基于加权基因共表达网络分析腹主动脉瘤免疫细胞浸润相关的关键基因

Identification of key genes associated with immune cell infiltration in abdominal aortic aneurysm by weighted gene co-expression network analysis

目的:通过加权基因共表达网络分析方法筛选参与腹主动脉瘤(AAA)免疫反应机制的关键基因。方法:从Gene Expression Omnibus(GEO)数据库下载人AAA组织基因芯片数据集(GSE7084),其中包含10个正常主动脉样本和9个AAA样本。使用加权基因共表达网络分析(WGCNA)和差异表达基因(DEGs)对样本进行分析。鉴定具有临床意义的模块,并与DEGs取交集,利用最大团中心性(MCC)方法从交集基因中筛选出枢纽基因。同时,利用CIBERSORT分析免疫细胞的富集情况。最后,对枢纽基因与免疫细胞进行相关性分析。结果:筛选出300个DEGs和两个最具临床意义的WGCNA模块。基因本体(GO)富集分析和京都基因与基因组百科全书(KEGG)通路富集分析表明,这些基因在免疫反应的功能通路中显著富集,包括白细胞细胞黏附、活化、T细胞与白细胞的黏附、单核细胞迁移等。AAA和正常主动脉中浸润免疫细胞的比例不同,特别是M0巨噬细胞、活化的肥大细胞和活化的记忆CD4 T细胞。整合素β2亚基(ITGB2)和跨膜免疫信号转接器(TYROBP)是与AAA相关的前2个枢纽基因。相关分析表明,ITGB2、TYROBP与差异表达免疫细胞比例显著正相关。结论:ITGB2和TYROBP与AAA的免疫应答显著相关,可能成为诊断和治疗人AAA潜在新的治疗靶点。

Objective To explore the immune response mechanism and regulatory genes of AAA through weighted gene co-expression networks analysis.Method The GSE7084 dataset related to AAA patients was download from Gene Expression Omnibus(GEO)database containing 10 normal aortic samples and 9 AAA samples.Weighted gene co-expression network analysis(WGCNA)and differentially expressed genes(DEGs)was selected to analyze the samples.Modules with clinical significance were identified,and intersected with DEGs.Gene Ontology and pathway enrichment analysis were conducted,and the hub genes were identified from intersection genes by MCC method.Meanwhile,CIBERSORT was used to analyze the enrichment of immune cells in the AAA and normal aorta samples.Finally,the correlation analysis between hub genes ang immune cells were conducted.Results We identified 300 DEGs and two modules with clinical significance.GO and KEGG enrichment analysis showed that these genes were significantly enriched in functional pathways of immune response,including leukocyte cell-cell adhesion,activation,adhesion of T cell and leukocyte cell,mononuclear cell migration.ITGB2 and TYROBP were the top 2 hub genes in the module correlated with AAA,and the areas under the curve(AUCs)by receiver operating characteristic(ROC)analysis of all the hub genes exceeded 0.9.In addition,we found that the proportions of infiltrating immune cells in AAA and normal aorta were different,especially in terms of M0 macrophages,activated mast cells and activated memory CD4 T cells.The correlation analysis suggested that ITGB2 and TYROBP were significantly positively correlated with the proportion differentially expressed immune cells.Conclusion ITGB2 and TYROBP was significantly correlated with immune response in AAA,and might serve as potential novel therapeutic targets for the diagnosis and treatment of human AAA.