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Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization
Albert Henry1,2,3, María Gordillo-Marañón1,2, Chris Finan1,2,4
1Institute of Cardiovascular Science (A.H., M.G.-M., C.F., A.F.S., A.D.H.), University College London, United Kingdom.
Circulation
|March 18, 2022
Summary
This study identified 44 proteins linked to heart failure (HF), with 8 showing a causal relationship. Adrenomedullin emerged as a promising therapeutic target for HF treatment.
Area of Science:
- Cardiovascular disease research
- Proteomics and genomics
- Drug discovery and development
Background:
- Heart failure (HF) is a widespread condition with incompletely understood disease mechanisms.
- Identifying disease-associated proteins with genetic evidence can reveal new therapeutic targets for HF.
Purpose of the Study:
- To investigate observational and causal associations between 90 cardiovascular proteins and incident heart failure.
- To identify druggable protein targets for potential HF therapies.
Main Methods:
- Meta-analysis of 4 population studies (3019 participants, 732 HF events) to assess protein-HF associations.
- Mendelian randomization using cis-protein quantitative loci from large GWAS (>30,000 individuals) to determine causal effects.
- Multiverse sensitivity analysis and cross-trait analysis to ensure robustness and explore mechanisms.
Main Results:
- 44 of 90 proteins were associated with incident HF risk (P<6.0x10^-4).
- 8 proteins demonstrated a robust causal association with HF: CSF-1, Gal-3, KIM-1 (positively associated), and ADM, CHI3L1, CTSL1, FGF-23, MMP-12 (protective).
- 7 of these proteins were druggable, with ADM and Gal-3 already in clinical trials.
Conclusions:
- Identified 44 circulating proteins associated with incident HF, with 8 showing causal links.
- Highlighted 7 druggable proteins, particularly adrenomedullin (ADM), as promising therapeutic targets for HF.
- Demonstrated a method for integrating genomic and proteomic data to prioritize targets for complex diseases.
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