Cross-Tissue Regulatory Gene Networks in Coronary Artery Disease.
Cross-Tissue Regulatory Gene Networks in Coronary Artery Disease.
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DOI：
10.1016/j.cels.2016.02.002
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发表时间：
2016-03-23
期刊：
影响因子：
9.3
通讯作者：
Björkegren JL
中科院分区：
文献类型：
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作者：
Talukdar HA;Foroughi Asl H;Jain RK;Ermel R;Ruusalepp A;Franzén O;Kidd BA;Readhead B;Giannarelli C;Kovacic JC;Ivert T;Dudley JT;Civelek M;Lusis AJ;Schadt EE;Skogsberg J;Michoel T;Björkegren JL
推断分子网络可以揭示遗传扰动如何与环境因素相互作用，导致常见的复杂疾病。我们分析了与冠状动脉疾病（CAD）相关的7个组织的遗传和基因表达数据，并确定了调控基因网络（rgn）及其关键驱动因素。通过整合来自全基因组关联研究的数据，我们确定了30个与cad相关的rgn，这些rgn在血管和代谢组织中相互关联，并使用杂交小鼠多样性小组的相应数据对它们进行了验证。为了证明这一概念，通过针对跨物种验证的涉及rna加工基因的动脉壁RGN中的关键驱动因素AIP， DRAP1， POLR2I和PQBP1，我们在THP-1泡沫细胞和CAD巨噬细胞和颈动脉病变的独立数据中重新鉴定了该RGN。这种CAD分子景观的表征将有助于更好地定义由全基因组关联研究鉴定的CAD候选基因的调控，是实现精准医学目标的第一步。
Inferring molecular networks can reveal how genetic perturbations interact with environmental factors to cause common complex diseases. We analyzed genetic and gene expression data from seven tissues relevant to coronary artery disease (CAD) and identified regulatory gene networks (RGNs) and their key drivers. By integrating data from genome-wide association studies, we identified 30 CAD-causal RGNs interconnected in vascular and metabolic tissues, and we validated them with corresponding data from the Hybrid Mouse Diversity Panel. As proof of concept, by targeting the key drivers AIP, DRAP1, POLR2I, and PQBP1 in a cross-species-validated, arterial-wall RGN involving RNA-processing genes, we re-identified this RGN in THP-1 foam cells and independent data from CAD macrophages and carotid lesions. This characterization of the molecular landscape in CAD will help better define the regulation of CAD candidate genes identified by genome-wide association studies and is a first step toward achieving the goals of precision medicine.