基于生物信息学分析急性心肌梗死的差异基因及预测潜在治疗药物

Bioinformatics-based analysis of differential genes and prediction of potential therapeutic agents in acute myocardial infarction

目的筛选急性心肌梗死(acute myocardial infarction,AMI)的核心基因,并预测相应基因的潜在治疗药物。方法从基因表达数据库(gene expression omnibus,GEO)中下载数据集GSE24519与GSE66360,筛选AMI与正常对照组的差异表达基因(differentially expressed genes,DEGs),进行基因本体(gene ontology,GO)和京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)富集分析,通过String、Cytoscape构建蛋白质-蛋白质相互作用网络,应用cytoHubba插件筛选出核心基因,并与DGIdb数据库相映射,揭示尚未被充分挖掘的、可能用于治疗AMI的药物靶点及潜在药物候选。结果2组数据集中共有43个基因被鉴定为交集DEGs(P<0.05),包括33个上调基因,10个下调基因;GO分析生物过程主要富集在细胞分化、细胞群增殖的正调控、丝裂原活化蛋白激酶(mitogen-activated protein kinases,MAPK)活性的负调控、细胞因子产生的正调控等;KEGG通路富集分析显示DEGs主要参与了晚期糖基化终末产物-晚期糖基化终末产物受体信号通路、MAPK信号通路等。通过cytoHubba筛选获得5个核心基因(RGS2、DUSP1、JUN、LRRK2、TNFAIP6),用DGIdb数据库预测这些基因相对应的潜在治疗药物,共获得了87个药物或化合物。其中RGS2、DUSP1、JUN及LRRK2分别获得1、15、46和25个药物或化合物,而TNFAIP6并未被预测到相应治疗药物。结论RGS2、DUSP1、JUN、LRRK2、TNFAIP6是AMI发生发展的核心基因;基于数据库预测的靶向DUSP1的羟基脲、伊马替尼,靶向JUN的秋水仙碱以及靶向LRRK2的帕博西尼等药物在治疗AMI方面具有潜在的治疗价值。

Objective To screen for core genes associated with acute myocardial infarction(AMI)and to predict potential therapeutics targeting these genes.Method The dataset GSE24519 and GSE66360 was downloaded from the Gene Expression Omnibus(GEO)and screened for differentially expressed genes(DEGs)between AMI and normal controls for Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG).Protein-Protein Interaction Networks(PPI)were constructed using String and Cytoscape,and the core genes were screened by cytoHubba and mapped to the DGIdb database to reveal the unexplored drug targets and potential drug candidates that may be used for the treatment of AMI.Result A total of 43 genes were identified as intersection DEGs in the two sets of datasets(P<0.05),including 33 up-regulated genes and 10 down-regulated genes.GO analysis revealed that the biological processes were mainly enriched in cell differentiation,positive regulation of cell population proliferation,negative regulation of mitogen-activated protein kinases(MAPK)activity and positive regulation of cytokine production.KEGG pathway enrichment analysis showed that the intersection DEGs were primarily involved in signaling pathways such as advanced glycation end products-receptor for advanced glycation end products(AGE-RAGE)signaling pathway in diabetic complications,and MAPK signaling pathway.Five core genes(RGS2,DUSP1,JUN,LRRK2,and TNFAIP6)were identified through cytoHubba screening,and potential therapeutic drugs corresponding to these genes were predicted using the DGIdb database,of which a total of 87 drugs or compounds were obtained.Among them,1,15,46 and 25 drugs or compounds were obtained for RGS2,DUSP1,JUN and LRRK2,respectively,whereas no corresponding therapeutic drug was predicted for TNFAIP6.Conclusion RGS2,DUSP1,JUN,LRRK2,and TNFAIP6 are the core genes in the development of AMI,and drugs such as hydroxyurea and imatinib targeting DUSP1,colchicine targeting JUN,and paboxinib targeting LRRK2 based on the predictions of databases are potentially therapeutic in the treatment of AMI.