基于生物信息学分析2型糖尿病动脉粥样硬化患者的铁死亡相关基因

Bioinformatics analysis of ferroptosis-related genes in patients with atherosclerosis in type 2 diabetes mellitus

目的:基于生物信息学探讨铁死亡(ferroptosis)参与2型糖尿病(type 2 diabetes mellitus,T2DM)患者发生动脉粥样硬化(atherosclerosis,AS)的枢纽基因和潜在机制。方法:从GEO数据库中获取数据集GSE20966(T2DM)和GSE43292(AS),利用Limma R包鉴定差异表达基因(differentially expressed genes,DEGs),绘制热图和火山图,交叉分析获得与2种疾病相关的DEGs;进行GO和KEGG富集分析探寻DEGs的生物功能。交联从FerrDb数据库获取的铁死亡相关基因(ferroptosis-related genes,FRGs),利用LASSO回归和随机森林分析筛选枢纽基因,使用ROC曲线以及验证集GSE76895(T2DM)和GSE28829(AS)进行验证。最后绘制基因-miRNA网络分析枢纽基因的作用机制。结果:在T2DM和AS数据集中共鉴定出606个相关DEGs。与FRGs交联获得了20个潜在相关基因。细胞周期蛋白依赖性激酶抑制因子1A(cyclin-depedent kinase inhibitors 1A,CDKN1A)、聚腺苷二磷酸核糖聚合酶8(poly ADP-ribose polymerase 8,PARP8)、磷脂酰乙醇胺结合蛋白1(phosphatidylethanolamine binding protein 1,PEBP1)和孕酮受体膜成分1(progesterone receptor membrane component 1,PGRMC1)是铁死亡参与T2DM患者AS的枢纽基因。4个基因在数据集GSE20966和GSE43292中ROC曲线下面积(area under the curve,AUC)均大于0.7,具有诊断价值。PEBP1和PGRMC1在验证集GSE76895和GSE28829中显著下调。此外,13个miRNAs与4个枢纽基因密切相关。结论:CDKN1A、PARP8、PEBP1和PGRMC1通过铁死亡参与T2DM患者AS,有望成为新的治疗靶点。

Objective:To explore the hub genes and potential mechanism of ferroptosis in the development of atherosclerosis(AS)in patients with type 2 diabetes mellitus(T2DM)based on bioinformatics.Methods:The datasets GSE20966(T2DM)and GSE43292(AS)were obtained from the GEO database.Differentially expressed genes(DEGs)were identified using the Limma R package.Heatmaps and volcano plots were drawn,and cross-analysis was performed to obtain DEGs associated with the two diseases.GO and KEGG enrichment analysis was performed to explore the biological functions of DEGs.Ferroptosis-related genes(FRGs)obtained from the FerrDb database were cross-linked,and hub genes were screened using LASSO regression and random forest analysis.ROC curves and validation sets GSE76895(T2DM)and GSE28829(AS)were used for verification.Finally,the gene-miRNA network was drawn.Results:A total of 606 DEGs were identified related to the T2DM and the AS datasets.Twenty potential genes were obtained by cross-analyzing with FRGs.Cyclin-depedent kinase inhibitors 1A(CDKN1A),poly ADP-ribose polymerase 8(PARP8),phosphatidylethanolamine binding protein 1(PEBP1),and progesterone receptor membrane component 1(PGRMC1)were hub genes that affected AS in T2DM patients through ferroptosis.The area under the curve(AUC)of the ROC curves in the datasets GSE20966 and GSE43292 of the four genes was all greater than 0.7,which had diagnostic value.PEBP1 and PGRMC1 were significantly down-regulated in the validation sets GSE76895 and GSE28829.In addition,13 miRNAs were closely associated with 4 hub genes.Conclusion:CDKN1A,PARP8,PEBP1 and PGRMC1 are involved in AS in T2DM patients through ferroptosis and may become new therapeutic targets.