Causal associations of BAFF-R on IgD+ CD24- B cell immune cell trait with hepatocellular carcinoma and the mediating role of phenylacetylglutamate levels: a Mendelian randomization study

Abstract Background We conducted a bi-directional two-sample Mendelian randomization (MR) analysis to investigate the causal associations between immune cell traits and hepatocellular carcinoma (HCC) and identify the mediating factor of metabolites. Methods The exposure factors were immune cell traits, the mediators were metabolites, and the outcome variable was HCC. Inverse-variance weighted method (IVW) was the main method. Weighted median, MR-Egger regression, weighted mode, simple mode, and MR pleiotropy residual sum and outlier (MRPRESSO) methods were used as complementary methods. Subsequently, the potential mediating effect was investigated by conducting a two-step Mediation analysis. Results We found 7 traits with positive correlations and 19 traits with negative correlations between immune cell traits and HCC. There were no causal correlations between HCC and immune cell traits in the reverse MR analysis. In the mediation analysis, we found a positive causal association between B cell-activating factor receptors (BAFF-R) on IgD+ CD24- B cell and HCC [IVW: odd ratio (OR), 0.845; 95% CI, 0.759-0.942; p = 0.002]. Phenylacetylglutamate (PAG) levels mediated 7.353% of the causal pathway from BAFF-R on IgD+ CD24- B cell and HCC. Conclusion BAFF-R on IgD+ CD24- B cell lowers risk of HCC, with PAG levels playing a mediating role.