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Differential genetic and functional background in inflammatory bowel disease phenotypes of a Greek population: a systems bioinformatics approach.
Gut Pathogens ( IF 4.3 ) Pub Date : 2019-06-15 , DOI: 10.1186/s13099-019-0312-y
Maria Gazouli 1 , Nikolas Dovrolis 2 , Andre Franke 3 , George M Spyrou 4 , Leonardo A Sechi 5 , George Kolios 2
Affiliation  

Background Crohn's disease (CD) and Ulcerative colitis (UC) are the two main entities of inflammatory bowel disease (IBD). Previous works have identified more than 200 risk factors (including loci and signaling pathways) in populations of predominantly European ancestry. Our study was conducted on an extended population-specific cohort of 573 Greek IBD patients (364 CD and 209 UC) and 445 controls. Aims To highlight the different genetic and functional background of IBD and its phenotypes, utilizing contemporary systems bioinformatics methodologies. Methods Disease-associated SNPs, obtained via our own 89 loci IBD risk GWAS panel, were detected with the whole genome association analysis toolset PLINK. These SNPs were used as input for 2 novel and different pathway analysis methods to detect functional interactions. Specifically, PathwayConnector was used to create complementary networks of interacting pathways whereas; the online database of protein interactions STRING provided protein-protein association networks and their derived pathways. Network analyses metrics were employed to identify proteins with high significance and subsequently to rank the signaling pathways those participate in. Results The reported complementary pathway and enriched protein-protein association networks reveal several novel and well-known key players, in the functional background of IBD like Toll-like receptor, TNF, Jak-STAT, PI3K-Akt, T cell receptor, Apoptosis, MAPK and B cell receptor signaling pathways. IBD subphenotypes are found to have distinct genetic and functional profiles which can contribute to their accurate identification and classification. As a secondary result we identify an extended network of diseases with common molecular background to IBD. Conclusions IBD's burden on the quality of life of patients and intricate functional background presents us constantly with new challenges. Our data and methodology provide researchers with new insights to a specific population, but also, to possible differentiation markers of disease classification and progression. This work, not only provides new insights into the interplay among IBD risk variants and their related signaling pathways, elucidates the mechanisms underlying IBD and its clinical sequelae, but also, introduces a generalized bioinformatics-based methodology which can be applied to studies of different disorders.

中文翻译:

希腊人群炎症性肠病表型的差异遗传和功能背景:系统生物信息学方法。

背景克罗恩病 (CD) 和溃疡性结肠炎 (UC) 是炎症性肠病 (IBD) 的两个主要实体。以前的工作已经确定了以欧洲血统为主的人群中的 200 多个风险因素(包括基因座和信号通路)。我们的研究是针对 573 名希腊 IBD 患者(364 名 CD 和 209 名 UC)和 445 名对照的扩展人群特定队列进行的。目的利用当代系统生物信息学方法突出 IBD 的不同遗传和功能背景及其表型。方法 通过我们自己的 89 个位点 IBD 风险 GWAS 面板获得的疾病相关 SNP,使用全基因组关联分析工具集 PLINK 进行检测。这些 SNP 被用作 2 种新颖和不同的途径分析方法的输入,以检测功能相互作用。具体来说,PathwayConnector 用于创建交互路径的互补网络,而;蛋白质相互作用的在线数据库 STRING 提供了蛋白质-蛋白质关联网络及其衍生途径。网络分析指标被用来识别具有重要意义的蛋白质,然后对参与的信号通路进行排名。结果报告的互补通路和丰富的蛋白质-蛋白质关联网络揭示了 IBD 功能背景中的几个新的和众所周知的关键参与者像 Toll 样受体、TNF、Jak-STAT、PI3K-Akt、T 细胞受体、细胞凋亡、MAPK 和 B 细胞受体信号通路。发现 IBD 亚表型具有不同的遗传和功能特征,这有助于它们的准确识别和分类。作为次要结果,我们确定了具有 IBD 共同分子背景的疾病扩展网络。结论 IBD对患者生活质量的负担和错综复杂的功能背景不断给我们带来新的挑战。我们的数据和方法为研究人员提供了对特定人群的新见解,也为疾病分类和进展的可能分化标志物提供了新见解。这项工作不仅为 IBD 风险变异及其相关信号通路之间的相互作用提供了新的见解,阐明了 IBD 的潜在机制及其临床后遗症,而且还介绍了一种基于生物信息学的广义方法,可应用于不同疾病的研究. 患者生活质量的负担和错综复杂的功能背景不断给我们带来新的挑战。我们的数据和方法为研究人员提供了对特定人群的新见解,也为疾病分类和进展的可能分化标志物提供了新见解。这项工作不仅为 IBD 风险变异及其相关信号通路之间的相互作用提供了新的见解,阐明了 IBD 的潜在机制及其临床后遗症,而且还介绍了一种基于生物信息学的广义方法,可应用于不同疾病的研究. 患者生活质量的负担和错综复杂的功能背景不断给我们带来新的挑战。我们的数据和方法为研究人员提供了对特定人群的新见解,也为疾病分类和进展的可能分化标志物提供了新见解。这项工作不仅为 IBD 风险变异及其相关信号通路之间的相互作用提供了新的见解,阐明了 IBD 的潜在机制及其临床后遗症,而且还介绍了一种基于生物信息学的广义方法,可应用于不同疾病的研究. 疾病分类和进展的可能分化标志物。这项工作不仅为 IBD 风险变异及其相关信号通路之间的相互作用提供了新的见解,阐明了 IBD 的潜在机制及其临床后遗症,而且还介绍了一种基于生物信息学的广义方法,可应用于不同疾病的研究. 疾病分类和进展的可能分化标志物。这项工作不仅为 IBD 风险变异及其相关信号通路之间的相互作用提供了新的见解,阐明了 IBD 的潜在机制及其临床后遗症,而且还介绍了一种基于生物信息学的广义方法,可应用于不同疾病的研究.
更新日期:2020-04-22
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