Clarification of the molecular mechanisms of pathogenesis caused by PBC susceptibility genes and their application to personalized medicine

• Project/Area Number: 17K15924
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Hoshi University (2019); The University of Tokyo (2017-2018)
• Principal Investigator: Hitomi Yuki 星薬科大学, 薬学部, 特任講師 (10525819)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 原発性胆汁性胆管炎（PBC） / ゲノムワイド関連解析（GWAS） / 疾患感受性遺伝子 / 日本人PBC感受性遺伝子領域 / ゲノムワイド関連解析 / 原発性胆汁性胆管炎 / 遺伝子多型 / 遺伝学 / 遺伝子 / ゲノム / 内科 / 免疫学

Outline of Final Research Achievements

Primary biliary cholangitis (PBC) is a chronic and cholestatic liver disease that is caused by the autoimmune destruction of bile ducts.
In this study, we identified novel susceptibility gene loci for PBC in the Japanese population by genome-wide association study (GWAS). Additionally, disease causal variants in these loci and their molecular mechanisms for disease susceptibility in PBC were clarified using Single Nucleotide Polymorphism (SNP) imputation analysis and in silico/ in vitro functional analysis.

Academic Significance and Societal Importance of the Research Achievements

本研究によって、胆管に症状が出る自己免疫疾患である原発性胆汁性胆管炎（PBC）の発症に寄与する遺伝要因の同定、および、そこから発症に至るまでのメカニズムが、それぞれ明らかにされた。
本研究を手掛かりに、マウスなどを用いた個体レベルでの研究に加え、遺伝情報を元にした創薬や、「発症予測キット・副作用予測キット」の開発を目指した臨床研究への発展、さらには、予防および治療の双方向からのアプローチによるPBCの制圧が期待される。

