The Mediating Factor of Immune Cell in the Causal Relationship Between Cardiovascular Disease‐Related Plasma Proteins and Parkinson’s Disease: A Network Mendelian Randomization Analysis

BACKGROUND: Cardiovascular diseases (CVDs) and their associated plasma proteins exhibit significant correlations with immunity and Parkinson's disease (PD). However, the specific contributions to the risk of developing PD remain unclear. This study aims to investigate the potential causal relationship between CVD-related plasma proteins and the risk of PD and explore the significant mediating role of immune cell phenotypes. METHODS: Using publicly available genetic data, we conducted Mendelian randomization (MR) analysis using the inverse variance weighting method to explore the causal relationship between 83 CVD-related plasma proteins and PD. Various MR analysis models were employed for sensitivity analysis. Concurrently, we utilized bioinformatics methods such as protein-protein interaction networks and pathway enrichment analysis to investigate the potential associations between CVD-related plasma proteins and PD-related genes. Finally, we employed a mediator MR design to identify the mediating effects of 731 immune cell phenotypes in the onset of PD. RESULTS: Elevated levels of Fas cell surface death receptors (p = 0.015) and nerve growth factor (p = 0.026) are associated with a reduced risk of PD, while increased levels of thrombomodulin (p = 0.028) are a risk factor for PD. Four immune phenotypes play a significant mediating role in the association between CVD-related proteins and the pathogenesis of PD. Sensitivity analysis indicates that the results are robust. CONCLUSIONS: Our study elucidates the close genetic association between CVD-related plasma proteins and PD and identifies the significant mediating role of immune cells, thereby providing valuable insights for future research and clinical applications.