Table1_Integrated identification of key immune related genes and patterns of immune infiltration in calcified aortic valvular disease: A network based meta-analysis.DOCX

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.

背景：作为最常见的瓣膜性心脏病，钙化主动脉瓣疾病（CAVD）已成为主动脉瓣狭窄和关闭不全的主要原因。本研究旨在阐述免疫相关基因（IRGs）及免疫细胞浸润在CAVD发生发展中的作用。方法：采用集成性元分析表达数据（INMEX）方法，整合了来自基因表达综合数据库（GEO）的多个CAVD基因表达数据集。通过将差异表达基因（DEGs）与“ImmPort”数据库中的IRGs进行匹配，筛选出差异表达的免疫相关基因（DEIRGs）。进行富集分析，发现CAVD中的DEIRGs与炎症反应和免疫细胞浸润密切相关。同时构建了DEIRGs的蛋白质-蛋白质相互作用（PPI）网络，并根据混合字符计算结果确定了CAVD中的5个关键DEIRGs。此外，利用CIBERSORT算法探索了CAVD中浸润免疫细胞的特征。基于Spearman秩相关方法，对关键DEIRGs与浸润免疫细胞之间的相关性进行了分析。结果：共鉴定出220个DEIRGs，富集分析表明它们在炎症反应中显著富集。构建了PPI网络，并确定了PTPN11、GRB2、SYK、PTPN6和SHC1为关键DEIRGs。与正常主动脉瓣组织样本相比，钙化主动脉瓣组织样本中中性粒细胞、CD4记忆活化T细胞和M0型巨噬细胞的比例升高，而M2型巨噬细胞和活化NK细胞的浸润减少。此外，本研究中鉴定出的关键DEIRGs，包括PTPN11、GRB2、PTPN6、SYK和SHC1，均与各种免疫细胞的浸润显著相关。结论：本次元分析表明，PTPN11、GRB2、PTPN6、SYK和SHC1可能为与免疫细胞浸润相关的关键DEIRGs，在CAVD的发病机制中发挥关键作用。