Mediating Role of Blood Metabolites in the Relationship Between Immune Cell Traits and Heart Failure: A Mendelian Randomization and Mediation Analysis

Background: Observational studies have shown a significant association between immune cells and heart failure (HF). Nevertheless, the precise biological mechanisms underlying this association remain unclear. Methods: To investigate the causative relationships and underlying mechanisms between immune cell traits and adult HF, 3 main methods of Mendelian randomization were used: 2-sample Mendelian randomization, multivariable Mendelian randomization with controlling for several factors affecting HF, and mediation analysis. Results from the inverse variance-weighted model indicated that genetic predispositions for human leukocyte antigen-type DR (HLA DR) on CD33dim HLA DR+ CD11b+ (odds ratio, 0.967 [95% CI, 0.939-0.996]; P=0.028) may be associated with a reduced risk of HF. Although the association between HF and HLA DR on CD33 dim HLA DR+ CD11b+ did not withstand multiple-testing correction, the Mendelian randomization results (P-IVW <0.05) decrease the likelihood that the observational results are due to chance. Results: Our 2-step mediation analysis demonstrated that genetic predispositions for HLA DR on CD33dim HLA DR+ CD11b+ (odds ratio,1.085 [95% CI, 1.020-1.155]; P=0.010) was associated with increased levels of the metabolite Octadecanedioate, while genetic predispositions for Octadecanedioate levels (odds ratio, 0.917 [95% CI, 0.849-0.991]; P=0.028) was associated with a reduced risk of HF. Moreover, our results also demonstrated that the association between HLA DR on CD33dim HLA DR+ CD11b+ and HF was possibly mediated by Octadecanedioate levels, with a mediation proportion of 21.4% [95% CI, 43.7 -0.998]. Conclusions: These findings underscore the importance of HLA DR on CD33dim HLA DR+ CD11b+ in the development of HF, with Octadecanedioate levels acting as a possible mediator in this pathway.