Comprehensive analysis of shared risk genes and immunity-metabolisms between non-alcoholic fatty liver disease and atherosclerosis via bulk and single-cell transcriptome analyses.

OBJECTIVE

and design: Considering the clinical link between non-alcoholic fatty liver disease (NAFLD) and atherosclerosis (AS), we performed bioinformatics analysis to uncover their pathogenic interrelationship.

METHODS AND RESULTS

Data from the U.S. National Health and Nutritional Examination Survey (NHANES) 1999-2018 were included. Among 4851 participants in NHANES, NAFLD was significantly associated with atherosclerotic cardiovascular disease risk (ASCVD risk) (OR = 2.32, 95%CI: 2.04-2.65, P < 0.0001). We conducted WGCNA analysis for NAFLD (GSE130970) and AS (GSE28829) and identified three modules positively related to NAFLD severity and two modules accelerating atherosclerosis plaque progression. 198 key-modules genes were obtained via overlapping these modules. Next, we mined the disease-controlled differentially expressed genes (DEGs) from NAFLD (GSE89632) and AS (GSE100927), respectively. The final common risk genes (, , , , , , and ) were defined by intersecting the upregulated DEGs with 198 genes and validated in new datasets (GSE48452 and GSE43292). Importantly, they showed good diagnostic ability for NAFLD and AS. Immune infiltration analysis showed both illnesses have dysregulated immunity. Analysis of single-cell sequencing datasets NAFLD (GSE179886) and AS (GSE159677) uncovered different abnormal expressions of seven common genes in different immune cells while highlighting metabolic disturbances including upregulation of fatty acid biosynthesis, downregulation of fatty acid degradation and elongation.

CONCLUSION

We found 7 shared hub genes with good diagnostic ability and depicted the landscapes of immune and metabolism involved in NAFLD and AS. Our results provided a comprehensive association between them and may contribute to developing potential intervention strategies for targeting both disorders based on these risk factors.