Identification of Key Genes in Atherosclerosis by Combined DNA Methylation and miRNA Expression Analyses

BACKGROUND: Atherosclerosis is a significant cause of coronary heart disease, cerebral infarction, and peripheral vascular disease. The objective of this study was to identify the key genes aberrantly expressed in atherosclerosis, which were regulated by microRNAs and DNA methylation. METHODS: We acquired data on DNA methylation and microRNA and messenger RNA expression from Gene Expression Omnibus data sets (GSE46394, GSE53675, and GSE12288, respectively) and identified differentially methylated genes, differentially expressed genes, and differentially expressed microRNAs between atherosclerosis and control samples. The miRDB, miRTarBase, and TargetScan databases were used to predict differentially expressed microRNAs-targeted genes, which were then intersected with differentially methylated genes and differentially expressed genes to identify genes associated with aberrant DNA methylation and microRNA activity. The DAVID database was used to perform functional enrichment analysis of differentially methylated genes and the key genes involved in atherosclerosis. Potential therapeutic agents for atherosclerosis were predicted by Connectivity Map analysis. RESULTS: In total, we identified 47 upregulated hypomethylated and 90 downregulated hypermethylated genes in atherosclerosis. Among them, 24 differentially expressed genes were found to be modulated both through aberrant DNA methylation and microRNA expression, and 10 such differentially expressed genes were defined as the key genes in atherosclerosis. Fifteen chemicals were selected for their potential effect in atherosclerosis. CONCLUSIONS: We identified 10 key genes significantly associated with aberrant DNA methylation and microRNA expression in atherosclerosis and suggested 15 chemicals with potential effects on these genes, which could be further investigated as candidate drugs for atherosclerosis.