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Gene-disease associations identify a connectome with shared molecular pathways in human cholangiopathies
Hepatology ( IF 12.9 ) Pub Date : 2018-01-02 , DOI: 10.1002/hep.29504
Zhenhua Luo 1 , Anil G. Jegga 2 , Jorge A. Bezerra 1
Affiliation  

Cholangiopathies are a diverse group of progressive diseases whose primary cell targets are cholangiocytes. To identify shared pathogenesis and molecular connectivity among the three main human cholangiopathies (biliary atresia [BA], primary biliary cholangitis [PBC], and primary sclerosing cholangitis [PSC]), we built a comprehensive platform of published data on gene variants, gene expression, and functional studies and applied network‐based analytics in the search for shared molecular circuits. Mining the data platform with largest connected component and interactome analyses, we validated previously reported associations and identified essential and hub genes. In addition to disease‐specific modules, we found a substantial overlap of disease neighborhoods and uncovered a group of 34 core genes that are enriched for immune processes and abnormal intestine/hepatobiliary mouse phenotypes. Within this core, we identified a gene subcore containing signal transduction and activator of transcription 3, interleukin‐6, tumor necrosis factor, and forkhead box P3 prominently placed in a regulatory connectome of genes related to cellular immunity and fibrosis. We also found substantial gene enrichment in the advanced glycation endproduct/receptor for advanced glycation endproducts (RAGE) pathway and showed that RAGE activation induced cholangiocyte proliferation. Conclusion: Human cholangiopathies share pathways enriched by immunity genes and a molecular connectome that links different pathogenic features of BA, PBC, and PSC. (Hepatology 2018;67:676‐689).

中文翻译:

基因疾病关联确定了人类胆管病中具有共享分子途径的连接组

胆管病是一组多样化的进行性疾病,其主要细胞靶标是胆管细胞。为了确定三种主要人类胆管病(胆道闭锁 [BA]、原发性胆汁性胆管炎 [PBC] 和原发性硬化性胆管炎 [PSC])之间的共同发病机制和分子连接性,我们建立了一个综合平台,其中包含有关基因变异、基因表达的已发表数据,以及功能研究和应用基于网络的分析,以寻找共享的分子电路。挖掘具有最大连接组件和交互组分析的数据平台,我们验证了先前报告的关联并确定了必需基因和中枢基因。除了特定疾病的模块,我们发现了疾病邻域的大量重叠,并发现了一组 34 个核心基因,这些基因富含免疫过程和异常肠/肝胆小鼠表型。在这个核心中,我们确定了一个基因亚核心,其中包含信号转导和转录激活因子 3、白细胞介素-6、肿瘤坏死因子和叉头盒 P3,它们突出放置在与细胞免疫和纤维化相关的基因的调节连接组中。我们还发现在晚期糖基化终末产物/晚期糖基化终末产物 (RAGE) 通路的受体中有大量基因富集,并表明 RAGE 激活诱导了胆管细胞增殖。结论:人类胆管病共享由免疫基因和连接 BA、PBC 和 PSC 不同致病特征的分子连接组富集的通路。(肝病学 2018 年;67:676-689)。
更新日期:2018-01-02
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