Rhodes, C.J., Otero-Núñez, P., Wharton, J. et al. (28 more authors) (2020) Whole blood RNA profiles associated with pulmonary arterial hypertension and clinical outcome. American Journal of Respiratory and Critical Care Medicine, 202 (4). pp. 586-594. ISSN 1073-449X
Abstract
Rationale: Idiopathic and hereditary 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 signalling pathways and stratify patients more robustly according to clinical risk.
Objectives: Using a three-stage design of RNA discovery, RNA validation/model construction and model validation to define a set of PAH-associated RNAs and a single summarising RNA model score. To define genes most likely to be involved in disease development, we performed Mendelian randomisation (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 eQTL and summary statistics from a PAH GWAS.
Measurements and Main Results: We identified 507 genes with differential RNA expression in PAH patients compared to controls. A model of 25 RNAs was able to distinguish PAH with 87% accuracy (AUC 95% CI: 0.791-0.945) in model validation. The RNA model score was associated with disease severity and long-term survival (p=4.66x10-6) in PAH. MR detected an association between SMAD5 levels and PAH disease susceptibility (OR:0.317, 95%CI: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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 American Thoracic Society. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/). |
Keywords: | pulmonary arterial hypertension; RNAseq; whole blood RNA |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number British Heart Foundation FS/18/13/33281 and RG68204 13/EE/0203 A092860 Academy Of Medical Sciences SBF004\1052 Medical Research Council MR/K020919/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 06 May 2020 10:10 |
Last Modified: | 22 Nov 2021 12:32 |
Status: | Published |
Publisher: | American Thoracic Society |
Refereed: | Yes |
Identification Number: | 10.1164/rccm.202003-0510oc |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:160368 |