Association between host factor and hepatocellular carcinoma in non-viral patients with type 2 diabetes

• Project/Area Number: 16K09388
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: MASAAKI KORENAGA 国立研究開発法人国立国際医療研究センター, その他部局等, その他 (70420536)
• Co-Investigator(Kenkyū-buntansha): 西田 奈央 国立研究開発法人国立国際医療研究センター, その他部局等, 上級研究員 (50456109)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 2型糖尿病 / 肝細胞癌 / PNPLA3 / JAZF1 / SNPs / 医歯薬学 / 内科系臨床医学 / 消化器内科学 / 肝臓学 / ゲノム医科学

Outline of Final Research Achievements

Type 2 diabetes mellitus (T2DM) is an established independent risk factor for hepatocellular carcinoma (HCC). We recruited 389 patients with These patients were divided into two groups, T2DM patients with HCC (DM-HCC, n = 59) or those without HCC (DM-non-HCC, n = 330). The SNP rs738409 located in PNPLA3 was the greatest risk factor associated with HCC in non-viral hepatitis patients with T2DM. The frequency of the PNPLA3 G allele was significantly higher among DM-HCC individuals than DM-non-HCC individuals. Among individuals homozygous for the PNPLA3 G allele , the frequency of the JAZF1 rs864745 G allele was significantly higher among DM-HCC individuals than DM-non-HCC individuals. The influence of PNPLA3 and JAZF1 was independent of age, sex, and body mass index after multivariable logistic regression analysis. There were no HCC patients who had risk SNPs after 5 years observation.　To explorer HCC patients with DM、we used other markers such as M2BPGi, IL-34,Fibroscan, and MRI.

Academic Significance and Societal Importance of the Research Achievements

本研究により、2型糖尿病合併症例から肝発癌・予後の実態が明らかとなった。また十分とは言えなものの、わが国でも増加中の2型糖尿病患者さんに対してPNPLA3, JAZF1という遺伝子を用いることで肝発癌危険群が抽出可能となることで、我が国の肝炎治療後・脂肪肝・2型闘病尿医療の均てん化に貢献でき、更なる遺伝子検索と礎となった。更に今後欧米化が顕著となり、糖代謝異常が増加すると予測される東アジア地域医療にも利用可能であると考えられ、多くの地域に貢献できると推測する

