Abstract
BACKGROUND: Obstructive sleep apnea (OSA) is linked to metabolic dysfunction-associated fatty liver disease (MAFLD), yet their exact causality and underlying mechanisms remain inconclusive. We aimed to investigate their causal associations and shared biomarkers using Mendelian randomization (MR) and bioinformatics approaches. METHODS: We used OSA-related and MAFLD-related GWAS data to explore their causal relationship and the role of body mass index (BMI) through two-sample and network MR analysis. Gene expression profiles were analyzed to identify intersection genes through differential expression analysis and weighted gene co-expression network analysis (WGCNA). Functional enrichment (GO and KEGG), protein-protein interaction (PPI) networks, and immune cell infiltration analyses (ssGSEA) were performed on the intersecting genes. We then conducted MR analysis to assess the relationship between immune cells and both diseases. Inverse variance weighting (IVW) served as the primary MR method, supplemented by MR-Egger regression, weighted median, and weighted mode. RESULTS: MR analysis revealed that OSA increased the risk of MAFLD [odds ratio (OR)=1.40, 95% CI 1.14-1.73, p= 0.002], with OSA potentially mediating the effect of BMI on MAFLD, accounting for 62.3% of the mediation. Bioinformatics identified 42 intersection genes. Four hub genes (FOS, EGR1, NR4A1, JUN) were ultimately obtained by PPI network, which were strongly linked to immune cell infiltration. Additionally, three immune cell phenotypes (CD4RA on TD CD4+, HLA DR on CD14+ CD16-monocytes, and HLA DR on CD14+ monocytes) were found to be associated with both OSA and MAFLD. CONCLUSION: OSA may causally influence MAFLD and mediate the effect of BMI on MAFLD. Four key genes and three immune cell phenotypes play crucial roles in the shared pathogenesis of both diseases.