Phosphatidylcholine and frailty: a Mendelian randomization study and immune mediation

OBJECTIVE: Lipid metabolism plays a significant role in the aging process, and the prevalence of frailty increases with advancing age. However, few studies have employed Mendelian randomization (MR) to investigate the associations between lipids and frailty. METHODS: This study utilized large-scale genome-wide association study (GWAS) and a bidirectional two-sample, two-step MR approach to explore the causal associations of 179 lipid species with the frailty index (FI) and the mediating effects of immune cells. The inverse variance weighted (IVW) method was used primarily to evaluate the MR results. Heterogeneity and horizontal pleiotropy were assessed via Cochran's Q, the MR-Egger intercept, MR-PRESSO and leave-one-out analysis. Phenome-wide MR (Phe-MR) was used to analyse the potential roles of frailty-related phosphatidylcholine species in diseases. RESULTS: MR analysis revealed a causal relationship between PC species and FI. Specifically, PC (18:0_20:5), LPC (18:0_0:0), LPC (16:0_0:0), and ether-PC (O-16:0_22:5) are positively correlated with the FI, whereas PC(18:1_20:2), PC(16:0_18:3), PC(16:0_20:1), ether-PC (O-18:0_16:1), and ether-PC (O-16:1_16:0) are negatively correlated with the FI. Reverse MR analysis indicated no strong association between the FI and the nine PCs. Mediation analysis revealed that Sw mem %lymphocyte partially mediated the effect of LPC (18:0_0:0) on FI. Phe-MR analysis revealed that nine frailty-related PCs were broadly associated with various diseases. CONCLUSION: This study provides novel evidence that supports the causal association between PC species and frailty, with the immune system playing a crucial role in this pathway. These findings offer new insights into potential targets for the intervention of frailty in the elderly population.