Whole-exome sequencing identifies a novel genetic susceptibility locus in autoimmune liver diseases

• Project/Area Number: 26460996
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Shinshu University
• Principal Investigator: UMEMURA Takeji 信州大学, 学術研究院医学系, 准教授 (30419345)
• Co-Investigator(Renkei-kenkyūsha): OTA Masao 信州大学, 学術研究院医学系, 准教授 (50115333)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2015: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: AIH / PBC / HLA / PTPN22 / sCD14 / IL-8 / M2BP / 細胞死

Outline of Final Research Achievements

The key findings in this study were: (1) HLA, PTPN22, and PRKCB genes are significantly associated with susceptibility and resistance to autoimmune liver diseases (autoimmune hepatitis and primary biliary cholangitis) in Japan; (2) Serum Mac-2-binding protein, cell death, soluble CD14, and IL-8 levels were simple, and reliable noninvasive surrogate marker of liver fibrosis and prognosis in patients with primary biliary cholangitis.

Research Products

• [Journal Article] Association between serum soluble CD14 and IL-8 levels and clinical outcome in primary biliary cholangitis (2017)
  • Author(s): Umemura, T. Sekiguchi, T. Joshita, S. Yamazaki, T. Fujimori, N. Shibata, S. Ichikawa, Y. Komatsu, M. Matsumoto, A. Shums, Z. Norman, G. L. Tanaka, E. Ota, M.
  • Journal Title: Liver International Volume: 印刷中 Issue: 6 Pages: 897-905
  • DOI: 10.1111/liv.13316
  • NAID: 120007100137
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Immunogenetics of IgG4-Related AIP (2017)
  • Author(s): Ota, M. Umemura, T. Kawa, S.
  • Journal Title: Curr Top Microbiol Immunol Volume: 401 Pages: 35-44
  • DOI: 10.1007/82_2016_37
  • ISBN: 9783319525419, 9783319525426
  • Peer Reviewed
• [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] Genetic Association of PTPN22 Polymorphisms with Autoimmune Hepatitis and Primary Biliary Cholangitis in Japan. (2016)
  • Author(s): Umemura T, Joshita S, Yamazaki T, Komatsu M, Katsuyama Y, Yoshizawa K, Tanaka E, Ota M
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 29770-29770
  • DOI: 10.1038/srep29770
  • NAID: 120007100139
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Histopathology of IgG4-Related Autoimmune Hepatitis and IgG4-Related Hepatopathy in IgG4-Related Disease (2016)
  • Author(s): Nakanuma, Y. Ishizu, Y. Zen, Y. Harada, K. Umemura, T.
  • Journal Title: Seminars in Liver Disease Volume: 36 Issue: 03 Pages: 229-241
  • DOI: 10.1055/s-0036-1584320
  • Peer Reviewed
• [Journal Article] Serum Wisteria floribunda Agglutinin-Positive Mac-2-Binding Protein Level Predicts Liver Fibrosis and Prognosis in Primary Biliary Cirrhosis (2015)
  • Author(s): Umemura T, Joshita S, Sekiguchi T, Usami Y, Shibata S, Kimura T, Komatsu M, Matsumoto A, Ota M, Tanaka E.
  • Journal Title: The American Journal of Gastroenterology Volume: 印刷中 Issue: 6 Pages: 857-64
  • DOI: 10.1038/ajg.2015.118
  • NAID: 120007100141
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Serum Cell Death Biomarkers for Prediction of Liver Fibrosis and Poor Prognosis in Primary Biliary Cirrhosis (2015)
  • Author(s): Sekiguchi T, Umemura T, Fujimori N, Ichikawa Y, Shibata S, Kimura T, Joshita S, Komatsu M, Matsumoto A, Tanaka E, Ota M
  • Journal Title: PLOS ONE Volume: 10 Issue: 6 Pages: 1-12
  • DOI: 10.1371/journal.pone.0131658
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genetic factors affect the etiology, clinical characteristics and outcome of autoimmune hepatitis (2015)
  • Author(s): Umemura T, Ota M
  • Journal Title: Clinical Journal of Gastroenterology Volume: 8 Issue: 6 Pages: 360-366
  • DOI: 10.1007/s12328-015-0620-9
  • NAID: 120007100140
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Human leukocyte antigen class II haplotypes affect clinical characteristics and progression of type 1 autoimmune hepatitis in Japan. (2014)
  • Author(s): Umemura T, Katsuyama Y, Yoshizawa K, Kimura T, Joshita S, Komatsu M, Matsumoto A, Tanaka E, Ota M.
