Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization - Université de Lorraine Accéder directement au contenu
Article Dans Une Revue Circulation Année : 2022

Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization

Albert Henry
Ravi Karra
Lars Lind

Résumé

Background: Heart failure (HF) is a highly prevalent disorder for which disease mechanisms are incompletely understood. The discovery of disease-associated proteins with causal genetic evidence provides an opportunity to identify new therapeutic targets. Methods: We investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity-based proteomic assays. First, we estimated the associations of 90 cardiovascular proteins with incident heart failure by means of a fixed-effect meta-analysis of four population-based studies, comprising a total of 3,019 participants with 732 HF events. The causal effects of HF-associated proteins were then investigated by Mendelian randomization (MR), using cis -protein quantitative loci genetic instruments identified from genome-wide association studies (GWAS) in over 30,000 individuals. To improve the precision of causal estimates, we implemented an MR model that accounted for linkage disequilibrium between instruments and tested the robustness of causal estimates through a multiverse sensitivity analysis that included up to 120 combinations of instrument selection parameters and MR models per protein. The druggability of candidate proteins was surveyed, and mechanism of action and potential on-target side effects were explored with cross-trait MR analysis. Results: 44/90 proteins were positively associated with risk of incident HF (P < 6.0 x 10-4). Among these, eight proteins had evidence of a causal association with HF that was robust to multiverse sensitivity analysis: higher CSF-1 (macrophage colony-stimulating factor 1), Gal-3 (galectin-3) and KIM-1 (kidney injury molecule 1) were positively associated with risk of HF, whereas higher ADM (adrenomedullin), CHI3L1 (chitinase-3-like protein 1), CTSL1 (cathepsin L1), FGF-23 (fibroblast growth factor 23) and MMP-12 (Matrix metalloproteinase-12) were protective. Therapeutics targeting ADM and Gal-3 are currently under evaluation in clinical trials, and all the remaining proteins were considered druggable, except KIM-1. Conclusions: We identified 44 circulating proteins that were associated with incident HF, of which eight showed evidence of a causal relationship and seven were druggable, including adrenomedullin which represents a particularly promising drug target. Our approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases.
Fichier principal
Vignette du fichier
CIRCULATIONAHA.121.056663.pdf (2.67 Mo) Télécharger le fichier
10.1161.circulationaha.121.056663 supplement.pdf (561.64 Ko) Télécharger le fichier
Origine : Fichiers produits par l'(les) auteur(s)

Dates et versions

hal-03613727 , version 1 (18-03-2022)

Identifiants

Citer

Albert Henry, María Gordillo-Marañón, Chris Finan, F Schmidt, João Pedro Ferreira, et al.. Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization. Circulation, 2022, ⟨10.1161/CIRCULATIONAHA.121.056663⟩. ⟨hal-03613727⟩
24 Consultations
38 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More