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@article{Rhodes:2020:10.1164/rccm.202003-0510OC,
author = {Rhodes, C and Otero-Núñez, P and Wharton, J and Swietlik, E and Kariotis, S and Harbaum, L and Dunning, M and Elinoff, J and Errington, N and Roger, T and Iremonger, J and Coghlan, G and Corris, P and Howard, L and Kiely, D and Church, C and Pepke-Zaba, J and Toshner, M and Stephen, W and Desai, A and Humbert, M and Nichols, W and Southgate, L and Tregouet, D-A and Trembath, R and Prokopenko, I and Graf, S and Morrell, N and Wang, D and Lawrie, A and Wilkins, M},
doi = {10.1164/rccm.202003-0510OC},
journal = {American Journal of Respiratory and Critical Care Medicine},
pages = {586--594},
title = {Whole blood RNA profiles associated with pulmonary arterial hypertension and clinical outcome},
url = {http://dx.doi.org/10.1164/rccm.202003-0510OC},
volume = {202},
year = {2020}
}

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TY  - JOUR
AB  - 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.
AU  - Rhodes,C
AU  - Otero-Núñez,P
AU  - Wharton,J
AU  - Swietlik,E
AU  - Kariotis,S
AU  - Harbaum,L
AU  - Dunning,M
AU  - Elinoff,J
AU  - Errington,N
AU  - Roger,T
AU  - Iremonger,J
AU  - Coghlan,G
AU  - Corris,P
AU  - Howard,L
AU  - Kiely,D
AU  - Church,C
AU  - Pepke-Zaba,J
AU  - Toshner,M
AU  - Stephen,W
AU  - Desai,A
AU  - Humbert,M
AU  - Nichols,W
AU  - Southgate,L
AU  - Tregouet,D-A
AU  - Trembath,R
AU  - Prokopenko,I
AU  - Graf,S
AU  - Morrell,N
AU  - Wang,D
AU  - Lawrie,A
AU  - Wilkins,M
DO  - 10.1164/rccm.202003-0510OC
EP  - 594
PY  - 2020///
SN  - 1073-449X
SP  - 586
TI  - Whole blood RNA profiles associated with pulmonary arterial hypertension and clinical outcome
T2  - American Journal of Respiratory and Critical Care Medicine
UR  - http://dx.doi.org/10.1164/rccm.202003-0510OC
UR  - https://www.atsjournals.org/doi/10.1164/rccm.202003-0510OC
UR  - http://hdl.handle.net/10044/1/79571
VL  - 202
ER  -

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