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Whole Blood RNA Profiles Associated with Pulmonary Arterial Hypertension and Clinical Outcome

dc.rights.licenseopenen_US
dc.contributor.authorRHODES, C. J.
dc.contributor.authorOTERO-NUNEZ, P.
dc.contributor.authorWHARTON, J.
dc.contributor.authorSWIETLIK, E. M.
dc.contributor.authorKARIOTIS, S.
dc.contributor.authorHARBAUM, L.
dc.contributor.authorDUNNING, M. J.
dc.contributor.authorELINOFF, J. M.
dc.contributor.authorERRINGTON, N.
dc.contributor.authorTHOMSON, A. A. R.
dc.contributor.authorIREMONGER, J.
dc.contributor.authorCOGHLAN, J. G.
dc.contributor.authorCORRIS, P. A.
dc.contributor.authorHOWARD, L. S.
dc.contributor.authorKIELY, D. G.
dc.contributor.authorCHURCH, C.
dc.contributor.authorPEPKE-ZABA, J.
dc.contributor.authorTOSHNER, M.
dc.contributor.authorWORT, S. J.
dc.contributor.authorDESAI, A. A.
dc.contributor.authorHUMBERT, M.
dc.contributor.authorNICHOLS, W. C.
dc.contributor.authorSOUTHGATE, L.
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorTREGOUET, David-Alexandre
dc.contributor.authorTREMBATH, R. C.
dc.contributor.authorPROKOPENKO, I.
dc.contributor.authorGRAF, S.
dc.contributor.authorMORRELL, N. W.
dc.contributor.authorWANG, D.
dc.contributor.authorLAWRIE, A.
dc.contributor.authorWILKINS, M. R.
dc.date.accessioned2021-02-25T13:52:05Z
dc.date.available2021-02-25T13:52:05Z
dc.date.issued2020
dc.identifier.issn1535-4970 (Electronic) 1073-449X (Linking)en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/26353
dc.description.abstractEnRationale: 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.
dc.language.isoENen_US
dc.rightsAttribution 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/us/*
dc.subjectVINTAGE
dc.title.enWhole Blood RNA Profiles Associated with Pulmonary Arterial Hypertension and Clinical Outcome
dc.title.alternativeAm J Respir Crit Care Meden_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1164/rccm.202003-0510OCen_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed32352834en_US
bordeaux.journalAmerican Journal of Respiratory and Critical Care Medicineen_US
bordeaux.page586-594en_US
bordeaux.volume202en_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - U1219en_US
bordeaux.issue4en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.teamVINTAGEen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-03152298
hal.version1
hal.date.transferred2021-02-25T13:52:14Z
hal.exporttrue
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