An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs.
An international genome-wide meta-analysis of primary biliary cholangitis: Novel risk loci and candidate drugs.
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原发性胆管炎的国际全基因组荟萃分析：新的风险位点和候选药物。
DOI：
10.1016/j.jhep.2021.04.055
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发表时间：
2021-09
影响因子：
25.7
通讯作者：
UK-PBC Consortium
中科院分区：
文献类型：
--
作者：
Cordell HJ;Fryett JJ;Ueno K;Darlay R;Aiba Y;Hitomi Y;Kawashima M;Nishida N;Khor SS;Gervais O;Kawai Y;Nagasaki M;Tokunaga K;Tang R;Shi Y;Li Z;Juran BD;Atkinson EJ;Gerussi A;Carbone M;Asselta R;Cheung A;de Andrade M;Baras A;Horowitz J;Ferreira MAR;Sun D;Jones DE;Flack S;Spicer A;Mulcahy VL;Byan J;Han Y;Sandford RN;Lazaridis KN;Amos CI;Hirschfield GM;Seldin MF;Invernizzi P;Siminovitch KA;Ma X;Nakamura M;Mells GF;PBC Consortia;Canadian PBC Consortium;Chinese PBC Consortium;Italian PBC Study Group;Japan-PBC-GWAS Consortium;US PBC Consortium;UK-PBC Consortium
原发性胆汁性胆管炎（PBC）是一种慢性肝病，其中肝内小胆管的自身免疫性破坏最终导致肝硬化。许多患者对许可的药物反应不足，促使人们寻找新的治疗方法。以前的PBC全基因组关联研究（GWAS）和荟萃分析（GWMA）已经确定了许多这种情况的风险位点，提供了对其病因学的深入了解。我们进行了迄今为止规模最大的PBC GWMA，旨在确定其他风险位点，并优先考虑用于计算机药物疗效筛选的候选基因。我们结合了来自5个欧洲和2个东亚队列的10，516例病例和20，772例对照的新的和现有的基因型数据。我们确定了56个全基因组显著位点（20个新位点），包括欧洲人46个，亚洲人13个，联合队列41个;在欧洲队列的条件分析中，我们确定了第57个全基因组显著位点（也是新位点）。新鉴定的基因座的候选基因包括FCRL 3、INAVA、PRDM 1、IRF 7、CCR 6、CD 226和IL 12 RB 1，它们各自在免疫中起关键作用。通路分析重申了模式识别受体和TNF信号传导，JAK-STAT信号传导和辅助性T细胞（TH）1和TH 17细胞的分化在这种疾病的发病机制中的可能重要性。药物疗效筛选确定了几种预测对PBC有治疗作用的药物，其中一些在治疗其他自身免疫性疾病方面已经得到了很好的证实。这项研究已经确定了PBC的其他风险位点，提供了一个可以在这种情况下进行试验的药物层次结构，并强调了遗传和基因组方法在复杂疾病药物发现中的价值。原发性胆汁性胆管炎（PBC）是一种慢性肝病，最终导致肝硬化。在这项研究中，我们分析了来自加拿大、中国、意大利、日本、英国或美国的10,516名PBC患者和20,772名健康个体的遗传信息。我们确定了几个与PBC相关的遗传区域。每个区域都包含几个基因。对于每个区域，我们使用不同的证据来源来帮助我们选择最有可能参与导致PBC的基因。我们使用这些“候选基因”来帮助我们识别目前用于治疗其他疾病的药物，这些药物也可能对PBC的治疗有用。原发性胆汁性胆管炎（PBC）易感性的跨种族全基因组荟萃分析（GWMA）。5个欧洲血统队列和2个东亚队列（n = 10，516例病例和20，772例对照）。确定PBC的21个额外的风险位点。初步证据表明PBC的遗传结构在欧洲和东亚人群中广泛共享。识别（使用计算机模拟药物疗效筛选）可能适合重新用于PBC的药物。
Primary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the small intrahepatic 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. We combined new and existing genotype data for 10,516 cases and 20,772 controls from 5 European and 2 East Asian cohorts. 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, which each play key roles in immunity. Pathway analysis reiterated the likely importance of pattern recognition receptor and TNF signalling, JAK-STAT signalling, and differentiation of T helper (TH)1 and TH17 cells in the pathogenesis of this disease. Drug efficacy screening identified several medications predicted to be therapeutic in PBC, some of which are well-established in the treatment of other autoimmune disorders. 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. 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, the UK, or the 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. Trans-ethnic genome-wide meta-analysis (GWMA) of susceptibility to primary biliary cholangitis (PBC). Five cohorts of European ancestry and two East Asian cohorts (n = 10,516 cases and 20,772 controls). Identification of 21 additional risk loci for PBC. Preliminary evidence that the genetic architecture of PBC is broadly shared across European and East Asian populations. Identification (using in silico drug efficacy screening) of medications potentially suitable for re-purposing to PBC.
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一项全基因组关联研究确定了原发性胆汁性胆管炎的六个新风险位点。
影响因子：
16.6
作者：
Qiu F;Tang R;Zuo X;Shi X;Wei Y;Zheng X;Dai Y;Gong Y;Wang L;Xu P;Zhu X;Wu J;Han C;Gao Y;Zhang K;Jiang Y;Zhou J;Shao Y;Hu Z;Tian Y;Zhang H;Dai N;Liu L;Wu X;Zhao W;Zhang X;Zang Z;Nie J;Sun W;Zhao Y;Mao Y;Jiang P;Ji H;Dong Q;Li J;Li Z;Bai X;Li L;Lin M;Dong M;Li J;Zhu P;Wang C;Zhang Y;Jiang P;Wang Y;Jawed R;Xu J;Zhang Y;Wang Q;Yang Y;Yang F;Lian M;Jiang X;Xiao X;Li Y;Fang J;Qiu D;Zhu Z;Qiu H;Zhang J;Tian W;Chen S;Jiang L;Ji B;Li P;Chen G;Wu T;Sun Y;Yu J;Tang H;He M;Xia M;Pei H;Huang L;Qing Z;Wu J;Huang Q;Han J;Xie W;Sun Z;Guo J;He G;Eric Gershwin M;Lian Z;Liu X;Seldin MF;Liu X;Chen W;Ma X
通讯作者：
Ma X
影响因子：
12.3
作者：
McLaren W;Gil L;Hunt SE;Riat HS;Ritchie GR;Thormann A;Flicek P;Cunningham F
通讯作者：
Cunningham F
影响因子：
16.6
作者：
Cordell HJ;Han Y;Mells GF;Li Y;Hirschfield GM;Greene CS;Xie G;Juran BD;Zhu D;Qian DC;Floyd JA;Morley KI;Prati D;Lleo A;Cusi D;Canadian-US PBC Consortium;Italian PBC Genetics Study Group;UK-PBC Consortium;Gershwin ME;Anderson CA;Lazaridis KN;Invernizzi P;Seldin MF;Sandford RN;Amos CI;Siminovitch KA
通讯作者：
Siminovitch KA
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
DOI：
10.1016/j.metabol.2020.154338
发表时间：
2021-01
期刊：
Metabolism: clinical and experimental
影响因子：
--
作者：
Christofides A;Konstantinidou E;Jani C;Boussiotis VA
通讯作者：
Boussiotis VA