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 c...
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Wiley
2025-03-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.124.037265 |
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| author | Yi Liu Chenfu Shen Yu Cao |
| author_facet | Yi Liu Chenfu Shen Yu Cao |
| author_sort | Yi Liu |
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| description | 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. |
| format | Article |
| id | doaj-art-c9d4b27f518e4eb0b0e074cdb5ce9e98 |
| institution | OA Journals |
| issn | 2047-9980 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Wiley |
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| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj-art-c9d4b27f518e4eb0b0e074cdb5ce9e982025-08-20T02:34:35ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802025-03-0114610.1161/JAHA.124.037265Mediating Role of Blood Metabolites in the Relationship Between Immune Cell Traits and Heart Failure: A Mendelian Randomization and Mediation AnalysisYi Liu0Chenfu Shen1Yu Cao2Department of Emergency Medicine, Laboratory of Emergency Medicine West China Hospital, West China School of Medicine, Sichuan University Chengdu ChinaDepartment of Neurosurgery Xiangya Hospital, Central South University Changsha Hunan ChinaDepartment of Emergency Medicine, Laboratory of Emergency Medicine West China Hospital, West China School of Medicine, Sichuan University Chengdu ChinaBackground 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.https://www.ahajournals.org/doi/10.1161/JAHA.124.037265blood metabolitesHFimmune cellmediation analysisMendelian randomization |
| spellingShingle | Yi Liu Chenfu Shen Yu Cao Mediating Role of Blood Metabolites in the Relationship Between Immune Cell Traits and Heart Failure: A Mendelian Randomization and Mediation Analysis Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease blood metabolites HF immune cell mediation analysis Mendelian randomization |
| title | Mediating Role of Blood Metabolites in the Relationship Between Immune Cell Traits and Heart Failure: A Mendelian Randomization and Mediation Analysis |
| title_full | Mediating Role of Blood Metabolites in the Relationship Between Immune Cell Traits and Heart Failure: A Mendelian Randomization and Mediation Analysis |
| title_fullStr | Mediating Role of Blood Metabolites in the Relationship Between Immune Cell Traits and Heart Failure: A Mendelian Randomization and Mediation Analysis |
| title_full_unstemmed | Mediating Role of Blood Metabolites in the Relationship Between Immune Cell Traits and Heart Failure: A Mendelian Randomization and Mediation Analysis |
| title_short | Mediating Role of Blood Metabolites in the Relationship Between Immune Cell Traits and Heart Failure: A Mendelian Randomization and Mediation Analysis |
| title_sort | mediating role of blood metabolites in the relationship between immune cell traits and heart failure a mendelian randomization and mediation analysis |
| topic | blood metabolites HF immune cell mediation analysis Mendelian randomization |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.124.037265 |
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