Background: Atherosclerotic cardiovascular diseases accounted for a quarter of global deaths. Most of these fatal diseases like coronary atherosclerotic disease (CAD) and stroke occur in the advanced stage of atherosclerosis, during which candidate therapeutic targets have not been fully established. This study aims to identify hub genes and possible regulatory targets involved in treatment of advanced atherosclerotic plaques.

Material/Methods: Microarray dataset GSE43292 and GSE28829, both containing advanced atherosclerotic plaques group and early lesions group, were obtained from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA) was conducted to identify advanced plaque-related modules. Module conservation analysis was applied to assess the similarity of advanced plaque-related modules between GSE43292 and GSE28829. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of these modules were performed by Metascape. Differentially expressed genes (DEGs) were mapped into advanced plaque-related modules and module membership values of DEGs in each module were calculated to identify hub genes. Hub genes were further validated for expression in atherosclerotic samples, for distinguishing capacity of CAD and for potential functions in advanced atherosclerosis.

Results: The lightgreen module (MElightgreen) in GSE43292 and the brown module (MEbrown) in GSE28829 were identified as advanced plaque-related modules. Conservation analysis of these two modules showed high similarity. GO and KEGG enrichment analysis revealed that genes in both MElightgreen and MEbrown were enriched in immune cell activation, secretory granules, cytokine activity, and immunoinflammatory signaling. RBM47, HCK, CD53, TYROBP, and HAVCR2 were identified as common hub genes, which were validated to be upregulated in advanced atherosclerotic plaques, to well distinguish CAD patients from non-CAD people and to regulate immune cell function-related mechanisms in advanced atherosclerosis.

Conclusions: We have identified RBM47, HCK, CD53, TYROBP, and HAVCR2 as immune-responsive hub genes related to advanced plaques, which may provide potential intervention targets to treat advanced atherosclerotic plaques.

背景：动脉粥样硬化性心血管疾病占全球死亡人数的四分之一。这些致命疾病中的大多数，例如冠状动脉粥样硬化疾病（CAD）和中风发生在动脉粥样硬化的晚期，在此期间尚未完全确立候选治疗靶标。这项研究旨在确定中枢基因和可能参与晚期动脉粥样硬化斑块治疗的调控靶标。

材料/方法： 微阵列数据集 GSE43292 和 GSE28829均包含晚期动脉粥样硬化斑块组和早期病变组，均从Gene Expression Omnibus数据库获得。进行加权基因共表达网络分析（WGCNA）以鉴定高级噬斑相关模块。应用模块保守性分析来评估高级斑块相关模块之间的相似性GSE43292 和 GSE28829。这些模块的基因本体论（GO）和《京都基因与基因组百科全书》（KEGG）富集分析由Metascape进行。将差异表达基因（DEG）定位到高级噬菌斑相关模块中，并计算每个模块中DEG的模块隶属度值，以识别轮毂基因。进一步验证了Hub基因在动脉粥样硬化样品中的表达，区分CAD的能力以及晚期动脉粥样硬化的潜在功能。

结果： 浅绿色模块（MElightgreen） GSE43292 和棕色模块（MEbrown）在 GSE28829被确定为与斑块相关的高级模块。这两个模块的保守性分析显示出高度相似性。GO和KEGG富集分析表明，MElightgreen和MEbrown中的基因均富含免疫细胞激活，分泌颗粒，细胞因子活性和免疫炎症信号。RBM47，HCK，CD53，TYROBP和HAVCR2被鉴定为常见的中枢基因，已被证实可在晚期动脉粥样硬化斑块中上调，以区分CAD患者与非CAD患者并调节晚期动脉粥样硬化中与免疫细胞功能相关的机制。

结论： 我们已经鉴定出RBM47，HCK，CD53，TYROBP和HAVCR2是与晚期斑块相关的免疫应答中枢基因，这可能为治疗晚期动脉粥样硬化斑块提供潜在的干预目标。