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. 2022 Jul 5;15(1):150.
doi: 10.1186/s12920-022-01300-1.

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

Yanan Chu  1 , Fangcong Yu  1 , Yakui Wu  1 , Jinxiu Yang  1 , Jiaran Shi  1 , Tianxin Ye  1 , Deheng Han  1 , Xingxiang Wang  2
Affiliations

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

Yanan Chu et al. BMC Med Genomics. .

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.

Keywords: Atrial fibrillation; Bioinformatic technology; Differentially expressed genes; Hub genes; Nonalcoholic fatty liver disease.

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Conflict of interest statement

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

Figures

Fig. 1
Fig. 1
Flow diagram of the study design. NAFLD, nonalcoholic fatty liver disease; AF, atrial fibrillation; DEGs, differentially expressed genes; co-DEGs, co-expressed differentially expressed genes; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; PPI, protein–protein interaction
Fig. 2
Fig. 2
A Volcano plot of DEGs in AF. Blue represents downregulated DEGs, red represents upregulated DEGs, and black represents no difference. B Heatmap of the DEGs in AF patients compared with normal controls. C Volcano plot of DEGs in NAFLD. Blue represents downregulated DEGs, red represents upregulated DEGs, and black represents no difference. D Heatmap of the DEGs in NAFLD patients compared with normal controls. E Venn diagram of co-DEGs from the intersection of two independent datasets GSE79768 and GSE63067. DEGs, differentially expressed genes; AF, atrial fibrillation; NAFLD, nonalcoholic fatty liver disease
Fig. 3
Fig. 3
The enrichment analysis of co-DEGs by the R package clusterProfiler and Metascape. Detailed information relating to GO term enrichment in A BP, CC, and MF. B KEGG analysis for co-DEGs. C Heatmap of enriched terms across the co-DEGs via the online program Metascape
Fig. 4
Fig. 4
The PPI network of the co-DEGs, the hub gene network, the correlation analyses among the hub genes, and the expression profile analyses of the hub genes. A The PPI network includes 54 edges and 26 nodes. B The hub gene network (S100A12, CXCR2, MNDA, S100A8, NCF2, CCR2, S100A9, PTPRC, CCL20, and CXCL1). C The Circos plot showing that there are intense correlations among the hub genes in GSE79768. D Significant correlations among the hub genes were also performed in the GSE63067 dataset. E The expression profile of the hub genes for the control and AF samples in GSE79768. F The expression profile of the hub genes for the healthy group and NAFLD samples in GSE63067. Red indicates that gene expression is upregulated, and blue indicates that gene expression is downregulated. In the same color, the darker the color, the more significant it was
Fig. 5
Fig. 5
The relationship between hub gene expression and AF using the method of binomial logistic regression for generalized linear models. A CCR2, B CXCR2, C MNDA, D NCF2, E PTPRC, F S100A8, G S100A9, and H S100A12
Fig. 6
Fig. 6
The enrichment analysis results of the hub genes. Specific information related to GO enrichment for the hub genes, including A BP, CC, and MF. B KEGG analysis for the hub genes
Fig. 7
Fig. 7
The ROC curves of the hub genes for AF. A S100A12, B CXCR2, C MNDA, D S100A8, E NCF2, F CCR2, G S100A9, and H PTPRC
Fig. 8
Fig. 8
Relationships between the hub genes and liver or cardiovascular diseases identified in the CTD database. A CCR2, B PTPRC, C CXCR2, D MNDA, E S100A9, F NCF2, G S100A12, and H S100A8. NAFLD, nonalcoholic fatty liver disease
Fig. 9
Fig. 9
The mRNA expression levels of 8 hub genes were measured in NAFLD cell model and control group. A CCR2, B CXCR2, C NCF2, D S100A9, E S100A12, F PTPRC. * P < 0.05; ** P < 0.01; **** P < 0.0001. Abbreviation: ns, non-significant
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