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. 2023 Apr 5:14:1151946.
doi: 10.3389/fneur.2023.1151946. eCollection 2023.

Investigation of shared genes and regulatory mechanisms associated with coronavirus disease 2019 and ischemic stroke

Hao Wu  1 , Fei Han  2
Affiliations

Investigation of shared genes and regulatory mechanisms associated with coronavirus disease 2019 and ischemic stroke

Hao Wu et al. Front Neurol. .

Abstract

Objective: Clinical associations between coronavirus disease (COVID-19) and ischemic stroke (IS) have been reported. This study aimed to investigate the shared genes between COVID-19 and IS and explore their regulatory mechanisms.

Methods: Published datasets for COVID-19 and IS were downloaded. Common differentially expressed genes (DEGs) in the two diseases were identified, followed by protein-protein interaction (PPI) network analysis. Moreover, overlapping module genes associated with the two diseases were investigated using weighted correlation network analysis (WGCNA). Through intersection analysis of PPI cluster genes and overlapping module genes, hub-shared genes associated with the two diseases were obtained, followed by functional enrichment analysis and external dataset validation. Moreover, the upstream miRNAs and transcription factors (TFs) of the hub-shared genes were predicted.

Results: A total of 91 common DEGs were identified from the clusters of the PPI network, and 129 overlapping module genes were screened using WGCNA. Based on further intersection analysis, four hub-shared genes in IS and COVID-19 were identified, including PDE5A, ITGB3, CEACAM8, and BPI. These hub-shared genes were remarkably enriched in pathways such as ECM-receptor interaction and focal adhesion pathways. Moreover, ITGB3, PDE5A, and CEACAM8 were targeted by 53, 32, and 3 miRNAs, respectively, and these miRNAs were also enriched in the aforementioned pathways. Furthermore, TFs, such as lactoferrin, demonstrated a stronger predicted correlation with the hub-shared genes.

Conclusion: The four identified hub-shared genes may participate in crucial mechanisms underlying both COVID-19 and IS and may exhibit the potential to be biomarkers or therapeutic targets for the two diseases.

Keywords: COVID-19; functional enrichment analysis; ischemic stroke; protein–protein interaction; weighted correlation network analysis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Identification of DEGs based on GSE16561 and GSE157103 datasets. (A) Volcano plot of DEGs between IS and normal samples based on the GSE16561 dataset. (B) Volcano plot of DEGs between COVID-19 and normal samples based on the GSE157103 dataset. (C) Venn diagram of up-regulated DEGs identified based on the two datasets. (D) Venn diagram of down-regulated DEGs identified based on the two datasets. DEGs, differentially expressed genes; IS, ischemic stroke; COVID-19, coronavirus disease 2019.
Figure 2
Figure 2
The clusters identified from the PPI network and functional enrichment analysis for cluster genes. (A) Ten clusters were identified from this PPI network. (B) GO term and KEGG pathway enrichment results. PPI, protein–protein interaction; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes.
Figure 3
Figure 3
The relationships between WCGNA modules and clinical features of IS and COVID-19. (A) Heat map of module–trait relationships in IS. (B) Heat map of module–trait relationships in COVID-19. (C) Venn diagram showed the shared genes of IS and COVID-19. WCGNA, Weighted correlation network analysis; IS, ischemic stroke; COVID-19, coronavirus disease 2019.
Figure 4
Figure 4
Functional enrichment analysis for hub shared genes in IS and COVID-19. IS, ischemic stroke; COVID-19, coronavirus disease 2019; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes.
Figure 5
Figure 5
Validation of hub-shared genes in IS and COVID-19 using two external validation datasets GSE22255 and GSE171110. (A) Common DEGs with consistent changes in the expression trends in the two diseases, including 16 up-regulated genes and 36 down-regulated genes. (B) The differential expression of four hub-shared genes (PDE5A, ITGB3, CEACAM8, and BPI) in the GSE171110 dataset. (C) The differential expression of hub-shared genes in the GSE22255 dataset. IS: ischemic stroke; COVID-19: coronavirus disease 2019.
Figure 6
Figure 6
Analysis of upstream miRNAs of hub-shared genes. (A) The miRNA-target network constructed by four hub-shared genes and their predicted miRNAs. (B) GO enrichment results for upstream miRNAs of hub shared genes. (C) KEGG pathway enrichment results for upstream miRNAs of hub-shared genes. GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes.
Figure 7
Figure 7
The TF-gene regulatory network constructed by hub shared genes and the top 10 predicted TFs. TF, transcription factor.
See this image and copyright information in PMC

References

    1. Bedair A, Okasha K, Mansour FR. Spectroscopic methods for COVID-19 detection and early diagnosis. Virol J. (2022) 19:022–01867. doi: 10.1186/s12985-022-01867-2 - DOI - PMC - PubMed
    1. Ahsan H, Arif A, Ansari S, Khan FH. The emergence of Covid-19: evolution from endemic to pandemic. J Immunoass Immunochem. (2022) 43:22–32. doi: 10.1080/15321819.2021.1991947 - DOI - PubMed
    1. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. . Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. (2020a) 323:1061–9. doi: 10.1001/jama.2020.1585, PMID: - DOI - PMC - PubMed
    1. Kim JH, Marks F, Clemens JD. Looking beyond COVID-19 vaccine phase 3 trials. Nat Med. (2021) 27:205–11. doi: 10.1038/s41591-021-01230-y, PMID: - DOI - PubMed
    1. Merkler AE, Parikh NS, Mir S, Gupta A, Kamel H, Lin E, et al. . Risk of ischemic stroke in patients with coronavirus disease 2019 (COVID-19) vs patients with influenza. JAMA Neurol. (2020) 77:1–7. doi: 10.1001/jamaneurol.2020.2730, PMID: - DOI - PMC - PubMed