Integrated identification of key immune related genes and patterns of immune infiltration in calcified aortic valvular disease: A network based meta-analysis

Background: As the most prevalent valvular heart disease, calcific aortic valve disease (CAVD) has become a primary cause of aortic valve stenosis and insufficiency. We aim to illustrate the roles of immune related genes (IRGs) and immune cells infiltration in the occurrence of CAVD. Methods: Integrative meta-analysis of expression data (INMEX) was adopted to incorporate multiple gene expression datasets of CAVD from Gene Expression Omnibus (GEO) database. By matching the differentially expressed genes (DEGs) to IRGs from "ImmPort " database, differentially expressed immune related genes (DEIRGs) were screened out. We performed enrichment analysis and found that DEIRGs in CAVD were closely related to inflammatory response and immune cells infiltration. We also constructed protein-protein interaction (PPI) network of DEIRGs and identified 5 key DEIRGs in CAVD according to the mixed character calculation results. Moreover, CIBERSORT algorithm was used to explore the profile of infiltrating immune cells in CAVD. Based on Spearman's rank correlation method, correlation analysis between key DEIRGs and infiltrating immune cells was performed. Results: A total of 220 DEIRGs were identified and the enrichment analysis of DEIRGs showed that they were significantly enriched in inflammatory responses. PPI network was constructed and PTPN11, GRB2, SYK, PTPN6 and SHC1 were identified as key DEIRGs. Compared with normal aortic valve tissue samples, the proportion of neutrophils, T cells CD4 memory activated and macrophages M0 was elevated in calcified aortic valves tissue samples, as well as reduced infiltration of macrophages M2 and NK cells activated. Furthermore, key DEIRGs identified in the present study, including PTPN11, GRB2, PTPN6, SYK, and SHC1, were all significantly correlated with infiltration of various immune cells. Conclusion: This meta-analysis suggested that PTPN11, GRB2, PTPN6, SYK, and SHC1 might be key DEIRGs associated with immune cells infiltration, which play a pivotal role in pathogenesis of CAVD.