Researchers Identify Hub Genes STAT1, IRF7, ISG15, MX1, And OAS1 That Increases COVID-19 Severity In Diabetic Kidney Disease Patients
: Researchers from the Autonomous University of Sinaloa – México and the University of Illinois at Urbana–Champaign – USA have identified five hub genes ie STAT1, IRF7, ISG15, MX1, and OAS1 that increases COVID-19 severity in diabetic kidney disease patients.
DKD or Diabetic kidney disease is a frequently chronic kidney pathology derived from diabetes comorbidity. This condition has irreversible damage, and its risk factor increases with SARS-CoV-2 infection. (Note that diabetics who do not have this kidney condition yet can develop it while contracting COVID-19 and also end up developing COVID-19 severity.)
To date, the prognostic outcome for diabetic patients with COVID-19 is dismal, even with intensive medical treatment. However, there is still scarce information on critical genes involved in the pathophysiological impact of COVID-19 on DKD.
The SARS-CoV-2 Research
team characterized differential expression gene (DEG) profiles and determine hub genes undergoing transcriptional reprogramming in both disease conditions.
Out of 995 DEGs, they identified 42 DEGs shared with COVID-19 pathways. Enrichment analysis elucidated that they are significantly induced with implications for immune and inflammatory responses.
By performing a protein-protein interaction (PPI) network and applying topological methods, the study team determined the following five hub genes STAT1, IRF7, ISG15, MX1, and OAS1. Then, by network deconvolution, they determined their co-expressed gene modules.
The study team also validated the conservancy of their upregulation using the Coronascape database (DB).
Tissue-specific regulation of the five predictive hub genes indicates that OAS1 and MX1 expression levels are lower in healthy kidney tissue.
The study findings suggest that these genes could play an essential role in developing severe outcomes of COVID-19 in DKD patients.
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2022.10.11.511826v1
Typically, hub genes are those genes that exhibit many interactions with other genes and, thus, play important roles in regulating vital biological processes.
It is already known that diabetes is a chronic endocrine disease that increases the risk of severe COVID-19. Evidence indicates that hyperinflammation is the primary causative factor of immunological complications during the clinical course of COVID-19. However, it is still uncertain how diabetes may increase the disease risk.
DKD or Diabetic kidney disease, also known as diabetic nephropathy, is a chronic kidney complication caused by hyperglycemia. About 30-40% of diabetic patients live with this health condition, and about 50% eventually develop end-stage kidney disease that requires dialysis or kidney transplantation.
Recent clinical data has highlighted that patients with both diabetic kidney disease and COVID-19 develop multiple pathophysiological mechanisms between the lu
ng and kidney. Patients with end-stage kidney disease also exhibit a higher risk of COVID-19-related mortality.
The study team had conducted transcriptomics and network analysis to identify critical genes shared by the pathways affected by COVID-19 and diabetic kidney disease.
The study team conducted bioinformatics analysis of transcriptomic data obtained from patients with diabetic kidney disease to identify predictive hub genes associated with COVID-19-related diabetic kidney complications.
The researchers characterized the genes that were differentially expressed in both disease conditions. Furthermore, the study team conducted a functional enrichment analysis of differentially expressed genes in the diabetic kidney disease dataset.
In order to identify the hub genes, the study team performed a protein-protein interaction network and topological analysis. Finally, the researchers determined the co-expression modules of the identified hub genes and assessed their tissue-specific regulation.
Altogether, a total of 995 differentially expressed genes were characterized in the diabetic kidney disease dataset. Of these genes, 42 were connected to the COVID-19-related pathways and showed an upregulated expression profile.
Interestingly, a particular group of upregulated differentially expressed genes was connected to the complement and coagulation systems, which are known to associate with the pathophysiological mechanisms of COVID-19.
The study team stressed that the interplay between complement- and coagulation-related biomolecules could significantly worsen COVID-19 outcomes in patients with diabetic kidney disease.
It was also found that another group of upregulated differentially expressed genes showed strong associations with pro-inflammatory, cell activation, oxidative stress, cell adhesion, and apoptosis pathways.
Furthermore, some upregulated genes were found to associate with pathogen recognition receptor pathways, which are the vital components of the innate immune system to fight against invading pathogens.
The study findings indicate that the overactivation of the innate immune system and inflammatory pathways due to aberrant gene expressions may act in a negative synergistic manner to cause the worst COVID-19 outcomes in patients with diabetic kidney disease.
The subsequent protein-protein network analysis identified a particular set of five hub genes, including STAT1, IRF7, ISG15, MX1, and OAS1. Besides being associated with COVID-19- and diabetic kidney disease-related biological and metabolic pathways, these hub genes showed strong connections with heart disease, impaired angiogenesis, and metabolic diseases.
The detailed interactome analysis findings revealed that the hub genes are co-expressed with other genes involved in cardiovascular disease, virus immune response, and genetic regulation at the transcriptional and post-transcriptional levels.
Further tissue-specific expression profile analysis of hub genes revealed that ISG15, STAT1, and MX1 have a consistently upregulated expression profile in the immune cells of COVID-19 patients. In addition, MX1 and OAS1 exhibited a lower expression profile in healthy kidney tissues.
The study team said that persistent activation of immune cells in chronic kidney disease together with higher expression of ISG15, STAT1, and MX1 can lead to higher production of pro-inflammatory cytokines and subsequent worsening of COVID-19 outcomes.
The research findings identify five hub genes that may play crucial roles in worsening COVID-19 outcomes in patients with diabetic kidney disease. These genes are associated with innate immune and inflammatory systems.
The study team says that these genes can serve as potential prognostic or therapeutic targets to facilitate the development of novel drugs against COVID-19.
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