Exploring the intrinsic links between diseases has become an area of close interest for scholars at present.Therefore, interaction between different diseases is a very promising area for future research. SARS-CoV-2 is a virus that causes autoimmune diseases (Halpert and Shoenfeld 2020). Sufficient research evidence suggests that patients have a significantly increased risk of 20 cardiovascular diseases in the year following SARS-CoV-2 infection (Sidik 2022). Recent studies have shown that AF patients with COVID-19 have a higher risk of death (Paris et al. 2021). Based on the large amount of clinical evidence that has been disclosed(Kebria et al. 2022; Wiersinga et al. 2020), the best treatment options for COVID-19 are still being explored, and therefore, the search for more effective and safer therapeutic agents has become a major challenge(Wiersinga et al. 2020). In the present study, 63 differentially expressed genes common to COVID-19 and AF were captured, and we performed a series of analyses on them.
GO analysis showed that inflammatory response, neutrophil chemotaxis, immune response, defense response to bacterium, and cellular response to lipopolysaccharide were the most dominant BP terms. When SARS-CoV-2 enters the body, it can cause inflammatory necrosis in monocytes and macrophages after infecting them, followed by release of powerful inflammatory alarm signals(Junqueira et al. 2022). Lipopolysaccharide, a recognized inflammatory initiator, can increase expression of inflammatory factors by stimulating immune cells and local neighboring tissue cells, which in turn induces a series of immune responses in the host(Simpson and Trent 2019). Neutrophils, as the main cells responding to acute inflammation, mobilize rapidly in response to chemokines(Adrover et al. 2020). Notably, although neutrophils have a role in regulating adaptive immunity, when in an acute severe inflammatory environment triggered by SARS-CoV-2, they uncontrollably release antimicrobial substances that perform antimicrobial defense functions while disrupting subsequent organismal immune functions and further triggering immune paralysis(Adrover et al. 2020; Zonneveld et al. 2016). An overactive cellular defense response may also directly lead to COVID-19 death(Middleton et al. 2020). In terms of the GO CC extracellular region, extracellular space, tertiary granule lumen, integral component of plasma membrane, and external side of plasma membrane ranked as the top 5. Tertiary granules are found mainly in mature neutrophils and serve as a reservoir of extracellular matrix-degrading enzymes and membrane receptors required for neutrophil extravasation and exudation (Jacobsen et al. 2007). The tertiary granule lumen may play an important role in the function of neutrophils in the context of COVID-19. CXCR chemokine receptor binding, protein binding, receptor binding, chemokine activity, receptor activity, and transmembrane signaling were the five most important aspects of GO MF. Chemokines and the CXCR chemokine receptor system are critical in all aspects of immune system function and thus play an important role in pathogen clearance, inflammatory response, wound repair, tumor formation and metastasis (Melchjorsen et al. 2003). Of interest, chemokines have been shown to be directly involved in the different phases of COVID-19, and analysis of chemokines and their receptors during the infection phase will help to determine the possible outcome of COVID-19 and the possibility of complication development (Khalil et al. 2021).
KEGG results showed that 18 pathways were associated with 63 dual disease codifferential genes: Rheumatoid arthritis, Cytokine‒cytokine receptor interaction, Leishmaniasis, Tuberculosis, Viral protein interaction with cytokine and cytokine receptor, Asthma, NF-κB signaling pathway, Graft-versus-host disease, Type l diabetes mellitus, Intestinal immune network for lgA production, Chemokine signaling pathway Inflammatory bowel disease, Pertussis, Antigen processing and presentation, and IL-17 signaling pathway. Once SARS-CoV-2-RNA enters a cell, nucleic acid molecules are recognized, which in turn induces an antiviral response and cytokine production, activating multiple signaling pathways, including the NF-κB signaling pathway (Catanzaro et al. 2020; Gudowska-Sawczuk and Mroczko 2022). NF-κB activates downstream anti-disease molecules and immune cells, promoting pathological inflammation(Mulero et al. 2019). Animal models suggest that inhibition of NF-κB expression may protect the lung and improve survival(Wang et al. 2007). In addition to direct regulation of the immune system by SARS-CoV-2, cytokine storms play a key role in the development of COVID-19 pathology(Catanzaro et al. 2020). COVID-19 cytokine storms can lead to altered vascular permeability, plasma leakage, and diffuse vascular coagulation, which are directly life threatening(Wiersinga et al. 2020). When patients are infected with SARS-CoV-2, IL-17 signaling pathway genes are upregulated in different organs and tissues(Hasan et al. 2021). It has been suggested that IL-17 may play a pathogenic role in the pulmonary inflammation and acute respiratory distress syndrome associated with severe COVID-19. In COVID-19 patients presenting with pulmonary complications, TH17 cell populations are amplified and activated(Mills 2023; Wu et al. 2021).
