Issue: 2 Pages: 210-218
  • DOI: 10.1002/jmv.25602
  • Peer Reviewed
• [Journal Article] Efficacy of glecaprevir and pibrentasvir treatment for genotype 1b hepatitis C virus drug resistance-associated variants in humanized mice. (2019)
  • Author(s): Osawa M, Uchida T, Imamura M, Teraoka Y, Fujino H, Nakahara T, Ono A, Murakami E, Kawaoka T, Miki D, Tsuge M, Hiramatsu A, Abe-Chayama H, Hayes CN, Makokha GN, Aikata H, Ishida Y, Tateno C, Miyayama Y, Hijikata M, Chayama K.
  • Journal Title: J Gen Virol. Volume: 100 Issue: 7 Pages: 1123-1131
  • DOI: 10.1099/jgv.0.001268
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of intracellular responses between HBV genotype A and C infection in human hepatocyte chimeric mice (2019)
  • Author(s): Tsushima K, Tsuge M, Hiraga N, Uchida T, Murakami E, Makokha GN, Kurihara M, Nomura Motonobu, Hiyama Y, Fujino H, Ono A, Nakahara T, Yamauchi M, Abe-Chayama H, Kawaoka T, Miki D, Imamura M, Aikata H, Hayes CN, Chayama K
  • Journal Title: Journal of Gastroenterology Volume: 印刷中 Issue: 7 Pages: 650-659
  • DOI: 10.1007/s00535-019-01558-w
  • Peer Reviewed / Open Access
• [Journal Article] Real-world efficacy of glecaprevir plus pibrentasvir for chronic hepatitis C patient with previous direct-acting antiviral therapy failures. (2019)
  • Author(s): Osawa M, Imamura M, Teraoka Y, Uchida T, Morio K, Fujino H, Nakahara T, Ono A, Murakami E, Kawaoka T, Miki D, Tsuge M, Hiramatsu A, Aikata H, Hayes CN, Chayama K; Hiroshima Liver Study Group.
  • Journal Title: J Gastroenterol. Volume: 54 Issue: 3 Pages: 291-296
  • DOI: 10.1007/s00535-018-1520-9
  • Peer Reviewed
• [Journal Article] The impact of interferon-free direct-acting antivirals on clinical outcome after curative treatment for hepatitis C virus-associated hepatocellular carcinoma: Comparison with interferon-based therapy. (2019)
  • Author(s): Nagaoki Y, Imamura M, Nishida Y, Daijo K, Teraoka Y, Honda F, Nakamura Y, Morio K, Fujino H, Nakahara T, Kawaoka T, Tsuge M, Hiramatsu A, Kawakami Y, Miki D, Hiyama Y, Ochi H, Chayama K, Aikata H.
  • Journal Title: J Med Virol. Volume: 91 Issue: 4 Pages: 650-658
  • DOI: 10.1002/jmv.25352
  • Peer Reviewed / Open Access
• [Journal Article] Levocarnitine Use Is Associated With Improvement in Sarcopenia in Patients With Liver Cirrhosis. (2019)
  • Author(s): Hiramatsu A, Aikata H, Uchikawa S, Ohya K, Kodama K, Nishida Y, Daijo K, Osawa M, Teraoka Y, Honda F, Inagaki Y, Morio K, Morio R, Fujino H, Nakahara T, Murakami E, Yamauchi M, Kawaoka T, Miki D, Tsuge M, Imamura M, Tanaka J, Chayama K.
  • Journal Title: Hepatol Commun. Volume: 22 Issue: 3 Pages: 348-355
  • DOI: 10.1002/hep4.1309
  • Peer Reviewed
• [Journal Article] Prevalence of NS5A resistance associated variants in NS5A inhibitor treatment failures and an effective treatment for NS5A-P32 deleted hepatitis C virus in humanized mice. (2018)
  • Author(s): Teraoka Y, Uchida T, Imamura M, Osawa M, Tsuge M, Abe-Chayama H, Hayes CN, Makokha GN, Aikata H, Miki D, Ochi H, Ishida Y, Tateno C, Chayama K; Hiroshima Liver Study Group.
