Role of Dendritic Cells in Mediating the Effect of Growth Differentiation Factor 15 on Nonalcoholic Fatty Liver Disease: Insights From Causal Inference and Single-Cell Profiling.

Background: Nonalcoholic fatty liver disease (NAFLD) represents one of the most prevalent chronic liver conditions worldwide. Previous studies have highlighted an association between circulating growth differentiation factor 15 (GDF-15) levels and NAFLD, as well as the involvement of immune cells in its pathogenesis and progression. However, the causal relationships remain unclear. Methods: We obtained summary-level data for circulating GDF-15 levels, NAFLD, and 731 immune cell phenotypes from large-scale genome-wide association studies (GWAS) and the FinnGen database. Mendelian randomization (MR) analysis was employed to explore the causal relationship between circulating GDF-15 levels and NAFLD. Additionally, a two-step MR approach was utilized to identify and assess the mediatory role of immune cells in this association. Finally, single-cell RNA sequencing analysis (scRNA-seq) was performed to validate the proportions of CD123 Results: Two-sample MR analysis revealed that elevated levels of GDF-15 are associated with an increased risk of NAFLD (OR = 1.16; 95% confidence interval [CI] = 1.03-1.30; Conclusions: Our findings propose a causal relationship between GDF-15 and NAFLD mediated by DCs, offering novel insights for potential therapeutic and preventive strategies for NAFLD.