According to on cytoHubba-MCC, FCGR3B, IL1B, CXCR4, CSF2RB, and SELL were identified as common hub genes for COVID-19 and AF. C-X-C motif chemokine receptor 4 (CXCR4), a representative G protein-coupled receptor (GPCR) member, is present in many tumors; its expression is enhanced, and it plays an important role in mediating tumor-directed migration, invasion and metastasis(Chatterjee et al. 2014). Chemokine CXCL12 is the only ligand for CXCR4 (De Paepe et al. 2004). CXCR4 plays a role in mediating immune and inflammatory responses by binding CXCL12(Asri et al. 2016). In addition, Zou et al. found that CXCR4 is involved in the onset and progression of AF by affecting inflammation-related signaling pathways and may serve as a target for early diagnosis and prophylactic therapy(Zhang et al. 2022). The Fc fragment of IgG receptor IIIb (FCGR3B) has been shown to be upregulated in the macrophage subtype (MoAM_CCL3L1). This is only seen in severe cases of neocrown, which is expected to lead to a severe course of COVID-19 (Nassir et al. 2021). IL-1B, a major cytokine in local and systemic inflammation, is thought to act in the late stages of macrophage recruitment to damaged tissues (Afonina et al. 2015). IL-1B is also thought to be a modulator of the immune response (Tang et al. 2020). The cytokine storm that occurs during COVID-19 involves release of a large number of cytokines and chemokines during activation of the immune system, resulting in an abnormal systemic inflammatory response, which is a key trigger for severe infections and even death(Arena et al. 2022; Hafezi et al. 2021; Spaner et al. 2022). It amplifies activation of monocyte-derived macrophages in an autocrine or paracrine manner, thereby promoting secretion of proinflammatory factors by a variety of immune cells, including CXCL8 and CXCL10, ultimately leading to a cytokine storm (Wahid et al. 2022; Zhu et al. 2022). Colony-stimulating Factor 2 receptor beta (CSF2RB), located on chromosome 22, encodes the β chain of the GM-CSF receptor (Hong et al. 2020). CSF2RB is strongly associated with immune infiltration of lung adenocarcinoma, and its low expression is closely related to late clinicopathological staging and poor prognosis of lung adenocarcinoma patients (Hong et al. 2020). The CSF2RB gene plays an important regulatory role in cell growth, proliferation, invasion and metastasis (Berraondo et al. 2019; Dashti et al. 2018; Dougan et al. 2019). SELL expression is increased in peripheral blood cells of systemic sclerosis (SSc) patients, and it plays an important role in mediating cell adhesion to the vascular endothelium and in the vasculopathy, inflammation and fibrosis of SSc disease(Lambert et al. 2018).
TF is a key cellular component in gene expression regulation(Bartel 2004). In the field of post-transcriptional regulation of RNA silencing and gene expression, microRNAs (miRNAs) play an important role(Rupaimoole and Slack 2017). Their activity determines cellular function and response to environmental perturbations(2019; Bartel 2004; Rupaimoole and Slack 2017). In the present study, CXCR4 was regulated by 1 TF. Studies have demonstrated that COVID-19 can trigger massive inflammation(Wiersinga et al. 2020) and that the CXCR4/CXCL12 axis plays an important role in the whole process of immune and inflammatory responses(Asri et al. 2016). When evaluating miRNA‒mRNA regulatory relationships, hsa-miR-204-5p deserves the most attention because it is closely involved in negative regulation of the inflammatory response, of the IL1B biosynthetic process, and of NIK/NF-κB signaling(Montani et al. 2022). Comprehensive interventions with TF-CXCR4-miRNA may provide new perspectives for clinicians managing patients with AF-associated COVID-19.
To explore the correlation between the 63 DEGs and other diseases, gene-disease analysis was performed. The results revealed various diseases of multiple systems involved in COVID-19, mainly including stomach neoplasms, cardiomyopathy, degenerative polyarthritis, hypertensive disease, hypersensitivity multiple sclerosis, mammary neoplasms, autosomal recessive predisposition, and rheumatoid arthritis, which are mainly related to the digestive, cardiovascular, immune, and reproductive systems. The findings suggest that clinical management of COVID-19 patients with a history of AF must be multidisciplinary. Exploration of various health events related to COVID-19 must be prioritized by investigators.