Role of FGF21 in mediating the effect of phosphatidylcholine on GBM

Objective The causal relationship and mechanisms between lipids and glioblastoma (GBM) remain unclear. This study aims to investigate the independent causal relationship between liposomal phosphatidylcholine 16:0_22:6 (PC16) and GBM, and to identify the potential mediating role of the inflammatory factor-fibroblast growth factor 21(FGF21). Methods Utilizing summary statistics from genome-wide association studies (GWAS) of lipids (179 types in 7174 Finnish individuals), GBM (243 cases and 287137 controls), and inflammatory factors (91 types in 14824 European individuals), a two-sample Mendelian Randomization (MR) approach was employed to establish the causal link between liposomal PC16 and GBM. Additionally, a two-step MR method was used to quantify the proportion of the causal effect of PC16 on GBM that is mediated by the inflammatory factor FGF21. Results MR analyses revealed a strong causal relationship between PC16 and GBM (OR=1.72, 95% CI: 1.11-2.68, P=0.016), but no reverse causality was observed from GBM to PC16 (OR=1.01, 95% CI: 0.99-1.02, P=0.38). Mediation analysis showed a strong causal relationship between PC16 and the FGF21 (OR = 0.94, 95% CI: 0.89-0.99, P=0.018) as well as between FGF21 and GBM (OR = 0.42, 95% CI: 0.25-0.71, P=0.001), with the mediation effect accounting for 9.78% of the total effect. This suggests that the causal relationship between PC16 and GBM is likely mediated by the intermediary factor FGF21. No evidence of pleiotropy was found in the sensitivity analysis of these positive results. Conclusion In summary, the findings of this study suggest that liposomal PC16 may increase the risk of GBM occurrence, and FGF21 may play a significant mediating role in this causal relationship.