Journal of the American Heart Association · 2025
Mediating Role of Blood Metabolites in the Relationship Between Immune Cell Traits and Heart Failure: A Mendelian Randomization and Mediation Analysis.
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Liu Yi, Shen Chenfu, Cao Yu
Аннотация
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 (PIVW <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.
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 (PIVW <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.