Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization

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Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization

Henry, Albert (författare): UCL, Inst Cardiovasc Sci, London, England.;UCL, British Heart Fdn Res Accelerator, London, England.;UCL, Inst Hlth Informat, 222 Euston Rd, London NW1 2DA, England.,Institute of Cardiovascular Science, University College London, London, UK; British Heart Foundation Research Accelerator, University College London, London, UK; Institute of Health Informatics, University College London, London, UK

Gordillo-Maranon, Maria (författare): UCL, Inst Cardiovasc Sci, London, England.;UCL, British Heart Fdn Res Accelerator, London, England.,Institute of Cardiovascular Science, University College London, London, UK; British Heart Foundation Research Accelerator, University College London, London, UK

Finan, Chris (författare): UCL, Inst Cardiovasc Sci, London, England.;UCL, British Heart Fdn Res Accelerator, London, England.;Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands.,Institute of Cardiovascular Science, University College London, London, UK; British Heart Foundation Research Accelerator, University College London, London, UK; Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan, Utrecht, the Netherlands

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Schmidt, Amand F. (författare): UCL, Inst Cardiovasc Sci, London, England.;UCL, British Heart Fdn Res Accelerator, London, England.;Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands.,Institute of Cardiovascular Science, University College London, London, UK; British Heart Foundation Research Accelerator, University College London, London, UK; Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Heidelberglaan, Utrecht, the Netherlands

Ferreira, Joao Pedro (författare): Univ Porto, Unidade Invest & Desenvolvimento Cardiovasc, Rede Invest Saude, Dept Surg & Physiol,Fac Med, Porto, Portugal.;Univ Lorraine, INSERM, Ctr Invest Clin Plurithemat 14 33, Nancy, France.;Ctr Hosp Reg Univ, Inserm U1116, French Clin Res Infrastruct Network, Invest Network Initiat Cardiovasc & Renal Clin Tr, Nancy, France.,Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal; Université de Lorraine, Inserm, Centre d'Investigations Cliniques, Nancy, France

Karra, Ravi (författare): Duke Univ, Med Ctr, Div Cardiol, Dept Med, Durham, NC 27710 USA.;Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA.,Division of Cardiology, Department of Medicine, Duke University Medical Center; Durham; Department of Pathology, Duke University Medical Center; Durham, NC

Sundström, Johan, Professor, 1971- (författare): Uppsala universitet,Klinisk epidemiologi,Univ New South Wales, George Inst Global Hlth, Sydney, NSW, Australia.,Department of Medical Sciences, Uppsala University, Uppsala, Sweden; The George Institute for Global Health, University of New South Wales, Sydney, Australia

Lind, Lars (författare): Uppsala universitet,Klinisk epidemiologi,Department of Medical Sciences, Uppsala University, Uppsala, Sweden

Ärnlöv, Johan, 1970- (författare): Högskolan Dalarna,Karolinska Institutet,Medicinsk vetenskap,Division of Family Medicine and Primary Care, Department of Neurobiology, Care Science and Society, Karolinska Institutet, Huddinge, Sweden

Zannad, Faiez (författare): Univ Lorraine, INSERM, Ctr Invest Clin Plurithemat 14 33, Nancy, France.;Ctr Hosp Reg Univ, Inserm U1116, French Clin Res Infrastruct Network, Invest Network Initiat Cardiovasc & Renal Clin Tr, Nancy, France.

Mälarstig, Anders (författare): Karolinska Inst, Dept Med Epidemiol & Biostat, Solna, Sweden.;Pfizer Worldwide Res Dev & Med, Emerging Sci & Innovat, Cambridge, MA USA.

Hingorani, Aroon D. (författare): UCL, Inst Cardiovasc Sci, London, England.;UCL, British Heart Fdn Res Accelerator, London, England.

Lumbers, R. Thomas (författare): UCL, British Heart Fdn Res Accelerator, London, England.;UCL, Inst Hlth Informat, 222 Euston Rd, London NW1 2DA, England.;UCL, Hlth Data Res UK London, London, England.,British Heart Foundation Research Accelerator, University College London, London, UK; Institute of Health Informatics, University College London, London, UK; Health Data Research UK London, University College London, London, UK

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UCL, Inst Cardiovasc Sci, London, England;UCL, British Heart Fdn Res Accelerator, London, England.;UCL, Inst Hlth Informat, 222 Euston Rd, London NW1 2DA, England. Institute of Cardiovascular Science, University College London, London, UK; British Heart Foundation Research Accelerator, University College London, London, UK; Institute of Health Informatics, University College London, London, UK (creator_code:org_t)

Ovid Technologies (Wolters Kluwer Health), 2022
2022
Engelska.
Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 145:16, s. 1205-1217

Relaterad länk:: https://doi.org/10.1...; visa fler...; https://uu.diva-port... (primary) (Raw object); https://du.diva-port... (primary) (Raw object); https://urn.kb.se/re...; https://doi.org/10.1...; http://kipublication...; https://urn.kb.se/re...; visa färre...

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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<6.0x10(-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.

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Av författaren/redakt...: Henry, Albert; Gordillo-Maranon ...; Finan, Chris; Schmidt, Amand F ...; Ferreira, Joao P ...; Karra, Ravi; visa fler...; Sundström, Johan ...; Lind, Lars; Ärnlöv, Johan, 1 ...; Zannad, Faiez; Mälarstig, Ander ...; Hingorani, Aroon ...; Lumbers, R. Thom ...; visa färre...

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Kardiologi

Artiklar i publikationen: Circulation

Av lärosätet: Uppsala universitet; Karolinska Institutet; Högskolan Dalarna

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Therapeutic Targets for Heart Failure Identified Using Proteomics and Mendelian Randomization

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