BACKGROUND Ankylosing spondylitis (AS) is a disease that causes pathological changes in the spine and sacroiliac joints. Numerous studies have shown that the characteristics of AS differ between males and females. The purpose of this study was to discover the key molecules that contribute to sex-associated differences in AS, which may provide a new molecular target for personalized treatment. MATERIAL AND METHODS The gene expression profile of GSE39340 was downloaded from the Gene Expression Comprehensive database, and 2 groups (AS vs. No-AS groups and male AS vs. female AS groups) of differentially expressed genes (EDGs) were obtained by GEO2R. The DAVID database was used for DEGs function and enrichment analysis. Based on data in the STRING online database, a protein-protein interaction (PPI) network was constructed in Cytoscape. Hub genes were selected from CytoHubba. With the intersection of the top 30 hub genes of 2 sets of EDGs, genes coexisting with the KEGG-related pathway were found. RESULTS We screened 560 genes between the AS and No-AS groups, and screened 710 genes that were differentially expressed between the male and female AS groups. GO analysis showed that DEGs were mainly co-enriched in molecular functions, including structural constituent of muscle. The KEGG pathway mainly included the structural constituent of muscle. Seven hub genes were obtained. Troponin C2 and fast skeletal type (TNNC2) were the key genes participating in the calcium signaling pathway. CONCLUSIONS This study contributes to understanding the molecular biological mechanism underlying sex-associated differences in AS. TNNC2 and calcium signaling pathway may be new targets for the individualized treatment of AS.