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The rupture of atherosclerotic plaques is essential for cardiovascular and cerebrovascular events. Identification of the key genes related to plaque rupture is an important approach to predict the status of plaque and to prevent the clinical events. In the present study, we downloaded two expression profiles related to the rupture of atherosclerotic plaques (GSE41571 and GSE120521) from GEO database. 11 samples in GSE41571 were used to identify the differentially expressed genes (DEGs) and to construct the weighted gene correlation network analysis (WGCNA) by R software. The gene oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment tool in DAVID website, and the Protein-protein interactions in STRING website were used to predict the functions and mechanisms of genes. Furthermore, we mapped the hub genes extracted from WGCNA to DEGs, and constructed a sub-network using Cytoscape 3.7.2. The key genes were identified by the molecular complex detection (MCODE) in Cytoscape. Further validation was conducted using dataset GSE120521 and human carotid endarterectomy (CEA) plaques. Results: In our study, 868 DEGs were identified in GSE41571. Six modules with 236 hub genes were identified through WGCNA analysis. Among these six modules, blue and brown modules were of the highest correlations with ruptured plaques (with a correlation of 0.82 and −0.9 respectively). 72 hub genes were identified from blue and brown modules. These 72 genes were the most likely ones being related to cell adhesion, extracellular matrix organization, cell growth, cell migration, leukocyte migration, PI3K-Akt signaling, focal adhesion, and ECM-receptor interaction. Among the 72 hub genes, 45 were mapped to the DEGs (logFC > 1.0, p-value < 0.05). The sub-network of these 45 hub genes and MCODE analysis indicated 3 clusters (13 genes) as key genes. They were LOXL1, FBLN5, FMOD, ELN, EFEMP1 in cluster 1, RILP, HLA-DRA, HLA-DMB, HLA-DMA in cluster 2, and SFRP4, FZD6, DKK3 in cluster 3. Further expression detection indicated EFEMP1, BGN, ELN, FMOD, DKK3, FBLN5, FZD6, HLA-DRA, HLA-DMB, HLA-DMA, and RILP might have potential diagnostic value. [ABSTRACT FROM AUTHOR]