Research Products

• [Journal Article] A Glycomarker for Short-term Prediction of Hepatocellular Carcinoma: A Longitudinal Study With Serial Measurements. (2018)
  • Author(s): 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.
  • Journal Title: Clin Transl Gastroenterol Volume: 20 Issue: 9 Pages: 183-183
  • DOI: 10.1038/s41424-018-0050-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ghly Sensitive Glycan Profiling of Hepatitis B Viral Particles and a Simple Method for Dane Particle Enrichment. (2018)
  • Author(s): Wagatsuma T, Kuno A, Angata K, Tajiri K, Takahashi J, Korenaga M, Mizokami M, Narimatsu H.
  • Journal Title: Anal Chem. Volume: 90 Issue: 17 Pages: 10196-10203
  • DOI: 10.1021/acs.analchem.8b01030
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 血液検査による肝臓の硬さの評価 M2BPGiと新規血清マーカー (2018)
  • Author(s): 是永匡紹 考藤達哉
  • Journal Title: 肝臓クリニカルアップデート Volume: 4 Pages: 147-152
• [Journal Article] 臨床検査 M2BPGiによるNASH診断 (2018)
  • Author(s): 是永匡紹 溝上雅史
  • Journal Title: 肝・胆・膵 Volume: 76 Pages: 621-625
• [Journal Article] Low incidence of hepatitis B virus reactivation and subsequent hepatitis in patients with chronic hepatitis C receiving direct-acting antiviral therapy (2017)
  • Author(s): Tamori A.、Abiru S.、Enomoto H.、Kioka K.、Korenaga M.、Tani J.、Enomoto M.、Sugiyama M.、Masaki T.、Kawada N.、Yatsuhashi H.、Nishiguchi S.、Mizokami M.
  • Journal Title: Journal of Viral Hepatitis Volume: - Issue: 5 Pages: 608-611
  • DOI: 10.1111/jvh.12840
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Quantitative assessment of liver fibrosis reveals a nonlinear association with fibrosis stage in nonalcoholic fatty liver disease. (2017)
  • Author(s): Masugi Y, Abe T, Tsujikawa H, Effendi K, Hashiguchi A, Abe M, Imai Y, Hino K, Hige S, Kawanaka M, Yamada G, Kage M, Korenaga M, Hiasa Y, Mizokami M, Sakamoto M
  • Journal Title: Hepatol Commun Volume: 27 Issue: 1 Pages: 58-68
  • DOI: 10.1002/hep4.1121
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serum Levels of M2BPGi as Short-Term Predictors of Hepatocellular Carcinoma in Untreated Chronic Hepatitis B Patients. (2017)
  • Author(s): Liu J, Hu HH, Lee MH, Korenaga M, Jen CL, Batrla-Utermann R, Lu SN, Wang LY, Mizokami M, Chen CJ, Yang HI.
  • Journal Title: Sci Rep Volume: 30 Issue: 1 Pages: 14352-14352
  • DOI: 10.1038/s41598-017-14747-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serum Wisteria Floribunda Agglutinin-Positive Sialylated Mucin 1 as a Marker of Progenitor/Biliary Features in Hepatocellular Carcinoma. (2017)
  • Author(s): Tamaki N, Kuno A, Matsuda A, Tsujikawa H, Yamazaki K, Yasui Y, Tsuchiya K, Nakanishi H, Itakura J, Korenaga M, Mizokami M, Kurosaki M, Sakamoto M, Narimatsu H, Izumi N.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 244-244
  • DOI: 10.1038/s41598-017-00357-8
  • Peer Reviewed / Open Access
• [Journal Article] 高度線維化NASHのスクリーニングにおけるFibroScanの有用性 (2017)
  • Author(s): 是永 圭子 澤部 祥子, 呉屋 薫, 伊藤 里美, 金沢 あずさ, 是永 匡紹, 溝上 雅史
  • Journal Title: Rad Fan Volume: 15 Pages: 64-68
  • Peer Reviewed
• [Journal Article] 【ウイルス肝炎のすべて】血液伝播するウイルス肝炎 B型肝炎 HBV遺伝子型と臨床的特徴(解 (2017)
  • Author(s): 是永 匡紹, 杉山真也
  • Journal Title: 医学のあゆみ Volume: 262 Pages: 1306-1310
• [Journal Article] 【進化するB型肝炎治療】 最新核酸アナログをどのように使い分けるか? TAFの最新情報も含めて (2017)
  • Author(s): 是永 匡紹,
  • Journal Title: 進化するB型肝炎治療】 最新核酸アナログをどのように使い分けるか? TAFの最新情報も含めて(解説/特集) Volume: 1 Pages: 405-410
• [Journal Article] The impact of PNPLA3 and JAZF1 on hepatocellular carcinoma in non-viral hepatitis patients with type 2 diabetes mellitus (2016)
  • Author(s): Ueyama, M., Nishida, N., Korenaga, M., Korenaga, K., Kumagai, E., et al.
  • Journal Title: Journal of Gastroenterology Volume: 51 Issue: 4 Pages: 370-379
  • DOI: 10.1007/s00535-015-1116-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Appropriate use of virtual touch quantification and FibroScan® M and XL probes according to the skin capsular distance. (2016)
  • Author(s): Kumagai E, Korenaga K, Korenaga M(corresponding Author), Imamura M, Ueyama M, Aoki Y, Sugiyama M, Murata K, Masaki N, Kanto T, Mizokami M, Watanabe S
  • Journal Title: J Gastroenterol. Volume: ５１ Issue: 5 Pages: 496-505
  • DOI: 10.1007/s00535-015-1127-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Interleukin-34 as a fibroblast-derived marker of liver fibrosis in patients with non-alcoholic fatty liver disease. (2016)
  • Author(s): Shoji H, Yoshio S, Mano Y, Kumagai E, Sugiyama M, Korenaga M, Arai T, Itokawa N, Atsukawa M, Aikata H, Hyogo H, Chayama K, Ohashi T, Ito K, Yoneda M, Nozaki Y, Kawaguchi T, Torimura T, Abe M, Hiasa Y, Kamiyama T, Fukai M, Taketomi A, Mizokami M, Kanto T*
