Objective To explore the causal relationship between DNA copy number and the risk of Alzheimer disease (AD) using Mendelian randomization (MR) methods, as well as to investigate the potential mediating effects of immune cells. Methods The data related to 731 immune cell types, DNA copy number and AD from the Genome-Wide Association Study database were collected. A bidirectional MR analysis was conducted to explore the causal relationship between DNA copy number and AD, primarily using the inverse-variance weighted method and MR-Egger method. Additionally, a two-step mediation analysis was performed to identify potential mediating immune cells. Results A total of 134 single-nucleotide polymorphisms were included for bidirectional MR analysis. The MR methods results showed a negative causal relationship between DNA copy number and the risk of AD (P<0.05), while the reverse analysis showed no statistical significance. Sensitivity analysis confirmed the robustness of these results. The mediation analysis indicated that the immune cell phenotype (HVEM on CD45RA-CD4+) partially mediated the causal relationship between DNA copy numbers and the risk of AD, with a mediation effect proportion of 4.6%. Conclusion An increase in DNA copy numbers may reduce the risk of AD, and immune cells partially mediate this causal relationship.
ObjectiveTo explore the causal relationship between immune cells and heart failure (HF), and the mediating role of serum metabolites, in order to identify potential biomarkers and therapeutic targets. MethodsWe employed a two-sample Mendelian randomization (MR) analysis method based on genome-wide association study (GWAS) data, analyzing the direct and indirect effects of 731 types of immune cells and 1 400 metabolites on HF. We selected valid instrumental variables and conducted statistical analyses using R software. The primary analysis was performed using the inverse variance weighted method, supplemented by MR-Egger analysis and weighted median method. The stability of the results was assessed through tests such as Cochran’s Q. ResultsOur research found a negative causal relationship between PD-L1 on CD14−CD16+ and HF. Sensitivity analysis supported this result. The reverse MR analysis did not find an effect of HF on PD-L1 on CD14−CD16+, indicating that PD-L1 on CD14−CD16+ may play a unidirectional role in reducing the risk of HF. Further mediation MR analysis showed that PD-L1 on CD14−CD16+ might influence the risk of HF onset by regulating the levels of sphingomyelin (d17:1/14:0, d16:1/15:0), with a mediation effect ratio of 6.7%. ConclusionPD-L1 on CD14−CD16+ might reduce the risk of HF by elevating the levels of sphingomyelin (d17:1/14:0, d16:1/15:0), providing a new perspective for understanding the pathogenesis of HF.