Kariotis, SokratisJammeh, EmmanuelSwietlik, Emilia M.Pickworth, Josephine A.Rhodes, Christopher J.Otero, PabloWharton, JohnIremonger, JamesDunning, Mark J.Pandya, DivyaMascarenhas, Thomas S.Errington, NiamhThompson, A. A. RogerRomanoski, Casey E.Rischard, FranzGarcia, Joe G. N.Yuan, Jason X.-J.Schwantes An, Tae-HwiDesai, Ankit A.Coghlan, GerryLordan, JimCorris, Paul A.Howard, Luke S.Condliffe, RobinKiely, David G.Church, ColinPepke-Zaba, JoannaToshner, MarkWort, StephenGräf, StefanMorrell, Nicholas W.Wilkins, Martin R.Lawrie, AllanWang, DennisUK National PAH Cohort Study Consortium2024-04-252024-04-252021-12-07Kariotis S, Jammeh E, Swietlik EM, et al. Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood [published correction appears in Nat Commun. 2022 Nov 25;13(1):7276]. Nat Commun. 2021;12(1):7104. Published 2021 Dec 7. doi:10.1038/s41467-021-27326-0https://hdl.handle.net/1805/40233Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH.en-USAttribution 4.0 InternationalClassification and taxonomyFunctional clusteringGenomic analysisCardiovascular diseasesArticle