Identification of novel biomarkers and immune infiltration characteristics of ischemic stroke based on comprehensive bioinformatic analysis and machine learning.

ABSTRACT

Background: Ischemic stroke (IS) is one of most common causes of disability in adults worldwide. However, there is still a lack of effective and reliable diagnostic markers and therapeutic targets in IS. Furthermore, immune cell dysfunction plays an important role in the pathogenesis of IS. Hence, in-depth research on immune-related targets in progressive IS is urgently needed. Methods: Expression profile data from patients with IS were downloaded from the Gene Expression Omnibus (GEO) database. Then, differential expression analysis and weighted gene coexpression network analysis (WGCNA) were performed to identify the significant modules and differentially expressed genes (DEGs). Key genes were obtained and used in functional enrichment analyses by overlapping module genes and DEGs. Next, hub candidate genes were identified by utilizing three machine learning algorithms least absolute shrinkage and selection operator (LASSO), random forest, and support vector machine-recursive feature elimination (SVM-RFE). Subsequently, a diagnostic model was constructed based on the hub genes, and receiver operating characteristic (ROC) curves were constructed to validate the performances of the predictive models and candidate genes. Finally, the immune cell infiltration landscape of IS was explored with the CIBERSORT deconvolution algorithm. Results: A total of 40 key DEGs were identified based on the intersection of the DEGs and module genes, and we found that these genes were mainly enriched in the regulation of lipolysis in adipocytes, neutrophil extracellular trap formation and complement and coagulation cascades. Based on the results from three advanced machine learning algorithms, we obtained 7 hub candidate genes (ABCA1, ARG1, C5AR1, CKAP4, HMFN0839, SDCBP and TLN1) as diagnostic biomarkers of IS and developed a reliable nomogram with high predictive performance (AUC = 0.987). In addition, immune cell infiltration dysregulation was implicated in IS, and compared with those in the normal group, IS patients had increased fractions of gamma delta T cells, monocytes, M0 macrophages, M2 macrophages and neutrophils and clearly lower percentages of naive B cells, CD8 T cells, CD4+ memory T cells, follicular helper T cells, regulatory T cells (Tregs) and resting dendritic cells. Furthermore, correlation analysis indicated a significant correlation between the hub genes and immune cells in progressive IS. Conclusion: In conclusion, our study identified 7 hub genes as diagnostic biomarkers and established a reliable model to predict the occurrence of IS. Meanwhile, we explored the immune cell infiltration pattern and investigated the relationship between candidate genes and immune cells in the pathogenesis of IS. Hence, our study provides new insights into the diagnosis and treatment of IS.