  • Journal Title: Scientific Reports Volume: 6:28814 Issue: 1 Pages: 1-10
  • DOI: 10.1038/srep28814
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Understanding of HLA-conferred susceptibility to chronic hepatitis B infection requires HLA genotyping-based association analysis. (2016)
  • Author(s): Nishida N, Ohashi J, Korenaga M, Mizokami M.et al
  • Journal Title: Sci Rep. Volume: 19 Pages: 24767-24767
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] IFN治療との比較とDAA治療前EOBMRIの有効性 (2018)
  • Author(s): 是永匡紹 考藤達哉 溝上雅史
  • Organizer: 日本肝臓学会東部会
• [Presentation] The risk of Hepatocellular Carcinoma development after Sustained Virologic Response are similar between Japanese patients with HCV Genotype 1 Infection treated Ledipasvir/Sofosbuvir and Protease inhibitor with Peg-Interferon Plus Ribavirin (2018)
  • Author(s): KorenagaM, Izumi N, Yokosuka O et al
  • Organizer: AASLD2018（アメリカ肝臓病学会）
  • Int'l Joint Research
• [Presentation] C型肝炎におけるDAA治療の成果と今後の課題 DAA治療後早期発癌予測を目指したEOBMRIとCXCL21の有用性 (2017)
  • Author(s): 是永匡紹 是永圭子 溝上雅史
  • Organizer: 日本肝臓学会西部支部会
• [Presentation] C型肝炎SVR後の問題点 レジパスビル/ソホスブビル治療後発癌は予測可能か? (2017)
  • Author(s): 是永匡紹 是永圭子 溝上雅史
  • Organizer: 日本肝臓学会総会
• [Presentation] 型肝炎治療の今後の課題 レジパスビル/ソホスブビル配合剤による肝発癌抑制効果(中間報告) (2017)
  • Author(s): 是永匡紹 考藤達哉 溝上雅史
  • Organizer: 日本肝臓学会総会
• [Presentation] SofosbuvirレジメンにおけるHBV再活性化の実態 (2017)
  • Author(s): 是永匡紹 考藤達哉 溝上雅史
  • Organizer: 日本消化器病学会総会
• [Presentation] C型肝炎の治療到達点と新たな課題 M2BPGiを用いたDAA治療予後予測と導入選択 (2017)
  • Author(s): 是永匡紹 是永圭子 溝上雅史
  • Organizer: 日本消化器病学会総会
• [Presentation] ustained virologic response by Ledipasvir/Sofosbuvir reduces the incidence of hepatocellular carcinoma in Japanese patients with HCV genotype 1 infection. - Comparison with Simeprevir with peginterferon plus ribavirin (2017)
  • Author(s): Masaaki Korenaga et al
  • Organizer: the International Liver Congress 2017
  • Int'l Joint Research
• [Presentation] Hepatocellular carcinoma development in Japanese patients with HCV genotype 1 infection who achieved sustained virologic response by ledipasvir/sofosbuvir (2017)
  • Author(s): Masaaki Korenaga et al
  • Organizer: The 68th Annual Meeting of the AASLD.
  • Int'l Joint Research
• [Presentation] Deferasirox prevents progression of non-alcoholic steatohepatitis in a mouse model with inhibition of hepatic fibrosis and hepatocellular ballooning. (2016)
  • Author(s): Korenaga M, Korenaga K, Sugiyama M, Mizokami M, Kanto T.
  • Organizer: The 67th Annual Meeting of the AASLD.
  • Place of Presentation: Boston, U.S.A.
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] WFA+-M2BP as a predictor of hepatocellular carcinoma in individuals who were seronegative for both HBV surface antigen and anti-HCV antibody. (2016)
  • Author(s): Hui-Han Hu, Chia-Lin Chang, Jessica Liu, Chin-Lan Jen, Wen-Sheng Luo, Yu-Ling Lin, Chien-Yu Su, Cheng-Ze Jiang, Mei-Hsuan Lee, Sheng-Nan Lu, Li-Yu Wang, Korenaga M, Mizokami M, Chien-Jen Chen, Hwai-I Yang.
  • Organizer: The 67th Annual Meeting of the AASLD.
  • Place of Presentation: Boston, U.S.A.
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Serum Levels of Wisteria Floribunda Agglutinin-Positive Mac-2 Binding Protein as a Time-Dependent Predictor of Hepatocellular Carcinoma in Chronic Hepatitis C Patients (2016)
  • Author(s): Chia-Lin Chang, Mei-Hsuan Lee, Hui-Han Hu, Jessica Liu, Chin-Lan Jen, Chien-Yu Su, Sheng-Nan Lu, Li-Yu Wang, Korenaga M, Mizokami M, Chien-Jen Chen, Hwai-I Yang.
  • Organizer: The 67th Annual Meeting of the AASLD.
  • Place of Presentation: Boston, U.S.A.
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Viral Hepatitis SVR後発癌を考慮したC型慢性肝疾患のDAAs治療前肝生検の重要性 (2016)
  • Author(s): 是永匡紹, 是永圭子 溝上雅史.
  • Organizer: 第52回日本肝臓学会総会.
  • Place of Presentation: 千葉
  • Year and Date: 2016-05-19
• [Presentation] 肝線維化診断におけるFibroScanの存在意義 ELF・M2BPGiとの比較 (2016)
  • Author(s): 是永圭子 是永匡紹, 溝上雅史.
  • Organizer: 第52回日本肝臓学会総会.
  • Place of Presentation: 千葉
  • Year and Date: 2016-05-19
• [Presentation] UTILITY OF MAC-2 BINDING PROTEIN GLYCOSYLATION ISOMER (M2BPGI) FOR ADVANCED FIBROSIS AND HEPATOCELLULAR CARCINOMA IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE. (2016)
  • Author(s): Korenaga M, Korenaga K, Imamura M, Aoki Y, Sugiyama M, Kanto T, Mizokami M.
  • Organizer: The International Liver Congress; 2016,
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2016-04-13
  • Int'l Joint Research
• [Presentation] FibroScanを用いた2型糖尿病におけるNAFLDのスクリーニング (2016)
  • Author(s): 是永圭子 是永匡紹, 今村雅俊、青木孝彦、村田一素、正木尚彦、考藤達哉、溝上雅史.
  • Organizer: 第３回 肝臓と糖尿病・代謝研究会
  • Place of Presentation: 金沢