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

• DOI: 10.1164/rccm.202109-2106oc
• Publication Date: 2022-04-08T15:31:10Z
• Authors: Lars Harbaum; Christopher J. Rh...; John Wharton; Allan Lawrie; Jason H. Karnes; Ankit A. Desai; William C. Nichols; Marc Humbert; David Montani; Barbara Girerd; Olivier Sitbon; Mario Boehm; Tatyana Novoyatleva; Ralph T. Schermuly; H. Ardeschir Ghof...; Mark Toshner; David G. Kiely; Luke S. Howard; Emilia M. Swietlik; Stefan Gräf; Maik Pietzner; Nicholas W. Morrell; Martin R. Wilkins; L Southgate; RD Machado; J Martin; WH Ouwehand; MW Pauciulo; A Arora; K Lutz; F Ahmad; SL Archer; R Argula; ED Austin; D Badesch; S Bakshi; C Barnett; R Benza; N Bhatt; CD Burger; M Chakinala; J Elwing; T Fortin; RP Frantz; A Frost; JGN Garcia; J Harley; H He; NS Hill; R Hirsch; D Ivy; J Klinger; T Lahm; K Marsolo; LJ Martin; SD Nathan; RJ Oudiz; Z Rehman; I Robbins; DM Roden; EB Rosenzweig; G Saydain; R Schilz; RW Simms; M Simon; H Tang; AY Tchourbanov; T Thenappan; F Torres; AK Walsworth; RE Walter; RJ White; J Wilt; D Yung; R Kittles; J Aman; J Knight; KB Hanscombe; H Gall; A Ulrich; HJ Bogaard; C Church; JG Coghlan; R Condliffe; PA Corris; C Danesino; CG Elliott; A Franke; S Ghio; JSR Gibbs; AC Houweling; G Kovacs; M Laudes; RV MacKenzie Ross; S Moledina; M Newnham; A Olschewski; H Olschewski; AJ Peacock; J Pepke-Zaba; L Scelsi; W Seeger; CM Shaffer; O Sitbon; J Suntharalingam; C Treacy; A Vonk Noordegraaf; Q Waisfisz; SJ Wort; RC Trembath; M Germain; I Cebola; J Ferrer; P Amouyel; S Debette; M Eyries; F Soubrier; DA Trégouët
• Keywords: Mendelian Randomization; Proteome

Rationale: Pulmonary arterial hypertension (PAH) is characterized by structural remodeling of pulmonary arteries and arterioles. Underlying biological processes are likely reflected in a perturbation circulating proteins. Objectives: To quantify analyze the plasma proteome patients with PAH using inherited genetic variation to inform on underlying molecular drivers. Methods: An aptamer-based assay was used measure proteins 357 idiopathic or heritable PAH, 103 healthy volunteers, 23 relatives PAH. In discovery replication subgroups, proteomes individuals were compared, relationship transplantation-free survival determined. examine causal relationships protein quantitative trait loci (pQTL) that influenced levels patient population as instruments for Mendelian randomization (MR) analysis. Measurements Main Results: From 4,152 annotated proteins, 208 differed between subjects, 49 predicted long-term survival. MR based cis-pQTL located proximity encoding gene prognostic distinguished from health estimated an adverse effect higher netrin-4 (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16–2.08) protective thrombospondin-2 (OR, 0.83; CI, 0.74–0.94) Both tracked development previously changes associated pressure at disease onset. Conclusions: Integrated analysis genome implicates two secreted matrix-binding thrombospondin-2, pathobiology