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Lookup NU author(s): Emeritus Professor Nick Europe-Finner
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Rationale: Idiopathic and heritable pulmonary arterial hypertension (PAH) are rare but comprise a genetically heterogeneous patient group. RNA sequencing linked to the underlying genetic architecture can be used to better understand the underlying pathology by identifying key signaling pathways and stratify patients more robustly according to clinical risk.Objectives: To use a three-stage design of RNA discovery, RNA validation and model construction, and model validation to define a set of PAH-associated RNAs and a single summarizing RNA model score. To define genes most likely to be involved in disease development, we performed Mendelian randomization (MR) analysis.Methods: RNA sequencing was performed on whole-blood samples from 359 patients with idiopathic, heritable, and drug-induced PAH and 72 age- and sex-matched healthy volunteers. The score was evaluated against disease severity markers including survival analysis using all-cause mortality from diagnosis. MR used known expression quantitative trait loci and summary statistics from a PAH genome-wide association study.Measurements and Main Results: We identified 507 genes with differential RNA expression in patients with PAH compared with control subjects. A model of 25 RNAs distinguished PAH with 87% accuracy (area under the curve 95% confidence interval: 0.791-0.945) in model validation. The RNA model score was associated with disease severity and long-term survival (P = 4.66 × 10-6) in PAH. MR detected an association between SMAD5 levels and PAH disease susceptibility (odds ratio, 0.317; 95% confidence interval, 0.129-0.776; P = 0.012).Conclusions: A whole-blood RNA signature of PAH, which includes RNAs relevant to disease pathogenesis, associates with disease severity and identifies patients with poor clinical outcomes. Genetic variants associated with lower SMAD5 expression may increase susceptibility to PAH.
Author(s): Rhodes CJ, Otero-Nunez P, Wharton J, Swietlik EM, Kariotis S, Harbaum L, Dunning MJ, Elinoff JM, Errington N, Thompson AAR, Iremonger J, Coghlan JG, Corris PA, Howard LS, Kiely DG, Church C, Pepke-Zaba J, Toshner M, Wort SJ, Desai AA, Humbert M, Nichols WC, Southgate L, Tregouet D-A, Trembath RC, Prokopenko I, Graf S, Morrell NW, Wang D, Lawrie A, Wilkins MR
Publication type: Article
Publication status: Published
Journal: American Journal of Respiratory and Critical Care Medicine
Year: 2020
Volume: 202
Issue: 4
Pages: 586-594
Print publication date: 15/08/2020
Online publication date: 30/04/2020
Acceptance date: 29/04/2020
Date deposited: 19/10/2020
ISSN (print): 1073-449X
ISSN (electronic): 1535-4970
Publisher: American Thoracic Society
URL: https://doi.org/10.1164/rccm.202003-0510OC
DOI: 10.1164/rccm.202003-0510OC
PubMed id: 32352834
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