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Genetic Evidence Linking Inflammatory Cytokines and Blood Metabolites to Heart Failure Risk.
Yanbing Yao1,2,3, Linghui Tang4, Peilin Zhou5
1Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China, gxmu.edu.cn.
Cardiovascular Therapeutics
|May 11, 2026
Summary
This Mendelian randomization study reveals that inflammatory cytokines and metabolites causally influence heart failure (HF) risk. Certain metabolites mediate the effects of cytokines on HF, offering new therapeutic targets.
Area of Science:
- Cardiovascular Genetics
- Metabolomics
- Immunology
Background:
- Heart failure (HF) is a major cause of morbidity and mortality, with inflammation and metabolic dysregulation implicated in its progression.
- Understanding the causal links between inflammatory markers, metabolites, and HF is crucial for developing effective interventions.
- Mendelian randomization (MR) offers a powerful approach to investigate these causal relationships using genetic variants.
Purpose of the Study:
- To elucidate the causal relationships between a wide range of inflammatory cytokines, metabolites, and the risk of heart failure (HF).
- To identify specific inflammatory cytokines and metabolites that causally impact HF development.
- To explore potential mediating roles of metabolites in the association between inflammatory cytokines and HF.
Main Methods:
- A two-sample Mendelian randomization (MR) analysis was conducted using large-scale genome-wide association study data.
- Genetic variants associated with 91 inflammatory cytokines and over 1400 metabolites were used as instrumental variables.
- Data from the FinnGen project (29,672 HF cases, 382,509 controls) were analyzed using inverse variance-weighted and other MR methods, with sensitivity analyses for robustness.
Main Results:
- Eight inflammatory cytokines showed significant causal associations with HF risk; three (FGF19, MMP-1, TNF-β) increased risk, while five (DNER, IL-10, uPA, TNFSF12, LIFR) decreased risk.
- Twelve metabolites were significantly associated with HF risk, with six (2PY, BCG, NAG/NAGal, X-24801, X-21283, X-22776) increasing risk and six (PC, 3HL, 2-BG, X-23659, X-25422, X-24546) showing protective effects.
- Mediation analysis revealed that metabolite X-22776 mediates the effect of cytokine uPA on HF risk.
Conclusions:
- This study provides robust genetic evidence for the causal roles of specific inflammatory cytokines and metabolites in heart failure pathogenesis.
- The findings highlight a potential mediating role of certain metabolites in the pathway from inflammation to heart failure.
- These insights suggest novel biomarkers and therapeutic targets for the prevention and treatment of heart failure.
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