{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:14:42Z","timestamp":1792455282666,"version":"4.5.0"},"reference-count":73,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"16","license":[{"start":{"date-parts":[[2022,4,19]],"date-time":"2022-04-19T00:00:00Z","timestamp":1650326400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2022,4,19]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>cis<\/jats:italic>\n                      -protein quantitative loci genetic instruments identified from genomewide association studies in more than 30\u2009000 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Forty-four of ninety proteins were positively associated with risk of incident HF (\n                      <jats:italic>P<\/jats:italic>\n                      &lt;6.0\u00d710\n                      <jats:sup>\u20134<\/jats:sup>\n                      ). 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.121.056663","type":"journal-article","created":{"date-parts":[[2022,3,18]],"date-time":"2022-03-18T05:30:59Z","timestamp":1647581459000},"page":"1205-1217","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":167,"title":["Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization"],"prefix":"10.1161","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7422-2288","authenticated-orcid":true,"given":"Albert","family":"Henry","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular Science (A.H., M.G.-M., C.F., A.F.S., A.D.H.), University College London, United Kingdom."},{"name":"British Heart Foundation Research Accelerator (A.H., M.G.-M., C.F., A.F.S., A.D.H., R.T.L.), University College London, United Kingdom."},{"name":"Institute of Health Informatics (A.H., R.T.L.), University College London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2993-6577","authenticated-orcid":true,"given":"Mar\u00eda","family":"Gordillo-Mara\u00f1\u00f3n","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Science (A.H., M.G.-M., C.F., A.F.S., A.D.H.), University College London, United Kingdom."},{"name":"British Heart Foundation Research Accelerator (A.H., M.G.-M., C.F., A.F.S., A.D.H., R.T.L.), University College London, United Kingdom."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Finan","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Science (A.H., M.G.-M., C.F., A.F.S., A.D.H.), University College London, United Kingdom."},{"name":"British Heart Foundation Research Accelerator (A.H., M.G.-M., C.F., A.F.S., A.D.H., R.T.L.), University College London, United Kingdom."},{"name":"Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, The Netherlands (C.F., A.F.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amand F.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Science (A.H., M.G.-M., C.F., A.F.S., A.D.H.), University College London, United Kingdom."},{"name":"British Heart Foundation Research Accelerator (A.H., M.G.-M., C.F., A.F.S., A.D.H., R.T.L.), University College London, United Kingdom."},{"name":"Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, The Netherlands (C.F., A.F.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2304-6138","authenticated-orcid":true,"given":"Jo\u00e3o Pedro","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Unidade de Investiga\u00e7\u00e3o e Desenvolvimento Cardiovascular, Rede de Investiga\u00e7\u00e3o em Sa\u00fade, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Portugal (J.P.F.)."},{"name":"Universit\u00e9 de Lorraine, Inserm, Centre d\u2019Investigations Cliniques - 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