Abstract
BackgroundSurface rupture of carotid plaque can cause severe cerebrovascular disease, including transient ischemic attack and stroke. The aim of this study was to elucidate the molecular mechanism governing carotid plaque progression and to provide candidate treatment targets for carotid atherosclerosis.MethodsThe microarray dataset GSE28829 and the RNA-seq dataset GSE104140, which contain advanced plaque and early plaque samples, were utilized in our analysis. Differentially expressed genes (DEGs) were screened using the “limma” R package. Gene modules for both early and advanced plaques were identified based on co-expression networks constructed by weighted gene co-expression network analysis (WGCNA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes Genomes (KEGG) analyses were employed in each module. In addition, hub genes for each module were identified. Crucial genes were identified by molecular complex detection (MCODE) based on the DEG co-expression network and were validated by the GSE43292 dataset. Gene set enrichment analysis (GSEA) for crucial genes was performed. Sensitivity analysis was performed to evaluate the robustness of the networks that we constructed.ResultsA total of 436 DEGs were screened, of which 335 were up-regulated and 81 were down-regulated. The pathways related to inflammation and immune response were determined to be concentrated in the black module of the advanced plaques. The hub gene of the black module was ARHGAP18 (Rho GTPase activating protein 18). NCF2 (neutrophil cytosolic factor 2), IQGAP2 (IQ motif containing GTPase activating protein 2) and CD86 (CD86 molecule) had the highest connectivity among the crucial genes. All crucial genes were validated successfully, and sensitivity analysis demonstrated that our results were reliable.ConclusionTo the best of our knowledge, this study is the first to combine DEGs and WGCNA to establish a DEG co-expression network in carotid plaques, and it proposes potential therapeutic targets for carotid atherosclerosis.
Highlights
Carotid atherosclerosis is characterized by lipid accumulation and inflammation, which underlie the thickening of the carotid intima where the plaque is formed (Libby et al, 2011)
A differentially expressed gene (DEG) co-expression network was constructed by mapping DEGs into the co-expression network of advanced plaque samples
Crucial genes were obtained based on this DEG co-expression network
Summary
MATERIALS AND METHODSCarotid atherosclerosis is characterized by lipid accumulation and inflammation, which underlie the thickening of the carotid intima where the plaque is formed (Libby et al, 2011). Surface rupture of the plaque leads to abrupt thrombus formation which, in turn, triggers cerebrovascular disease, including transient ischemic attack and stroke (Golledge et al, 2000). A large meta-analysis of GWAS implicated one novel locus (PIK3CG) involved in carotid plaque and eight novel susceptibility loci linked with carotid artery intima thickness (Franceschini et al, 2018). Despite this progress, the molecular mechanisms involved in the formation and progression of carotid plaques have not been fully elucidated. Surface rupture of carotid plaque can cause severe cerebrovascular disease, including transient ischemic attack and stroke. The aim of this study was to elucidate the molecular mechanism governing carotid plaque progression and to provide candidate treatment targets for carotid atherosclerosis
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