Whole-blood RNA profiles associated with pulmonary arterial hypertension and clinical outcome

Christopher J. Rhodes, Pablo Otero-Núñez, John Wharton, Emilia M. Swietlik, Sokratis Kariotis, Lars Harbaum, Mark J. Dunning, Jason M. Elinoff, Niamh Errington, A. A.Roger Thompson, James Iremonger, J. Gerry Coghlan, Paul A. Corris, Luke S. Howard, David G. Kiely, Colin Church, Joanna Pepke-Zaba, Mark Toshner, Stephen J. Wort, Ankit A. DesaiMarc Humbert, William C. Nichols, Laura Southgate, David Alexandre Trégouët, Richard C. Trembath, Inga Prokopenko, Stefan Gräf, Nicholas W. Morrell, Dennis Wang, Allan Lawrie, Martin R. Wilkins

Research output: Contribution to journalArticlepeer-review

43 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)586-594
Number of pages9
JournalAmerican journal of respiratory and critical care medicine
Issue number4
StatePublished - Aug 15 2020


  • Pulmonary arterial hypertension
  • RNAseq
  • Wholeblood RNA

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


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