  • Journal Title: Biochem Biophys Res Commun. Volume: 500 Issue: 2 Pages: 152-157
  • DOI: 10.1016/j.bbrc.2018.04.005
  • Peer Reviewed
• [Journal Article] Limitations of daclatasvir/asunaprevir plus beclabuvir treatment in cases of NS5A inhibitor treatment failure. (2018)
  • Author(s): Teraoka Y, Uchida T, Imamura M, Hiraga N, Osawa M, Kan H, Saito Y, Tsuge M, Abe-Chayama H, Hayes CN, Makokha GN, Aikata H, Miki D, Ochi H, Ishida Y, Tateno C, Chayama K.
  • Journal Title: J Gen Virol. Volume: 99 Issue: 8 Pages: 1058-1065
  • DOI: 10.1099/jgv.0.001091
  • Peer Reviewed
• [Journal Article] Advanced liver fibrosis effects on the response to sofosbuvir-based antiviral therapies for chronic hepatitis C. (2018)
  • Author(s): Morio K, Imamura M, Kawakami Y, Nakamura Y, Hatooka M, Morio R, Fujino H, Nakahara T, Murakami E, Kawaoka T, Tsuge M, Hiramatsu A, Aikata H, Hayes CN, Miki D, Ochi H, Katamura Y, Arataki K, Moriya T, Ito H, Tsuji K, Kohno H, Waki K, Tamura T, Nakamura T, Chayama K; Hiroshima Liver Study Group.
  • Journal Title: J Med Virol. Volume: 90 Issue: 12 Pages: 1834-1840
  • DOI: 10.1002/jmv.25267
  • Peer Reviewed
• [Journal Article] Involvement of Porphyromonas gingivalis in the progression of non-alcoholic fatty liver disease. (2018)
  • Author(s): Nakahara T, Hyogo H, Ono A, Nagaoki Y, Kawaoka T, Miki D, Tsuge M, Hiraga N, Hayes CN, Hiramatsu A, Imamura M, Kawakami Y, Aikata H, Ochi H, Abe-Chayama H, Furusho H, Shintani T, Kurihara H, Miyauchi M, Takata T, Arihiro K, Chayama K.
  • Journal Title: J Gastroenterol. Volume: 53 Issue: 2 Pages: 269-280
  • DOI: 10.1007/s00535-017-1368-4
  • Peer Reviewed
• [Journal Article] Serum HMGB1 concentrations at 4 weeks is a useful predictor of extreme poor prognosis for advanced hepatocellular carcinoma treated with sorafenib and hepatic arterial infusion chemotherapy. (2018)
  • Author(s): Masuda K, Ono A, Aikata H, Kawaoka T, Nelson Hayes C, Teraoka Y, Daijo K, Nakamura-Inagaki Y, Morio K, Fujino H, Kan H, Uchida T, Masaki K, Kobayashi T, Nakahara T, Makokha GN, Zhang Y, Nagaoki Y, Miki D, Tsuge M, Hiramatsu A, Imamura M, Abe-Chayama H, Kawakami Y, Ochi H, Chayama K.
  • Journal Title: J Gastroenterol. Volume: 53 Issue: 1 Pages: 107-118
  • DOI: 10.1007/s00535-017-1348-8
  • Peer Reviewed
• [Journal Article] The risks of hepatocellular carcinoma development after HCV eradication are similar between patients treated with peg-interferon plus ribavirin and direct-acting antiviral therapy. (2017)
  • Author(s): Nagaoki Y, Imamura M, Aikata H, Daijo K, Teraoka Y, Honda F, Nakamura Y, Hatooka M, Morio R, Morio K, Kan H, Fujino H, Kobayashi T, Masaki K, Ono A, Nakahara T, Kawaoka T, Tsuge M, Hiramatsu A, Kawakami Y, Hayes CN, Miki D, Ochi H, Chayama K.
