Dataset Information

Identification of genes and key pathways underlying the pathophysiological association between nonalcoholic fatty liver disease and atrial fibrillation.

ABSTRACT:

Background

Atrial fibrillation (AF) is one of the most prevalent sustained cardiac arrhythmias. The latest studies have revealed a tight correlation between nonalcoholic fatty liver disease (NAFLD) and AF. However, the exact molecular mechanisms underlying the association between NAFLD and AF remain unclear. The current research aimed to expound the genes and signaling pathways that are related to the mechanisms underlying the association between these two diseases.

Materials and methods

NAFLD- and AF- related differentially expressed genes (DEGs) were identified via bioinformatic analysis of the Gene Expression Omnibus (GEO) datasets GSE63067 and GSE79768, respectively. Further enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), the construction of a protein-protein interaction (PPI) network, the identification of significant hub genes, and receiver operator characteristic curve analysis were conducted. The gene-disease interactions were analyzed using the Comparative Toxicogenomics Database. In addition, the hub genes were validated by quantitative Real-Time PCR (qRT-PCR) in NAFLD cell model.

Results

A total of 45 co-expressed differentially expressed genes (co-DEGs) were identified between the NAFLD/AF and healthy control individuals. GO and KEGG pathway analyses revealed that the co-DEGs were mostly enriched in neutrophil activation involved in the immune response and cytokine-cytokine receptor interactions. Moreover, eight hub genes were selected owing to their high degree of connectivity and upregulation in both the NAFLD and AF datasets. These genes included CCR2, PTPRC, CXCR2, MNDA, S100A9, NCF2, S100A12, and S100A8.

Conclusions

In summary, we conducted the gene differential expression analysis, functional enrichment analysis, and PPI analysis of DEGs in AF and NAFLD, which provides novel insights into the identification of potential biomarkers and valuable therapeutic leads for AF and NAFLD.

SUBMITTER: Chu Y

PROVIDER: S-EPMC9258143 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Background: Non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) are major health burdens, with emerging evidence suggesting NAFLD as a significant risk factor for AF, but the mechanism is remain unclear. Methods: In this study, we analyzed gene expression data from NAFLD (GSE89632) and AF (GSE75092) datasets from the Gene Expression Omnibus. We identified co-upregulated and co-downregulated genes between NAFLD and AF, assessed diagnostic potential of specific genes, conducted immune infiltration analysis, and performed molecular docking studies with sodium glucose co-transporter 2 inhibitors (SGLT2i). Results: We identified eight co-upregulated and 31 co-downregulated genes between NAFLD and AF. Genes such as AMOT, PDE11A, TYMS, TMEM98, and PTGS2 demonstrated substantial diagnostic potential for identifying NAFLD patients at risk of AF. Immune infiltration analysis discovered an elevated presence of CD8 T cells, γδ T cells, and M2 macrophages in NAFLD livers, linking systemic inflammation to NAFLD and AF. Additionally, studies have shown that a connection between mitochondrial dysfunction and several hub genes like DGAT1, TYMS, and PTGS2, suggesting that mitochondrial disturbances may underpin the systemic inflammation in NAFLD, which possibly exacerbating AF. Molecular docking studies indicated that empagliflozin's binding affinity with key genes such as DGAT1, TYMS, and PTGS2 presents a novel therapeutic avenue for NAFLD-associated AF. Conclusion: Our study firstly discovered that AMOT, PDE11A, TYMS, TMEM98, and PTGS2 are associated with NAFLD-related AF and hold strong diagnostic values. Our study also indicates that mitochondrial dysfunction and systemic inflammation may be potential mechanisms bridging NAFLD and AF. Additionally, we identified empagliflozin as a potentially effective therapeutic agent for NAFLD-related AF at the molecular structure level. These novel insights contribute to the further understanding, diagnosis, and intervention of NAFLD-related AF.

Project description:BackgroundAtherosclerosis (AS) is one of the leading causes of the cardio-cerebral vascular incident. The constantly emerging evidence indicates a close association between nonalcoholic fatty liver disease (NAFLD) and AS. However, the exact molecular mechanisms underlying the correlation between these two diseases remain unclear. This study proposed exploring the common signature genes, pathways, and immune cells among AS and NAFLD.MethodsThe common differentially expressed genes (co-DEGs) with a consistent trend were identified via bioinformatic analyses of the Gene Expression Omnibus (GEO) datasets GSE28829 and GSE49541, respectively. Further, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed. We utilized machine learning algorithms of lasso and random forest (RF) to identify the common signature genes. Then the diagnostic nomogram models and receiver operator characteristic curve (ROC) analyses were constructed and validated with external verification datasets. The gene interaction network was established via the GeneMANIA database. Additionally, gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and immune infiltration analysis were performed to explore the co-regulated pathways and immune cells.ResultsA total of 11 co-DEGs were identified. GO and KEGG analyses revealed that co-DEGs were mainly enriched in lipid catabolic process, calcium ion transport, and regulation of cytokine. Moreover, three common signature genes (PLCXD3, CCL19, and PKD2) were defined. Based on these genes, we constructed the efficiently predictable diagnostic models for advanced AS and NAFLD with the nomograms, evaluated with the ROC curves (AUC = 0.995 for advanced AS, 95% CI 0.971-1.0; AUC = 0.973 for advanced NAFLD, 95% CI 0.938-0.998). In addition, the AUC of the verification datasets had a similar trend. The NOD-like receptors (NLRs) signaling pathway might be the most crucial co-regulated pathway, and activated CD4 T cells and central memory CD4 T cells were significantly excessive infiltration in advanced NAFLD and AS.ConclusionWe identified three common signature genes (PLCXD3, CCL19, and PKD2), co-regulated pathways, and shared immune features of NAFLD and AS, which might provide novel insights into the molecular mechanism of NAFLD complicated with AS.