Causal associations of immunophenotypes with metabolic dysfunction-associated fatty liver disease and mediating...

Increasing evidence suggests that immunophenotypes play a crucial role in Metabolic dysfunction-associated fatty liver disease (MAFLD), but the specific immunophenotypes contributing to its pathogenesis remain unclear.

This study aimed to elucidate the causal associations between immunophenotypes and MAFLD and identify the underlying mediation pathways involved.

Mendelian randomization (MR) study.

This study is a quasi-causal inference analysis using univariable and multivariable MR (UVMR and MVMR). Five MAFLD genome-wide association studies (GWASs) and the largest immunophenotype GWAS were analyzed to assess their causal associations. Two-step MR identified potential mediators and quantified their mediation proportions. Comprehensive MR methods, multiple sensitivity analyses, meta-analyses, and false discovery rate (FDR) further enhanced the robustness of our findings.

Pooled inverse-variance weighted (IVW) estimates in UVMR identified 47 immunophenotypes having a suggestive causal association with MAFLD. After adjusting for FDR, three lymphocyte phenotypes remained significant: CD20 on IgD^-CD24^- B cells (OR: 1.035, p _fdr: 0.006), terminally differentiated CD8⁺ T cells %T cells (OR: 1.052, p _fdr: 0.006), and CD4 on CD39⁺ secreting CD4⁺ regulatory T cells (OR: 1.036, p _fdr: 0.046). Meta-analysis of IVW MVMR estimates with confounders adjustment confirmed that CD20 on IgD^-CD24^- B cells and terminally differentiated CD8⁺ T cells %T cells had significant direct causal associations on MAFLD (p _fdr < 0.05). Additionally, two-step MR analysis identified the waist-to-hip ratio as a mediator, accounting for 42.64% of the causal association between CD20 on IgD^-CD24^- B cells and MAFLD.

The causal associations of three lymphocyte phenotypes with increased MAFLD risk were identified in this study. CD20 on IgD^-CD24^- B cells may both directly and indirectly elevate MAFLD risk, while terminally differentiated CD8⁺ T cells have a direct causal relationship with MAFLD. These findings suggest new possibilities for targeted therapies and underscore the potential for personalized immunotherapy in managing MAFLD.