Clarification of the molecular mechanisms of pathogenesis caused by PBC susceptibility polymorphisms

• Project/Area Number: 15K19314
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: Hitomi Yuki 東京大学, 大学院医学系研究科(医学部), 助教 (10525819)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: ゲノムワイド関連解析 / 原発性胆汁性胆管炎 / 遺伝子多型 / ゲノムワイド関連解析（GWAS） / 原発性胆汁性胆管炎（PBC） / 原発性胆汁性肝硬変

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 eight susceptibility gene loci for PBC 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, in silico analysis, and in vitro functional analysis.

Research Products

• [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
• [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] Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn's disease and leprosy. (2016)
  • Author(s): Sun Y, Irwanto A, Toyo-Oka L, Hong M, Liu H, Andiappan AK, Choi H, Hitomi Y, Yu G, Yu Y, Bao F, Wang C, Fu X, Yue Z, Wang H, Zhang H, Kawashima M, Kojima K, Nagasaki M, Nakamura M, Yang SK, Ye BD, Denise Y, Rotzschke O, Song K, Tokunaga K, Zhang F, Liu J.
  • Journal Title: Sci Rep. Volume: 10(6) Issue: 1 Pages: 31429-31429
  • DOI: 10.1038/srep31429
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
• [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
• [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 population. (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 NFKB1/MANBA. (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 cholangitis in a Japanese population. (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
• [Presentation] Identification of the causal variants in human primary biliary cirrhosis (PBC) by the combination of a genome-wide association study, whole-genome sequencing, and in silico/ in vitro functional analyses. (2016)
  • Author(s): 人見祐基、相葉佳洋、中村稔、徳永勝士
  • Organizer: 日本免疫学会
  • Place of Presentation: 沖縄コンベンションセンター（沖縄県那覇市）
  • Year and Date: 2016-12-05
• [Presentation] Identification of the primary functional variants for primary biliary cirrhosis (PBC) susceptibility loci by high-density association mapping and in silico/ in vitro functional analyses. (2016)
  • Author(s): Hitomi Y, Kojima K, Kawashima M, Kawai Y, Nishida N, Aiba Y, Yasunami M, Nagasaki M, Nakamura M, Tokunaga K.
  • Organizer: American Society of Human Genetics
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2016-10-16
  • Int'l Joint Research
• [Presentation] Genome-wide association study identifies PRKCB as a novel genetic factor for primary biliary cirrhosis in the Japanese population. (2016)
  • Author(s): Kawashima M, Hitomi Y, Nishida N, Kojima K, Kawai Y, Nakamura H, Yasunami M, Chayama K, Aiba Y, Nagasaki M, Tokunaga K, Nakamura M, PBC Consortium in Japan (PBCCSJ).
  • Organizer: American Society of Human Genetics
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2016-10-16
  • Int'l Joint Research
• [Presentation] 日本人原発性胆汁性肝硬変（PBC）の発症と関連する機能的遺伝子多型（causal variant）の同定 (2016)
  • Author(s): 人見祐基、中村稔
  • Organizer: 日本肝臓学会
  • Place of Presentation: 東京ベイ幕張ホール（千葉県千葉市）
  • Year and Date: 2016-05-19
• [Presentation] Imputation analysis using reference panel of 1,070 Japanese individuals (1KJPN) and in silico / in vitro functional analyses identified functional variants for primary biliary cirrhosis (PBC) susceptibility. (2016)
  • Author(s): Hitomi Y, Kojima K, Kawashima M, Kawai Y, Nishida N, Aiba Y, Yasunami M, Nagasaki M, Nakamura M, Tokunaga K.
  • Organizer: International Congress of Human Genetics
  • Place of Presentation: 京都国際会議場（京都府京都市）
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] Fine-mapping analysis of TNFSF15 across leprosy, Crohn’s disease and primary biliary cirrhosis (2016)
  • Author(s): Irwanto A, Sun Y, Hitomi Y, Toyo-oka L, Choi H, Zhang F, Song K, Tokunaga K, Liu JJ, Andiappan AK, Rotzschke O.
  • Organizer: International Congress of Human Genetics
  • Place of Presentation: 京都国際会議場（京都府京都市）
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] Fine-mapping analysis of TNFSF15 across leprosy, Crohn’s disease and primary biliary cirrhosis. (2016)
  • Author(s): Irwanto A, Sun Y, Hitomi Y, Toyo-oka L, Choi H, Zhang F, Song K, Tokunaga K, Liu JJ, Andiappan AK, Rotzschke O.
  • Organizer: International Congress of Human Genetics
  • Place of Presentation: 京都国際会議場（京都府京都市）
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] ゲノムワイド関連解析から同定された日本人原発性胆汁性肝硬変発症に抑制的なHLAハプロタイプの効果 (2015)
  • Author(s): 安波道郎、中村仁美、徳永勝士、川嶋実苗、西田奈央、人見祐基、中村稔
  • Organizer: 日本人類遺伝学会
  • Place of Presentation: 京王プラザホテル（東京都新宿区）
  • Year and Date: 2015-10-15
• [Presentation] Dissection of HLA class II in Japanese primary biliary cirrhosis: epistasis of protective HLA-DQ allele and additional contribution of HLA-DP allele. (2015)
  • Author(s): Yasunami M, Nakamura H, Tokunaga K, Kawashima M, Nishida N, Hitomi Y, Nakamura M.
  • Organizer: American Society for Human Genetics
  • Place of Presentation: Boltimore（USA）
  • Year and Date: 2015-10-06
  • Int'l Joint Research
• [Presentation] 原発性胆汁性肝硬変（PBC）感受性遺伝子TNFSF15に存在するrs4979462は、NF-1結合を介したTNFSF15発現量の亢進に寄与する (2015)
  • Author(s): 人見祐基、相葉佳洋、中村稔
  • Organizer: 日本肝臓学会
  • Place of Presentation: 熊本ホテルキャッスル（熊本県熊本市）
  • Year and Date: 2015-05-21
• [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、川嶋実苗、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: 日本肝臓学会
  • Place of Presentation: 熊本ホテルキャッスル（熊本県熊本市）
  • Year and Date: 2015-05-21
• [Remarks] 東京大学大学院医学系研究科人類遺伝学教室
  • URL: http://www.humgenet.m.u-tokyo.ac.jp/