Research Products

• [Journal Article] Integrated GWAS and mRNA microarray analysis identified IFNG and CD40L as the most significant upstream regulators in primary biliary cholangitis. (2020)
  • Author(s): Ueno K, Aiba Y, Hitomi Y, et al.
  • Journal Title: Hepatology Communications Volume: 4(5) Issue: 5 Pages: 724-738
  • DOI: 10.1002/hep4.1497
  • Peer Reviewed / Open Access
• [Journal Article] POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33 (2019)
  • Author(s): Hitomi, Y. Ueno, K. Kawai, Y. Nishida, N. , Umemura, T. et al
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 102-102
  • DOI: 10.1038/s41598-018-36490-1
  • NAID: 120007179055
  • Peer Reviewed / Open Access
• [Journal Article] NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese population (2018)
  • Author(s): Nishida Nao、Aiba Yoshihiro、Hitomi Yuki、Nagasaki Masao、Tokunaga Katsushi、Nakamura Minoru et al.
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 8071-8071
  • DOI: 10.1038/s41598-018-26369-6
  • NAID: 120006551764
  • Peer Reviewed / Open Access
• [Journal Article] Increased expression and altered localization of cathepsin Z are associated with progression to jaundice stage in primary biliary cholangitis (2018)
  • Author(s): Aiba Yoshihiro、Harada Kenichi、Ito Masahiro、Suematsu Takashi、Aishima Shinichi、Hitomi Yuki、Nishida Nao、Kawashima Minae、Takatsuki Mitsuhisa、Eguchi Susumu、Shimoda Shinji、Nakamura Hitomi、Komori Atsumasa、Abiru Seigo、Nagaoka Shinya、Migita Kiyoshi、Yatsuhashi Hiroshi、Tokunaga Katsushi、Nakamura Minoru
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 11808-11808
  • DOI: 10.1038/s41598-018-30146-w
  • Peer Reviewed / Open Access
• [Journal Article] NFKB1 and MANBA Confer Disease Susceptibility to Primary Biliary Cholangitis via Independent Putative Primary Functional Variants. (2018)
  • Author(s): Hitomi Y, Nakatani K, Kojima K, Nishida N, Kawai Y, Kawashima M, Aiba Y, Nagasaki M, Nakamura M, Tokunaga K.
  • Journal Title: Cell Mol Gastroenterol Hepatol Volume: 7 Issue: 3 Pages: 515-532
  • DOI: 10.1016/j.jcmgh.2018.11.006
  • Peer Reviewed / Open Access
• [Journal Article] Principal contribution of HLA-DQ alleles, DQB1*06:04 and DQB1*03:01, to disease resistance against primary biliary cholangitis in a Japanese population (2017)
  • Author(s): Yasunami Michio、Nakamura Hitomi、Tokunaga Katsushi、Kawashima Minae、Nishida Nao、Hitomi Yuki、Nakamura Minoru
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 11093-11093
  • DOI: 10.1038/s41598-017-11148-6
  • Peer Reviewed / Open Access
• [Presentation] The role of PRKCB in the development of primary biliary cholangitis. (2019)
  • Author(s): Aiba Y, Ueno K, Hitomi Y, Kawashima M, Nishida N, Kawai Y, Komori A, Yatsuhashi H, Nagasaki M, Tokunaga K, Nakamura M and PBC-GWAS consortium in Japan.
  • Organizer: American Association for the study of liver diseases (AASLD)
  • Int'l Joint Research
• [Presentation] Integrated analysis of GWAS and mRNA expression array identified IFNG and CD40L as the most significant upstream-regulators in primary biliary cholangitis. (2019)
  • Author(s): Ueno K, Aiba Y, Hitomi Y, Shimoda S, Gervais O, Kawai Y, Kawashima M, Nishida N, Kojima K, Nagasaki M, Tokunaga K, Nakamura M.
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] POGLUT1, the effector gene driven by rs2293370 in primary biliary cholangitis (PBC) susceptibility locus chromosome 3q13.33 in the Japanese population. (2019)
  • Author(s): Hitomi Y, Ueno K, Kawai Y, Nishida N, Kojima K, Kawashima M, Aiba Y, Shimoda S, Tanaka A, Nagasaki M, Tokunaga K, nakamura M, PBC-GWAS consortium in Japan.
  • Organizer: APASL single topic conference
  • Int'l Joint Research
• [Presentation] Pathway-Analysis Using Datasets of GWAS and mRNA Expression Array Identified IFNG as the Most Significant Upstream-Regulator in Primary Biliary Cholangitis (2019)
  • Author(s): Ueno K, Aiba Y, Hitomi Y, Shimoda S, Tanaka A, Gervais O, Kawai Y, Kawashima M, Nishida N, Kojima K, Nagasaki M, Tokunaga K, nakamura M, PBC-GWAS consortium in Japan.
  • Organizer: APASL single topic conference
  • Int'l Joint Research
• [Presentation] 原発性胆汁性胆管炎（PBC）感受性遺伝子領域に起因する発症機序の解明におけるゲノム編集技術の応用 (2019)
  • Author(s): 人見祐基、河合洋介、植野和子、西田奈央、川嶋実苗、相葉佳洋、Olivier Gervais、Seik-Soon Khor、築地信、長﨑正朗、中村稔、徳永勝士
  • Organizer: 第64回日本人類遺伝学会
• [Presentation] 原発性胆汁性胆管炎（PBC）感受性遺伝子領域を対象とした機能的遺伝子多型（causal variant）の同定 (2019)
  • Author(s): 人見祐基、河合洋介、植野和子、西田奈央、川嶋実苗、相葉佳洋、築地信、長﨑正朗、中村稔、徳永勝士
