Analysis of molecular mechanisms involved in progression to jaundice and liver failure in primary biliary cholangitis

• Project/Area Number: 15K19357
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Department of Clinical Research, National Hospital Organization Nagasaki Medical Center
• Principal Investigator: AIBA YOSHIHIRO 独立行政法人国立病院機構(長崎医療センター臨床研究センター), 臨床研究センター, 研究員 (70450955)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 原発性胆汁性胆管炎 / 原発性胆汁性肝硬変 / GWAS / CTSZ / カテプシン / 重症化機構 / 疾患関連遺伝子 / 肝不全

Outline of Final Research Achievements

We identified NELFCD/CTSZ as loci associated with progression to jaundice and liver failure (end-stage) in primary biliary cholangitis (PBC).Serum CTSZ levels were significantly higher in end-stage　than other stages (early-stage or late-stage) in PBC. The levels of CTSZ were significantly correlated with those of aspartate transaminase, total bilirubin, platelet count, and albumin in the blood of PBC. The levels of CTSZ protein in hepatocytes were increased with the progression of PBC. In end-stage PBC, the localization of CTSZ was translocated from peri-bile canalicular region to inner cytoplasmic region of hepatocytes, where a part of CTSZ was not co-localized with endsomal/lysosomal vesicles. Chloroquine and amino acid starvation enhanced cell death in CTSZ transfected HuH7. These results indicated that the increased expression and altered localization of CTSZ might be implicated in the progression of PBC via cell death.

Research Products

• [Journal Article] Genome-wide association studies identify PRKCB as a novel genetic susceptibility locus for primary biliary cholangitis in the Japanese population. (2017)
  • Author(s): Kawashima M, Honda M, Nakamura M. et al.
  • Journal Title: Hum Mol Genet. Volume: - Pages: 650-659
  • DOI: 10.1093/hmg/ddw406
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Disease susceptibility genes shared by primary biliary cirrhosis and Crohn’s disease in the Japanese population (2015)
  • Author(s): Yoshihiro Aiba, Keiko Yamazaki, Nao Nishida, Minae Kawashima, Yuki Hitomi, Hitomi Nakamura, Atsumasa Komori, Yuta Fuyuno, Atsushi Takahashi, Takaaki Kawaguchi, Masakazu Takazoe, Yasuo Suzuki, Satoshi Motoya Toshiyuki Matsui Motohiro Esaki, Takayuki Matsumoto, Michiaki Kubo, Katsushi Tokunaga, Minoru Nakamura
  • Journal Title: Journal of Human Genetics Volume: 印刷中 Issue: 9 Pages: 525-531
  • DOI: 10.1038/jhg.2015.59
  • NAID: 40020589506
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Human primary biliary cirrhosis-susceptible allele of rs4979462 enhances TNFSF15 expression by binding NF-1. (2015)
  • Author(s): Hitomi Y, Kawashima M, Aiba Y, Nishida N, Matsuhashi M, Okazaki H, Nakamura M, Tokunaga K
  • Journal Title: Human Genetics Volume: 印刷中 Issue: 7 Pages: 737-747
  • DOI: 10.1007/s00439-015-1556-3
  • Peer Reviewed
• [Presentation] Cathepsin Z variants are associated with progression to end-stage hepatic failure in Japanese patients with primary biliary cholangitis (2017)
  • Author(s): Nao Nishida, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Hitomi Nakamura, Noriyo Yamashiki, Tomohiro Tanaka, Sumito Tamura, Akira Mori, Shintaro Yagi, Yuji Soejima, Ken Shirabe, Atsushi Tanaka, Kenichi Harada, Shinji Shimoda Atsumasa Komori, Katsushi Tokunaga, Minoru Nakamura et al.
  • Organizer: ヨーロッパ肝臓学会総会
  • Place of Presentation: アムステルダム
  • Int'l Joint Research
• [Presentation] 日本人原発性胆汁性肝硬変における黄疸・肝不全型進行関連遺伝子の同定 (2016)
  • Author(s): 相葉佳洋、西田奈央、中村稔
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張
• [Presentation] 原発性胆汁性肝硬変におけるTL1Aの役割 (2015)
  • Author(s): 相葉佳洋、小森敦正、中村 稔
  • Organizer: 第41回日本肝臓学会西部会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2015-12-03
• [Presentation] 日本人原発性胆汁性肝硬変の新規疾患感受性遺伝子PRKCB, ETS1 の同定 (2015)
  • Author(s): 相葉佳洋、川嶋美苗、 西田奈央、 人見祐基、小森敦正、 茶山一彰、安波道郎、徳永勝士、 中村 稔
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 熊本ホテル日航
  • Year and Date: 2015-05-21
• [Presentation] Shared Disease-Susceptibility genes between primary biliary cirrhosis and Crohn's disease in the Japanese population (2015)
  • Author(s): Yoshihiro Aiba, Keiko Yamazaki,Nao Nishida, Minae Kawashima, Yuki Hitomi, Atsumasa Komori, Michiaki Kubo, Katsushi Tokunaga, Minoru Nakamura
  • Organizer: ヨーロッパ肝臓学会総会
  • Place of Presentation: ウィーン
  • Year and Date: 2015-04-22