Molecular genetic analysis to elucidate the pathogenesis of primary biliary cholangitis and develop personalized medicine.

• Project/Area Number: 19K08413
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Hoshi University
• Principal Investigator: Hitomi Yuki 星薬科大学, 薬学部, 特任講師 (10525819)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• 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 / 疾患感受性遺伝子領域 / ゲノム編集 / PBC感受性遺伝子領域 / PBC / Post-GWAS研究

Outline of Research at the Start

申請者らは、慢性進行性の胆汁鬱滞性肝疾患である原発性胆汁性胆管炎（PBC）の発症のしやすさに関わる遺伝要因を、GWAS（ゲノムワイド関連解析）という手法を用いて網羅的に探索した。
本研究では、その成果を PBCの 発症機序の解明や医療応用へと展開するための「橋渡し」（post-GWAS研究）を目的として、次世代シークエンサー・生物情報学的解析・機能解析を融合した多角的かつ網羅的な解析を実施する。

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. However, the mechanism of disease onset and progression remains unclear.
In this study, we comprehensively identified PBC susceptibility loci by international genome-wide association study (GWAS). Additionally, disease causal variants in these loci and the molecular mechanisms of disease susceptibility in PBC have been elucidated.

Academic Significance and Societal Importance of the Research Achievements

本研究によって、PBCの発症に寄与する遺伝要因の網羅的な同定、および、そこから発症に至るまでの分子メカニズムが、世界最大規模のPBC遺伝要因探索研究によって、それぞれ明らかにされた。
本研究を手掛かりとして、「発症予測キット・副作用予測キット」の開発や個々の遺伝情報に応じた医療（個別化医療）の実現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

