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dc.contributor.author | Cordell, Heather J. | en |
dc.contributor.author | Fryett, James J. | en |
dc.contributor.author | Ueno, Kazuko | en |
dc.contributor.author | Darlay, Rebecca | en |
dc.contributor.author | Aiba, Yoshihiro | en |
dc.contributor.author | Hitomi, Yuki | en |
dc.contributor.author | Kawashima, Minae | en |
dc.contributor.author | Nishida, Nao | en |
dc.contributor.author | Khor, Seik-Soon | en |
dc.contributor.author | Gervais, Olivier | en |
dc.contributor.author | Kawai, Yosuke | en |
dc.contributor.author | Nagasaki, Masao | en |
dc.contributor.author | Tokunaga, Katsushi | en |
dc.contributor.author | Tang, Ruqi | en |
dc.contributor.author | Shi, Yongyong | en |
dc.contributor.author | Li, Zhiqiang | en |
dc.contributor.author | Juran, Brian D. | en |
dc.contributor.author | Atkinson, Elizabeth J. | en |
dc.contributor.author | Gerussi, Alessio | en |
dc.contributor.author | Carbone, Marco | en |
dc.contributor.author | Asselta, Rosanna | en |
dc.contributor.author | Cheung, Angela | en |
dc.contributor.author | de Andrade, Mariza | en |
dc.contributor.author | Baras, Aris | en |
dc.contributor.author | Horowitz, Julie | en |
dc.contributor.author | Ferreira, Manuel A.R. | en |
dc.contributor.author | Sun, Dylan | en |
dc.contributor.author | Jones, David E. | en |
dc.contributor.author | Flack, Steven | en |
dc.contributor.author | Spicer, Ann | en |
dc.contributor.author | Mulcahy, Victoria L. | en |
dc.contributor.author | Byan, Jinyoung | en |
dc.contributor.author | Han, Younghun | en |
dc.contributor.author | Sandford, Richard N. | en |
dc.contributor.author | Lazaridis, Konstantinos N. | en |
dc.contributor.author | Amos, Christopher I. | en |
dc.contributor.author | Hirschfield, Gideon M. | en |
dc.contributor.author | Seldin, Michael F. | en |
dc.contributor.author | Invernizzi, Pietro | en |
dc.contributor.author | Siminovitch, Katherine A. | en |
dc.contributor.author | Ma, Xiong | en |
dc.contributor.author | Nakamura, Minoru | en |
dc.contributor.author | Mells, George F. | en |
dc.contributor.author | Canadian PBC Consortium | en |
dc.contributor.author | Chinese PBC Consortium | en |
dc.contributor.author | Italian PBC Study Group | en |
dc.contributor.author | Japan-PBC-GWAS Consortium | en |
dc.contributor.author | US PBC Consortium | en |
dc.contributor.author | UK-PBC Consortium | en |
dc.contributor.alternative | 植野, 和子 | 3 |
dc.contributor.alternative | 相葉, 佳洋 | 5 |
dc.contributor.alternative | 人見, 祐基 | 6 |
dc.contributor.alternative | 川嶋, 実苗 | 7 |
dc.contributor.alternative | 西田, 奈央 | 8 |
dc.contributor.alternative | 河合, 洋介 | 11 |
dc.contributor.alternative | 長﨑, 正朗 | 12 |
dc.contributor.alternative | 徳永, 勝士 | 13 |
dc.contributor.alternative | 中村, 稔 | 42 |
dc.date.accessioned | 2022-10-31T00:08:48Z | - |
dc.date.available | 2022-10-31T00:08:48Z | - |
dc.date.issued | 2021-09 | - |
dc.identifier.uri | http://hdl.handle.net/2433/276949 | - |
dc.description | 原発性胆汁性胆管炎のゲノムワイド関連解析 --国際メタ解析による新規疾患感受性遺伝子と治療薬候補の同定--. 京都大学プレスリリース. 2021-06-28. | ja |
dc.description.abstract | [BACKGROUND & AIMS] Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intra-hepatic bile ducts eventually leads to cirrhosis. Many patients have inadequate response to licensed medications, motivating the search for novel therapies. Previous genome-wide association studies (GWAS) and meta-analyses (GWMA) of PBC have identified numerous risk loci for this condition, providing insight into its aetiology. We undertook the largest GWMA of PBC to date, aiming to identify additional risk loci and prioritise candidate genes for in silico drug efficacy screening. [METHODS] We combined new and existing genotype data for 10, 516 cases and 20, 772 controls from five European and two East Asian cohorts. [RESULTS] We identified 56 genome-wide significant loci (20 novel) including 46 in European, 13 in Asian, and 41 in combined cohorts; and a 57th genome-wide significant locus (also novel) in conditional analysis of the European cohorts. Candidate genes at newly identified loci include FCRL3, INAVA, PRDM1, IRF7, CCR6, CD226, and IL12RB1, each having key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, Jak-STAT signalling, and differentiation of TH1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some well-established in the treatment of other autoimmune disorders. [CONCLUSIONS] This study has identified additional risk loci for PBC, provided a hierarchy of agents that could be trialled in this condition, and emphasised the value of genetic and genomic approaches to drug discovery in complex disorders. [Lay summary] Primary biliary cholangitis (PBC) is a chronic liver disease that eventually leads to cirrhosis. In this study, we analysed genetic information from 10, 516 people with PBC and 20, 772 healthy individuals recruited in Canada, China, Italy, Japan, UK, or USA. We identified several genetic regions associated with PBC. Each of these regions contains several genes. For each region, we used diverse sources of evidence to help us choose the gene most likely to be involved in causing PBC. We used these ‘candidate genes’ to help us identify medications that are currently used for treatment of other conditions, which might also be useful for treatment of PBC. | en |
dc.language.iso | eng | - |
dc.publisher | Elsevier | en |
dc.rights | © 2022 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. | en |
dc.rights | This is an open access article under the Creative Commons Attribution 4.0 International license. | en |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | - |
dc.subject | UK-PBC | en |
dc.subject | ERN RARE LIVER | en |
