Henry, Albert, Gordillo-Maranon, Maria, Finan, Chris, Schmidt, Amand F., Ferreira, Joao Pedro, Karra, Ravi, Sundström, Johan, Lind, Lars, Ärnlöv, Johan, Zannad, Faiez, Mälarstig, Anders, Hingorani, Aroon D., Lumbers, R. Thomas, University College of London [London] (UCL), University Medical Center [Utrecht], Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Centre d'investigation clinique plurithématique Pierre Drouin [Nancy] (CIC-P), Centre d'investigation clinique [Nancy] (CIC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Faculdade de Medicina da Universidade do Porto (FMUP), Universidade do Porto = University of Porto, Duke University Medical Center, Uppsala Universitet [Uppsala], University of New South Wales [Sydney] (UNSW), Karolinska Institutet [Stockholm], Dalarna University, Pfizer, This work is supported by the University College London (UCL) Hospitals National Institute for Health Research (NIHR) Biomedical Research Centre, the British Heart Foundation (BHF) Research Accelerator Award (AA/18/6/34223), and UK Research and Innovation / NIHR funded Multimorbidity Mechanism and Therapeutics Research Collaborative (MR/V033867/1). A. H. (FS/18/65/34186) and M.G. (FS/17/70/33482) acknowledge support by the BHF Cardiovascular Biomedicine PhD studentship. A.D.H. is an NIHR Senior Investigator. A.F.S is supported by BHF grant PG/18/503383, and acknowledges support by grant R01 LM010098 from the National Institutes of Health (USA). R.K. acknowledges support by the Walker-Inman Endowment, the Mandel Foundation, and by grant R03 HL144812-01. L.L. is supported by a grant from the Swedish Heart-Lung Foundation. J.Ä. is supported by grants from Swedish Research Council (2019-01015 and 2020-00243), the Swedish Heart-Lung Foundation (20180343 and 20210357). R.T.L. is supported by a UK Research and Innovation Rutherford Fellowship hosted by Health Data Research UK (MR/S003754/1) and BigData@Heart Consortium funded by the Innovative Medicines Initiative-2 Joint Undertaking under grant agreement No. 116074. C.F., A.F.S., and R.T.L. acknowledge additional support from UCL Hospitals NIHR Biomedical Research Centre., and BOZEC, Erwan
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 4 population-based studies, composed of a total of 3019 participants with 732 HF events. The causal effects of HF-associated proteins were then investigated by Mendelian randomization, using cis -protein quantitative loci genetic instruments identified from genomewide association studies in more than 30 000 individuals. To improve the precision of causal estimates, we implemented an Mendelian randomization 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 Mendelian randomization 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 Mendelian randomization analysis. Results: Forty-four of ninety proteins were positively associated with risk of incident HF ( P –4 ). Among these, 8 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 8 showed evidence of a causal relationship and 7 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.