  • Journal Title: PLoS One Volume: 9 Issue: 6 Pages: e100565-e100565
  • DOI: 10.1371/journal.pone.0100565
  • Peer Reviewed / Open Access
• [Journal Article] STAT4 gene polymorphisms are associated with susceptibility and ANA status in primary biliary cirrhosis. (2014)
  • Author(s): Joshita S, Umemura T, Nakamura M, Katsuyama Y, Shibata S, Kimura T, Morita S, Komatsu M, Matsumoto A, Yoshizawa K, Ishibashi H, Tanaka E, Ota M.
  • Journal Title: Disease Markers Volume: Epub Pages: 727393-727393
  • DOI: 10.1155/2014/727393
  • NAID: 120007107427
  • Peer Reviewed / Open Access
• [Journal Article] AST/platelet ratio index associates with progression to hepatic failure and correlates with histological fibrosis stage in Japanese patients with primary biliary cirrhosis (2014)
  • Author(s): Joshita S, Umemura T, Ota M, Tanaka E.
  • Journal Title: Journal of Hepatology Volume: 61 Issue: 6 Pages: 1443-5
  • DOI: 10.1016/j.jhep.2014.07.036
  • Peer Reviewed
• [Presentation] 原発性胆汁性胆管炎の線維化進行と病態進展におけるIL-33/ST2 pathwayの役割 (2016)
  • Author(s): 城下智、梅村武司、田中榮司
  • Organizer: 第41回日本肝臓学会東部会
  • Place of Presentation: 東京 京王プラザホテル
  • Year and Date: 2016-12-08
• [Presentation] PTPN22遺伝子多型は自己免疫性肝疾患の疾患抵抗性と関連する (2016)
  • Author(s): 城下智、梅村武司、山崎智生、齊藤博美、平山敦大、赤羽由紀、山崎麻美、田中栄司、勝山善彦、太田正穂
  • Organizer: 第25回日本組織適合性学会大会
  • Place of Presentation: 札幌 北海道大学
  • Year and Date: 2016-10-22
• [Presentation] Association of PTPN22 Haplotypes With Autoimmune Liver Disease in the Japanese Population (2016)
  • Author(s): Yamazaki T, Joshita S, Umemura T, Tanaka E, Ota M
  • Organizer: DDW 2016
  • Place of Presentation: San Diego, USA San Diego Convention Center
  • Year and Date: 2016-05-22
  • Int'l Joint Research
• [Presentation] 自己免疫性肝疾患におけるPTPN22遺伝子多型の検討 (2016)
  • Author(s): 梅村武司、城下智、田中榮司
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: 千葉 ホテルニューオータニ幕張
  • Year and Date: 2016-05-19
• [Presentation] 自己免疫性肝疾患における PTPN22 遺伝子多型の検討 (2016)
  • Author(s): 梅村武司、城下智、田中榮司
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: 千葉 ホテルニューオータニ幕張
  • Year and Date: 2016-05-19
• [Presentation] 無症候性および症候性原発性胆汁性肝硬変の予後解析 (2016)
  • Author(s): 城下智、梅村武司、吉澤要、田中榮司
  • Organizer: 第113回日本内科学会講演会
  • Place of Presentation: 東京 東京国際フォーラム
  • Year and Date: 2016-04-15
• [Presentation] 原発性胆汁性肝硬変の進展に関連する因子の解析 (2015)
  • Author(s): 梅村武司、関口智裕、田中榮司
  • Organizer: 第19回日本肝臓学会大会
  • Place of Presentation: 東京 グランドプリンスホテル新高輪
  • Year and Date: 2015-10-08
• [Presentation] 原発性胆汁性肝硬変と血中sCD14，EndoCAbIgM，I-FABPの関係について (2015)
  • Author(s): 関口智裕、梅村武司、田中榮司
  • Organizer: 第19回日本肝臓学会大会
  • Place of Presentation: 東京 グランドプリンスホテル新高輪
  • Year and Date: 2015-10-08
• [Presentation] SS-SBT法を用いたHLA-DNAタイピング結果（64検体について） (2015)
  • Author(s): 梅村武司、鈴木進悟、尾崎有紀、赤羽由紀、山崎麻美、勝山善彦、益尾清恵、 猪子英俊、椎名隆、太田正穂
  • Organizer: 第24回日本組織適合性学会大会
  • Place of Presentation: 水戸、ホテルレイクビュー水戸
  • Year and Date: 2015-09-10
• [Presentation] 原発性胆汁性肝硬変における血中サイトカイン・ケモカインの網羅的検討 (2015)
  • Author(s): 梅村武司、城下智、関口智裕、田中榮司
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 熊本 ホテル日航熊本
  • Year and Date: 2015-05-21
• [Presentation] 原発性胆汁性肝硬変の病態と関連するバイオマーカーの検討～サイトケラチン18とその断片～ (2015)
  • Author(s): 関口智裕、梅村武司、田中榮司
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: 熊本 ホテル日航熊本
  • Year and Date: 2015-05-21
• [Presentation] 原発性胆汁性肝硬変患者におけるWFA+-M2BPの臨床的意義の検討 (2015)
  • Author(s): 梅村武司、城下智、田中榮司
  • Organizer: 第101回日本消化器病学会総会
  • Place of Presentation: 仙台 仙台国際センター
  • Year and Date: 2015-04-23
• [Presentation] 自己免疫性肝炎の病態と抗アクチンIgG抗体、抗Chromatin抗体との関連 (2014)
  • Author(s): 吉澤要、梅村武司、城下智、松本晶博、田中榮司
  • Organizer: 第50回日本肝臓学会総会
  • Place of Presentation: 東京 ホテルニューオータニ
  • Year and Date: 2014-05-29 – 2014-05-30
• [Book] IgG4-related Autoimmune Hepatitis Autoimmune Lier Diseases Perspectives from Japan (2014)
  • Author(s): Umemura T
  • Total Pages: 305
  • Publisher: Springer
• [Book] Epidemiology and Natural History in Japan Autoimmune Lier Diseases Perspectives from Japan (2014)
  • Author(s): Yoshizawa K, Matsumoto A, Umemura T.
  • Total Pages: 305
  • Publisher: Springer