• [Int'l Joint Research] ケンブリッジ大学(英国)
• [Int'l Joint Research] ケンブリッジ大学(英国)
• [Int'l Joint Research] ケンブリッジ大学(英国)
• [Journal Article] rs9459874 and rs1012656 in CCR6/FGFR1OP confer susceptibility to primary biliary cholangitis (2022)
  • Author(s): Hitomi Yuki、Aiba Yoshihiro、Ueno Kazuko、Nishida Nao、Kawai Yosuke、Kawashima Minae、Yasunami Michio、Gervais Olivier、Ito Masahiro、Cordell Heather J.、Mells George F.、Nagasaki Masao、Tokunaga Katsushi、Tsuiji Makoto、Nakamura Minoru
  • Journal Title: Journal of Autoimmunity Volume: 126 Pages: 102775-102775
  • DOI: 10.1016/j.jaut.2021.102775
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] X Chromosome Contribution to the Genetic Architecture of Primary Biliary Cholangitis (2021)
  • Author(s): Rosanna Asselta, et al.
  • Journal Title: Gastroenterology Volume: 160 Issue: 7 Pages: 2483-2495.e26
  • DOI: 10.1053/j.gastro.2021.02.061
  • Peer Reviewed
• [Journal Article] Regional heritability mapping identifies several novel loci (STAT4, 3 ULK4, and KCNH5) for primary biliary cholangitis in the Japanese 4 population (2021)
  • Author(s): Olivier Gervais, Kazuko Ueno, Yosuke Kawai, Yuki Hitomi, Yoshihiro Aiba, Mayumi Ueta, Minoru Nakamura, Katsushi Tokunaga & Masao Nagasaki
  • Journal Title: European Journal of Human Genetics Volume: － Issue: 8 Pages: 1282-1291
  • DOI: 10.1038/s41431-021-00854-5
  • Peer Reviewed / Open Access
• [Journal Article] An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs (2021)
  • Author(s): Heather J Cordell, et al.
  • Journal Title: Journal of Hepatology Volume: 75 Issue: 3 Pages: 572-581
  • DOI: 10.1016/j.jhep.2021.04.055
  • Peer Reviewed / Open Access
• [Journal Article] rs1944919 on chromosome 11q23.1 and its effector genes COLCA1/COLCA2 confer susceptibility to primary biliary cholangitis (2021)
  • Author(s): Hitomi Yuki、Aiba Yoshihiro、Kawai Yosuke、Kojima Kaname、Ueno Kazuko、Nishida Nao、Kawashima Minae、Gervais Olivier、Khor Seik-Soon、Nagasaki Masao、Tokunaga Katsushi、Nakamura Minoru、Tsuiji Makoto
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 4557-4557
  • DOI: 10.1038/s41598-021-84042-x
  • Peer Reviewed / Open Access
• [Journal Article] An international genome-wide meta-analysis of primary biliary cholangitis: novel risk loci and a hierarchy of candidate drugs. (2021)
  • Author(s): Heather J. Cordell, James J. Fryett, Kazuko Ueno, Rebecca Darlay, Yoshihiro Aiba, Yuki Hitomi, Minae Kawashima, Nao Nishida, Seik-Soon Khor, Olivier Gervais, et al.
  • Journal Title: Journal of Hepatology Volume: -
  • Peer Reviewed
• [Journal Article] Genomic heritabilities and correlations of 17 traits related to obesity and associated conditions in the Japanese population (2020)
  • Author(s): Olivier Gervais, Kazuko Ueno, Yosuke Kawai, Yuki Hitomi, Kazuharu Misawa, Shunsuke Teraguchi, Yen-Yen Wang, Katsushi Tokunaga, Masao Nagasaki
  • Journal Title: G3: Genes|Genomes|Genetics Volume: ー Issue: 7 Pages: 2221-2228
  • DOI: 10.1534/g3.120.401242
  • Peer Reviewed / Open Access
• [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
• [Presentation] rs1944919 on human chromosome 11q23.1 and its effector genes COLCA1 and COLCA2 confer susceptibility to primary biliary cholangitis. (2021)
  • Author(s): Hitomi Y, Aiba Y, Kawai Y, Kojima K, Ueno K, Nishida N, Kawashima M, Gervais O, Khor SS, Nagasaki M, Tokunaga K, Tsuiji M, Nakamura M.
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] Applying the regional heritability mapping method to primary biliary cholangitis in the Japanese population. (2021)
  • Author(s): Gervais O, Ueno K, Kawai Y, Hitomi Y, Aiba Y, Ueta M, Nakamura M, Tokunaga K, Nagasaki M
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] Transcriptome and GWAS identified rs2238678 as a critical SNP for eosinophilia in primary biliary cholangitis. (2021)
  • Author(s): Ueno K, Hitomi Y, Aiba Y, Gervais O, Kawai Y, Khor SS, Kawashima M, Nishida N, Kojima K, Nagasaki M, Tokunaga K, Nakamura M.
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] Identification of seven primary functional variants in primary biliary cholangitis susceptibility loci in the Japanese population. (2021)
  • Author(s): Hitomi Y, Aiba Y, Ueno K, Kawai Y, Nishida N, Kawashima M, Gervais O, Nagasaki M, Tokunaga K, Tsuiji M, Nakamura M.
  • Organizer: American Society of Histocompatibility and Immunogenetics
  • Int'l Joint Research
• [Presentation] COLCA1 and COLCA2, the effector genes driven by rs1944919 in primary biliary cholangitis (PBC) susceptibility locus chromosome 11q23.1 in the Japanese population. (2021)
  • Author(s): Hitomi Y, Aiba Y, Kawai Y, Kojima K, Ueno K, Nishida N, Kawashima M, Gervais O, Khor SS, Nagasaki M, Tokunaga K, Tsuiji M, Nakamura M.
  • 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CCR6/FGFR1OPにおけるprimary functional variantsの同定 (2021)
  • Author(s): 人見祐基、相葉佳洋、植野和子、西田奈央、河合洋介、川嶋実苗、安波道朗、Gervais O、長﨑正朗、徳永勝士、築地信、中村稔
  • Organizer: 日本人類遺伝学会
• [Presentation] 原発性胆汁性胆管炎における疾患感受性遺伝子POU2AF1とその関連遺伝子の解析 (2021)
  • Author(s): 相葉佳洋, 植野和子, 人見祐基, 西田奈央, 下田慎司, 小森敦正, 橋元悟, 戸次鎮宗, 阿比留正剛, 長岡進矢, 八橋弘, 中村稔
  • Organizer: 日本肝臓学会
• [Presentation] Identification of the primary functional variants in primary biliary cholangitis susceptibility gene CCR6/FGFR1OP. (2021)
  • Author(s): 人見祐基、相葉佳洋、築地信、中村稔
  • Organizer: 日本免疫学会
• [Presentation] The analysis of POU2AF1 and its related molecules in the pathogenesis of primary biliary cholangitis by using GWAS and transcriptome datasets. (2020)
  • Author(s): Aiba Y, Ueno K, Hitomi Y, Gervais O, Kawai Y, Kawashima M, Nishida N, Komori A, Kojima K, Nagasaki M, Tokunaga K, Nakamura M.
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] Transcriptome and GWAS identified androgen receptor as a central regulator for eosinophilia in primary biliary cholangitis. (2020)
  • Author(s): Ueno K, Aiba Y, Hitomi Y, Kawai Y, Khor SS, Gervais O, Kawashima M, Nishida N, Kojima K, Nagasaki M, Tokunaga K, Nakamura M.
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research
• [Presentation] COLCA1/COLCA2, the effector genes in primary biliary cholangitis susceptibility locus chromosome 11q23.1. (2020)
  • Author(s): 人見祐基、相葉佳洋、河合洋介、小島要、植野和子、西田奈央、川嶋実苗、Garveis O、Khor SS、長﨑正朗、徳永勝士、中村稔、築地信
  • Organizer: 第65回日本人類遺伝学会
• [Presentation] 日本人原発性胆汁性胆管炎（PBC）感受性遺伝子領域11番染色体長腕23.1に位置するcausal variantおよびエフェクター遺伝子の同定 (2020)
  • Author(s): 人見祐基、中村稔
  • Organizer: 第56回日本肝臓学会
• [Presentation] 原発性胆汁性胆管炎に関与する遺伝子の共発現ネットワーク解析 (2020)
  • Author(s): 相葉佳洋、植野和子、人見祐基、小森敦正、橋元悟、戸次鎮宗、阿比留正剛、長岡進矢、八橋弘、中村稔
  • Organizer: 第56回日本肝臓学会
• [Presentation] The role of PRKCB in the development of primary biliary cholangitis. (2019)
  • Author(s): 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] 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): 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