TY - JOUR
T1 - Mining the Plasma Proteome for Insights into the Molecular Pathology of Pulmonary Arterial Hypertension
AU - Harbaum, Lars
AU - Rhodes, Christopher J.
AU - Wharton, John
AU - Lawrie, Allan
AU - Karnes, Jason H.
AU - Desai, Ankit A.
AU - Nichols, William C.
AU - Humbert, Marc
AU - Montani, David
AU - Girerd, Barbara
AU - Sitbon, Olivier
AU - Boehm, Mario
AU - Novoyatleva, Tatyana
AU - Schermuly, Ralph T.
AU - Ardeschir Ghofrani, H.
AU - Toshner, Mark
AU - Kiely, David G.
AU - Howard, Luke S.
AU - Swietlik, Emilia M.
AU - Graf, Stefan
AU - Pietzner, Maik
AU - Morrell, Nicholas W.
AU - Wilkins, Martin R.
N1 - Publisher Copyright: Copyright © 2022 by the American Thoracic Society
PY - 2022/6/15
Y1 - 2022/6/15
N2 - 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.
AB - 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.
KW - Mendelian randomization
KW - case-control studies
KW - genome
KW - protein quantitative trait loci
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U2 - 10.1164/rccm.202109-2106OC
DO - 10.1164/rccm.202109-2106OC
M3 - Article
C2 - 35394406
SN - 1073-449X
VL - 205
SP - 1449
EP - 1460
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 12
ER -