ダウンロード数: 42
このアイテムのファイル:
ファイル | 記述 | サイズ | フォーマット | |
---|---|---|---|---|
j.jhep.2021.04.055.pdf | 1.96 MB | Adobe PDF | 見る/開く |
タイトル: | An international genome-wide meta-analysis of primary biliary cholangitis: novel risk loci and candidate drugs |
著者: | Cordell, Heather J. Fryett, James J. Ueno, Kazuko Darlay, Rebecca Aiba, Yoshihiro Hitomi, Yuki Kawashima, Minae Nishida, Nao Khor, Seik-Soon Gervais, Olivier Kawai, Yosuke Nagasaki, Masao https://orcid.org/0000-0002-4292-8785 (unconfirmed) Tokunaga, Katsushi Tang, Ruqi Shi, Yongyong Li, Zhiqiang Juran, Brian D. Atkinson, Elizabeth J. Gerussi, Alessio Carbone, Marco Asselta, Rosanna Cheung, Angela de Andrade, Mariza Baras, Aris Horowitz, Julie Ferreira, Manuel A.R. Sun, Dylan Jones, David E. Flack, Steven Spicer, Ann Mulcahy, Victoria L. Byan, Jinyoung Han, Younghun Sandford, Richard N. Lazaridis, Konstantinos N. Amos, Christopher I. Hirschfield, Gideon M. Seldin, Michael F. Invernizzi, Pietro Siminovitch, Katherine A. Ma, Xiong Nakamura, Minoru Mells, George F. Canadian PBC Consortium Chinese PBC Consortium Italian PBC Study Group Japan-PBC-GWAS Consortium US PBC Consortium UK-PBC Consortium |
著者名の別形: | 植野, 和子 相葉, 佳洋 人見, 祐基 川嶋, 実苗 西田, 奈央 河合, 洋介 長﨑, 正朗 徳永, 勝士 中村, 稔 |
キーワード: | UK-PBC ERN RARE LIVER ALSPAC Genomic co-localization Network-based in silico drug efficacy screening |
発行日: | Sep-2021 |
出版者: | Elsevier |
誌名: | Journal of Hepatology |
巻: | 75 |
号: | 3 |
開始ページ: | 572 |
終了ページ: | 581 |
抄録: | [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. |
記述: | 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. |
著作権等: | © 2022 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the Creative Commons Attribution 4.0 International license. |
URI: | http://hdl.handle.net/2433/276949 |
DOI(出版社版): | 10.1016/j.jhep.2021.04.055 |
PubMed ID: | 34033851 |
関連リンク: | https://www.kyoto-u.ac.jp/ja/research-news/2021-06-28 |
出現コレクション: | 学術雑誌掲載論文等 |
このアイテムは次のライセンスが設定されています: クリエイティブ・コモンズ・ライセンス