Functional analysis of polymorphism of receptor-type tyrosin-protein phosphatase delta gene in the development of non-alcoholic fatty liver disease

• Project/Area Number: 16K19327
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Asahikawa Medical College
• Principal Investigator: Nakajima Shunsuke 旭川医科大学, 医学部, 助教 (80596289)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
• Keywords: PTPRD / SNP / NAFLD / rs35929428 / 遺伝子多型 / STAT3 / 肝脂肪化 / 肝線維化 / 内科

Outline of Final Research Achievements

We performed a high-throughput sequencing to identify a novel genetic variant in non-alcoholic fatty liver disease (NAFLD). PTPRD rs35929428 was a novel single-nucleotide polymorphism (SNP) in patients with NAFLD. PTPRD rs35929428 associated with the development of NAFLD. In addition, PTPRD rs35929428 was associated with higher Fib-4 index and with heaptic fat droplets.
Biochemical analysis in cultured hepatocytes and liver tissues indicated that PTPRD R995C, which was encoded PTPRD rs35929428, attenuated the pSTAT3 (Tyr 705) in the liver, thereby enhancing hepatic fibrosis and steatosis.

Academic Significance and Societal Importance of the Research Achievements

非アルコール性脂肪性肝疾患(NAFLD)に関連する疾患関連遺伝子多型(SNP)として従来からPNPLA3 rs738409が報告されていたが、海外ではその他複数のSNPが報告されており、研究開始段階では一定の見解が得られていなかった。今回日本人において新規に発見したSNPが、STAT3を介した肝脂肪化や肝線維化といったNAFLDの基本的病態と関連する可能性のあるSNPであったことは臨床的に意義のある成果であると考える。

Research Products

• [Journal Article] Polymorphism of receptor-type tyrosine-protein phosphatase delta gene in the development of non-alcoholic fatty liver disease (2018)
  • Author(s): Nakajima Shunsuke、Tanaka Hiroki、Sawada Koji、Hayashi Hidemi、Hasebe Takumu、Abe Masami、Hasebe Chitomi、Fujiya Mikihiro、Okumura Toshikatsu
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: 33 Issue: 1 Pages: 283-290
  • DOI: 10.1111/jgh.13820
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Genetic polymorphism of PTPRD (rs35929428) and risk of non-alcoholic fatty liver disease in Japanese (2017)
  • Author(s): Nakajima Shunsuke、Tanaka Hiroki、Sawada Koji、Hayashi Hidemi、Hasebe Takumu、Abe Masami、Hasebe Chitomi、Fujiya Mikihiro、Okumura Toshikatsu
  • Organizer: The International Liver Congress 2017
  • Int'l Joint Research
• [Presentation] NASH/NAFLD新規遺伝子多型PTPRD rs35929428の同定と機能解析の検討 (2016)
  • Author(s): 中嶋 駿介
  • Organizer: 第41回日本肝臓学会東部会
  • Place of Presentation: 東京
  • Year and Date: 2016-12-08
• [Presentation] ゲノム解析を用いた非アルコール性脂肪性肝疾患の疾患感受性遺伝子多型の探索 (2016)
  • Author(s): 中嶋 駿介
  • Organizer: 第20回日本肝臓学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2016-11-03