  • Journal Title: PLoS One. Volume: 12 Issue: 8 Pages: e0182710-e0182710
  • DOI: 10.1371/journal.pone.0182710
  • Peer Reviewed / Open Access
• [Presentation] ASSOCIATION OF FNDC5, PNPLA3 AND TM6SF2 POLYMORPHISMS WITH HEPATIC STEATOSIS IN NAFLD PATIENTS (2019)
  • Author(s): Daiki Miki, Takashi Nakahara, Eisuke Murakami, Hiromi Abe-Chayama, Hatsue Fujino, Atsushi Ono, Masami Yamauchi, Tomokazu Kawaoka, Masataka Tsuge, Akira Hiramatsu, Michio Imamura, Hiroshi Aikata, Nelson Hayes, Grace Naswa Makokha, Tatsuhiko Tsunoda, Kazuaki Chayama
  • Organizer: The Liver Meeting 2019
  • Int'l Joint Research
• [Presentation] DIFFERENTIAL EFFECTS OF HOST GENETIC FACTORS ON HCV PERSISTENCE ACCORDING TO HCV GENOTYPES (2019)
  • Author(s): Daiki Miki, Tomokazu Kawaoka, Nelson Hayes, Hiromi Abe-Chayama, Hatsue Fujino, Grace Naswa Makokha, Atsushi Ono, Takashi Nakahara, Eisuke Murakami, Masami Yamauchi, Masataka Tsuge, Akira Hiramatsu, Michio Imamura, Hiroshi Aikata, Tatsuhiko Tsunoda, Kazuaki Chayama
  • Organizer: The Liver Meeting 2019
  • Int'l Joint Research
• [Presentation] Multiple genetic factors affecting nonalcoholic fatty liver disease and nonalcoholic steatohepatitis-related hepatocellular carcinoma in the Japanese population (2019)
  • Author(s): Daiki Miki, Yuichi Hiyama, Atsushi Ono, Masami Yamauchi, Masataka Tsuge, Hiroshi Aikata, Tatsuhiko Tsunoda, Kazuaki Chayama
  • Organizer: 11th AACR-JCA Joint Conference on Breakthroughs in Cancer Research: Biology to Precision Medicine
  • Int'l Joint Research
• [Presentation] 日本人における非アルコール性脂肪性肝疾患・非アルコール性脂肪肝炎関連肝細胞癌の発症に関連する宿主遺伝的要因 (2018)
  • Author(s): 三木大樹、柘植雅貴、山内理海、相方浩、茶山一彰
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Prevalence of NS5A Resistance Associated Variants in NS5A Inhibitor Treatment Failures and an Effective Treatment for NS5A-P32 Deleted Hepatitis C Virus in Humanized Mice (2018)
  • Author(s): Yuji Teraoka, Takuro Uchida, Michio Imamura, Mitutaka Osawa, Tomokazu Kawaoka, Masataka Tsuge, Hiromi Abe-Chayama, Nelson Hayes, Grace Naswa Makokha, Hiroshi Aikata, Daiki Miki, Hidenori Ochi, Yuji Ishida, Chise Tateno, Kazuaki Chayama
  • Organizer: The Liver Meeting 2018
  • Int'l Joint Research
• [Presentation] Association of TLL1 Polymorphism with Development of Hepatocellular Carcinoma after Hepatitis C Virus Eradication and Fibrosis Severity (2018)
  • Author(s): Daiki Miki, Tomokazu Kawaoka, Yuko Nagaoki, Nelson Hayes, Atsushi Ono, Takashi Nakahara, Eisuke Murakami, Masami Yamauchi, Masataka Tsuge, Akira Hiramatsu, Michio Imamura, Hiroshi Aikata, Hiromi Abe-Chayama, Hidenori Ochi, Tatsuhiko Tsunoda, Kazuaki Chayama
  • Organizer: The Liver Meeting 2018
  • Int'l Joint Research