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首页> 外文期刊>PLoS Genetics >Multi-Organ Expression Profiling Uncovers a Gene Module in Coronary Artery Disease Involving Transendothelial Migration of Leukocytes and LIM Domain Binding 2: The Stockholm Atherosclerosis Gene Expression (STAGE) Study
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Multi-Organ Expression Profiling Uncovers a Gene Module in Coronary Artery Disease Involving Transendothelial Migration of Leukocytes and LIM Domain Binding 2: The Stockholm Atherosclerosis Gene Expression (STAGE) Study

机译：多器官表达分析揭示了涉及白细胞经内皮迁移和LIM结构域结合的冠状动脉疾病的基因模块2：斯德哥尔摩动脉粥样硬化基因表达（STAGE）研究

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Environmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n?=?66/tissue) and atherosclerotic and unaffected arterial wall (n?=?40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n?=?15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n?=?3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n?=?49/48) and one visceral fat (n?=?59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P?=?0.008 and P?=?0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably, in one cluster (n?=?55/54) relating to carotid stenosis (P?=?0.04), 27 genes in the two clusters relating to coronary stenosis were confirmed (n?=?16/17, P?27and?30). Genes in the transendothelial migration of leukocytes (TEML) pathway were overrepresented in all three clusters, referred to as the atherosclerosis module (A-module). In a second validation step, using three independent cohorts, the A-module was found to be genetically enriched with CAD risk by 1.8-fold (PLDB2, and by the expression of 13 TEML genes in Ldb2–deficient arterial wall. Thus, the A-module appears to be important for atherosclerosis development and, together with LDB2, merits further attention in CAD research.
机译：通过每个人的基因组成过滤掉的环境暴露会改变代谢稳态中枢器官的转录谱，从而影响动脉脂质的积累，炎症和冠状动脉疾病（CAD）的发展。斯德哥尔摩动脉粥样硬化基因表达（STAGE）研究的主要目的是确定是否存在对CAD发展重要的功能相关基因（而非单个基因）。为此，对从CAD分离的278种肝脏，骨骼肌和内脏脂肪（n？=？66 /组织）和动脉粥样硬化和未受影响的动脉壁（n？=？40 /组织）的转录谱进行了双向聚类。患者在冠状动脉搭桥手术期间。第一步，跨每个组织中的所有mRNA信号（n = 15042/12621 RefSeqs /基因），产生总共60个组织簇（n = 3958个基因）。在第二步中（在组织簇内进行），一个动脉粥样硬化病变（n？=？49/48）和一个内脏脂肪（n？=？59）簇将患者分为两组，其冠状动脉狭窄程度不同（ P≥0.008且P≥0.00015）。通过分析颈动脉粥样硬化表达谱，验证了这些簇与冠状动脉粥样硬化的关联。值得注意的是，在一个与颈动脉狭窄有关的聚类中（n = 55/54）（P = 0.04），在两个与冠状动脉狭窄有关的聚类中已确认了27个基因（n = 16/17，P = 27和。 30）。白细胞的跨内皮迁移（TEML）途径中的基因在所有三个簇中都被过度代表，被称为动脉粥样硬化模块（A-module）。在第二个验证步骤中，使用三个独立的队列，发现A模块在遗传上富含CAD风险1.8倍（PLDB2，并且在Ldb2缺陷的动脉壁中表达了13个TEML基因。） -模块似乎对动脉粥样硬化的发展很重要，并且与LDB2一起在CAD研究中值得进一步关注。

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