Mining the Plasma Proteome for Insights into the Molecular Pathology of Pulmonary Arterial Hypertension.

Autor:	Harbaum L; National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom., Rhodes CJ; National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom., Wharton J; National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom., Lawrie A; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Medical School, Sheffield, United Kingdom., Karnes JH; Department of Pharmacy Practice and Science, University of Arizona College of Pharmacy, Tucson, Arizona., Desai AA; Department of Medical and Molecular Genetics, and Krannert Institute of Cardiology, Department of Medicine, Indiana University, Indianapolis, Indiana., Nichols WC; Division of Human Genetics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio., Humbert M; Université Paris-Saclay, AP-HP, INSERM UMR_S 999, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, Hôpital de Bicêtre, Le Kremlin Bicêtre, France., Montani D; Université Paris-Saclay, AP-HP, INSERM UMR_S 999, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, Hôpital de Bicêtre, Le Kremlin Bicêtre, France., Girerd B; Université Paris-Saclay, AP-HP, INSERM UMR_S 999, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, Hôpital de Bicêtre, Le Kremlin Bicêtre, France., Sitbon O; Université Paris-Saclay, AP-HP, INSERM UMR_S 999, Department of Respiratory and Intensive Care Medicine, Pulmonary Hypertension National Referral Centre, Hôpital de Bicêtre, Le Kremlin Bicêtre, France., Boehm M; Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany., Novoyatleva T; Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany., Schermuly RT; Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany., Ghofrani HA; Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany., Toshner M; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom., Kiely DG; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Medical School, Sheffield, United Kingdom., Howard LS; National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom., Swietlik EM; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom., Gräf S; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.; National Institute for Health Research BioResource for Translational Research, University of Cambridge, Cambridge, United Kingdom.; Department of Haematology, University of Cambridge, Cambridge, United Kingdom., Pietzner M; Computational Medicine, Berlin Institute of Health (BIH) at Charité-Universitätsmedizin Berlin, Germany; and.; Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom., Morrell NW; Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom., Wilkins MR; National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom.
Jazyk:	angličtina
Zdroj:	American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2022 Jun 15; Vol. 205 (12), pp. 1449-1460.
DOI:	10.1164/rccm.202109-2106OC
Abstrakt:	Rationale: Pulmonary arterial hypertension (PAH) is characterized by structural remodeling of pulmonary arteries and arterioles. Underlying biological processes are likely reflected in a perturbation of circulating proteins. Objectives: To quantify and analyze the plasma proteome of patients with PAH using inherited genetic variation to inform on underlying molecular drivers. Methods: An aptamer-based assay was used to measure plasma proteins in 357 patients with idiopathic or heritable PAH, 103 healthy volunteers, and 23 relatives of patients with PAH. In discovery and replication subgroups, the plasma proteomes of PAH and healthy individuals were compared, and the relationship to transplantation-free survival in PAH was determined. To examine causal relationships to PAH, protein quantitative trait loci (pQTL) that influenced protein levels in the patient population were used as instruments for Mendelian randomization (MR) analysis. Measurements and Main Results: From 4,152 annotated plasma proteins, levels of 208 differed between patients with PAH and healthy subjects, and 49 predicted long-term survival. MR based on cis -pQTL located in proximity to the encoding gene for proteins that were prognostic and distinguished PAH from health estimated an adverse effect for higher levels of netrin-4 (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.08) and a protective effect for higher levels of thrombospondin-2 (OR, 0.83; 95% CI, 0.74-0.94) on PAH. Both proteins tracked the development of PAH in previously healthy relatives and changes in thrombospondin-2 associated with pulmonary arterial pressure at disease onset. Conclusions: Integrated analysis of the plasma proteome and genome implicates two secreted matrix-binding proteins, netrin-4 and thrombospondin-2, in the pathobiology of PAH.
Databáze:	MEDLINE
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