dc.subject | ALSPAC | en |
dc.subject | Genomic co-localization | en |
dc.subject | Network-based in silico drug efficacy screening | en |
dc.title | An international genome-wide meta-analysis of primary biliary cholangitis: novel risk loci and candidate drugs | en |
dc.type | journal article | - |
dc.type.niitype | Journal Article | - |
dc.identifier.jtitle | Journal of Hepatology | en |
dc.identifier.volume | 75 | - |
dc.identifier.issue | 3 | - |
dc.identifier.spage | 572 | - |
dc.identifier.epage | 581 | - |
dc.relation.doi | 10.1016/j.jhep.2021.04.055 | - |
dc.textversion | publisher | - |
dc.address | Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University | en |
dc.address | Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University | en |
dc.address | Genome Medical Science Project, National Center for Global Health and Medicine (NCGM) | en |
dc.address | Population Health Sciences Institute, Faculty of Medical Sciences, Newcastle University | en |
dc.address | Clinical Research Center, National Hospital Organization, Nagasaki Medical Center | en |
dc.address | Department of Human Genetics, Graduate School of Medicine, The University of Tokyo | en |
dc.address | Department of Human Genetics, Graduate School of Medicine, The University of Tokyo | en |
dc.address | Department of Human Genetics, Graduate School of Medicine, The University of Tokyo | en |
dc.address | Genome Medical Science Project, National Center for Global Health and Medicine (NCGM) | en |
dc.address | Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research, Kyoto University; Center for Genomic Medicine, Graduate School of Medicine, Kyoto University | en |
dc.address | Genome Medical Science Project, National Center for Global Health and Medicine (NCGM) | en |
dc.address | Human Biosciences Unit for the Top Global Course Center for the Promotion of Interdisciplinary Education and Research, Kyoto University; Center for Genomic Medicine, Graduate School of Medicine, Kyoto University | en |
dc.address | Genome Medical Science Project, National Center for Global Health and Medicine (NCGM) | en |
dc.address | Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease | en |
dc.address | Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University; Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University | en |
dc.address | Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University; Affiliated Hospital of Qingdao University and Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University | en |
dc.address | Division of Gastroenterology and Hepatology, Mayo Clinic | en |
dc.address | Division of Biomedical Statistics and Informatics, Mayo Clinic | en |
dc.address | Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital | en |
dc.address | Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital | en |
dc.address | Department of Biomedical Sciences, Humanitas University; Humanitas Clinical and Research Center, IRCCS | en |
dc.address | Division of Gastroenterology and Hepatology, Mayo Clinic | en |
dc.address | Division of Biomedical Statistics and Informatics, Mayo Clinic | en |
dc.address | Regeneron Genetics Center | en |
dc.address | Regeneron Genetics Center | en |
dc.address | Regeneron Genetics Center | en |
dc.address | Regeneron Genetics Center | en |
dc.address | Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University | en |
dc.address | Academic Department of Medical Genetics, University of Cambridge | en |
dc.address | Academic Department of Medical Genetics, University of Cambridge | en |
dc.address | Academic Department of Medical Genetics, University of Cambridge | en |
dc.address | Institute for Clinical and Translational Research, Baylor College of Medicine | en |
dc.address | Institute for Clinical and Translational Research, Baylor College of Medicine | en |
dc.address | Academic Department of Medical Genetics, University of Cambridge | en |
dc.address | Division of Gastroenterology and Hepatology, Mayo Clinic | en |
dc.address | Institute for Clinical and Translational Research, Baylor College of Medicine | en |
dc.address | Toronto Centre for Liver Disease, Division of Gastroenterology and Hepatology, University of Toronto | en |
dc.address | University of California, Davis | en |
dc.address | Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital | en |
dc.address | Departments of Medicine, Immunology and Medical Sciences, University of Toronto; Mount Sinai Hospital, Lunenfeld-Tanenbaum Research Institute and Toronto General Research Institute | en |
dc.address | Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai JiaoTong University, Shanghai Institute of Digestive Disease | en |
dc.address | Clinical Research Center, National Hospital Organization, Nagasaki Medical Center; Department of Hepatology, Nagasaki Graduate School of Biomedical Sciences | en |
dc.address | Academic Department of Medical Genetics, University of Cambridge | en |
dc.identifier.pmid | 34033851 | - |
dc.relation.url | https://www.kyoto-u.ac.jp/ja/research-news/2021-06-28 | - |
dcterms.accessRights | open access | - |
datacite.awardNumber | 26293181 | - |
datacite.awardNumber | 17H04169 | - |
datacite.awardNumber.uri | https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-26293181/ | - |
datacite.awardNumber.uri | https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17H04169/ | - |
dc.identifier.pissn | 0168-8278 | - |
jpcoar.funderName | 日本学術振興会 | ja |
jpcoar.funderName | 日本学術振興会 | ja |
jpcoar.awardTitle | 原発性胆汁性肝硬変の疾患感受性遺伝子による病態の解明と新しい分子標的治療法の開発 | ja |
jpcoar.awardTitle | 原発性胆汁性胆管炎の発症と重症化機構解明のためのGWASを基盤とした統合解析 | ja |
出現コレクション: | 学術雑誌掲載論文等 |
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