ObjectiveTo identify the core genes involved in the great saphenous varicose veins (GSVVs) through bioinformatics methods. MethodsThe transcriptional data of GSVVs tissues and normal great saphenous vein tissues (control tissues) were downloaded from the gene expression omnibus (GEO) database. The single sample gene set enrichment analysis (ssGSEA) was used to calculate Hallmark score. The Weighted Gene Co-expression Network Analysis (WGCNA) combined with machine learning algorithms was used to screen the key genes relevant GSVVs. The protein-protein interaction (PPI) analysis was performed using the String database, and the receiver operating characteristic (ROC) curve was used to reflect the discrimination ability of the target genes for GSVVs. ResultsCompared with the control tissues, there were 548 up-regulated genes and 706 down-regulated genes in the GSVVs tissues, the Hallmark points of KRAS signaling and apical junction were down-regulated, while which of peroxisomes, coagulation, reactive oxygen species pathways, etc. were up-regulated in the GSVVs tissues. A total of 639 differentially expressed genes related to GSVVs were obtained and 165 interaction relation between proteins encoded by 372 genes, and the top 10 genes with the highest betweenness values, ADAM10, APP, NCBP2, SP1, ASB6, ADCY4, HP, UBE2C, QSOX1, and CXCL1, were located at the center of the interaction relation. And the core genes were mainly related to copper ion homeostasis, neutrophil degranulation G protein coupled receptor signaling, response to oxidative stress, and regulation of amide metabolism processes. The SP1 and QSOX1 are both Hub genes. The expressions of the SP1 and QSOX1 in the GSVVs tissues were significantly up-regulated as compared with the control tissues. The area under the ROC curve of SP1 and QSOX1 in distinguishing GSVVs tissues from normal tissues was 0.972 and 1.000, respectively. ConclusionsSP1 and QSOX1 are core genes in the occurrence and development of GSVVs. Regulation of SP1 and QSOX1 genes is expected to achieve precise treatment of GSVVs.