  • Organizer: 第28回日本組織適合性学会
• [Presentation] 日本人原発性胆汁性胆管炎（PBC）感受性遺伝子領域3番染色体長腕13.33に位置するcausal variantおよびエフェクター遺伝子 POGLUT1 の同定 (2019)
  • Author(s): 人見祐基、中村稔
  • Organizer: 第55回日本肝臓学会
• [Presentation] Role of PRKCB in the development of primary biliarycholangitis (2019)
  • Author(s): 相葉佳洋、人見祐基、植野和子、中村稔
  • Organizer: 第48回日本免疫学会
• [Presentation] Short tandem repeat (STR) profile of pentanucleotide repeats and high-resolution STR typing solution for the Japanese population (2018)
  • Author(s): Saito M, Hirata S, Kojima K, Misawa K, Mimori T, Gervais O, Kawai Y, Hitomi Y, Tokunaga K, Nakamura M, Nagasaki M
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] Genotype imputation of structural polymorphism with whole genome sequencing based haplotypes reference panel. (2018)
  • Author(s): Kawai Y, Mimori T, Ueno K, Hitomi Y, Gervais O, Khor SS, Kawashima M, Nishida N, Nakamura M, Nagasaki M, Tokunaga K
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] Pathway-analysis using datasets of GWAS and mRNA expression array identified IFNG as the most significant upstream-regulator in primary biliary cholangitis in the Japanese population. (2018)
  • Author(s): Ueno K, Aiba Y, Gervais O, Kawai Y, Hitomi Y, Kojima K, Kawashima M, Nishida N, Shimoda S, Nagasaki M, Tokunaga K, Nakamura M
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] Genome-wide meta-analysis and functional analysis identified POGLUT1 as the effector gene driven by rs2293370 in primary biliary cholangitis (PBC) susceptibility locus chromosome 3q13.33 in the Japanese population. (2018)
  • Author(s): Hitomi Y, Ueno K, Kawai Y, Nishida N, Kojima K, Kawashima M, Aiba Y, Nagasaki M, Tokunaga K, Nakamura M
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] 日本人原発性胆汁性胆管炎の疾患感受性遺伝子POU2AF1、PRKCBの役割の検討 (2018)
  • Author(s): 相葉佳洋、原田憲一、伊東正博、人見祐基、植野和子、小森敦正、八橋弘、長崎正朗、徳永勝士、中村稔
  • Organizer: 日本肝臓学会
• [Presentation] 日本人原発性胆汁性胆管炎（PBC）感受性遺伝子領域NFKB1/MANBAにおける機能的遺伝子多型（causal variant）の同定 (2018)
  • Author(s): 人見祐基、中村稔
  • Organizer: 日本肝臓学会
• [Presentation] 集団ゲノム配列解析による構造多型の探索 (2018)
  • Author(s): 河合洋介、三森隆広、植野和子、人見祐基、Garvais O、Seik SS、川嶋実苗、西田奈央、中村稔、長﨑正朗、徳永勝士
  • Organizer: 日本人類遺伝学会
• [Presentation] Identification of POGLUT1 as the effector gene in primary biliary cholangitis susceptibility locus chromosome 3q13.33 (2018)
  • Author(s): 人見祐基、植野和子、河合洋介、西田奈央、小島要、川嶋実苗、相葉佳洋、長崎正朗、徳永勝士、中村稔
  • Organizer: 日本人類遺伝学会
• [Presentation] Identification of POGLUT1 as the effector gene in human primary biliary cholangitis (PBC) susceptibility locus chromosome 3q13.33 (2018)
  • Author(s): 人見祐基、相葉佳洋、中村稔
  • Organizer: 日本免疫学会
• [Presentation] 日本人の5塩基短鎖重複反復配列のプロファイルと高解像度の反復配列タイピングの検証 (2018)
  • Author(s): 齋藤真梨恵、平田智士、小島要、三沢計治、三森隆広、Gervais O、河合洋介、人見祐基、徳永勝士、中村稔、長﨑正朗
  • Organizer: 日本人類遺伝学会
• [Presentation] Identification of the primary functional variants in primary biliary cholangitis susceptibility gene loci NFKB1/MANBA. (2017)
  • Author(s): Hitomi Y, Nakatani K, Kojima K, Nishida N, Kawai Y, Kawashima M, Aiba Y, Nagasaki M, Nakamura M, Tokunaga K.
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] NELFCD and CTSZ loci are associated with jaundice-stage progression in primary biliary cholangitis in the Japanese (2017)
  • Author(s): Kawashima M, Nishida N, Hitomi Y, Kojima K, Kawai Y, Aiba Y, Nakamura H, Nagasaki M, Tokunaga K, Nakamura M.
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] GWAS polygenic model approach applied to primary biliary cholangitis (PBC) in a Japanese population. (2017)
  • Author(s): Gervais O, Ueno K, Kojima K, Aiba Y, Kawashima M, Kawai Y, Hitomi Y, Tokunaga K, Nakamura M, Nagasaki M.
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] 日本人原発性胆汁性胆管炎（PBC）感受性遺伝子領域Chr.17q12-21における機能的遺伝子多型（causal variant）の同定 (2017)
  • Author(s): 人見祐基、西田奈央、相葉佳洋、安波道郎、中村稔
  • Organizer: 日本肝臓学会
• [Presentation] Identification of the primary functional variants in primary biliary cholangitis susceptibility gene loci NFKB1/MANBA. (2017)
  • Author(s): 人見祐基、仲谷健、小島要、西田奈央、河合洋介、川嶋実苗、相葉佳洋、長崎正朗、中村稔、徳永勝士
  • Organizer: 日本人類遺伝学会
• [Presentation] Identification of the disease causal variants in human primary biliary cholangitis (PBC) susceptibility gene loci (2017)
  • Author(s): 人見祐基、相葉佳洋、中村稔、徳永勝士
  • Organizer: 日本免疫学会
• [Presentation] Principal contribution of HLA-DQ alleles, DQB1*06:04 and DQB1*03:01, to disease resistance against primary biliary (2017)
  • Author(s): 安波道朗、中村仁美、徳永勝士、川嶋実苗、西田奈央、人見祐基、中村稔
  • Organizer: 日本免疫学会