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Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

Lookup NU author(s): Dr James Lordan, Emeritus Professor Nick Europe-Finner



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2021, The Author(s).Idiopathic 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.

Publication metadata

Author(s): Kariotis S, Jammeh E, Swietlik EM, Pickworth JA, Rhodes CJ, Otero P, Wharton J, Iremonger J, Dunning MJ, Pandya D, Mascarenhas TS, Errington N, Thompson AAR, Romanoski CE, Rischard F, Garcia JGN, Yuan JX-J, An T-HS, Desai AA, Coghlan G, Lordan J, Corris PA, Howard LS, Condliffe R, Kiely DG, Church C, Pepke-Zaba J, Toshner M, Wort S, Graf S, Morrell NW, Wilkins MR, Lawrie A, Wang D, Bleda M, Hadinnapola C, Haimel M, Auckland K, Tilly T, Martin JM, Yates K, Treacy CM, Day M, Greenhalgh A, Shipley D, Peacock AJ, Irvine V, Kennedy F, Moledina S, MacDonald L, Tamvaki E, Barnes A, Cookson V, Chentouf L, Ali S, Othman S, Ranganathan L, Gibbs JSR, DaCosta R, Pinguel J, Dormand N, Parker A, Stokes D, Ghedia D, Tan Y, Ngcozana T, Wanjiku I, Polwarth G, Mackenzie Ross RV, Suntharalingam J, Grover M, Kirby A, Grove A, White K, Seatter A, Creaser-Myers A, Walker S, Roney S, Elliot CA, Charalampopoulos A, Sabroe I, Hameed A, Armstrong I, Hamilton N, Rothman AMK, Swift AJ, Wild JM, Soubrier F, Eyries M, Humbert M, Montani D, Girerd B, Scelsi L, Ghio S, Gall H, Ghofrani A, Bogaard HJ, Noordegraaf AV, Houweling AC, Veld AH, Schotte G, Trembath RC

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2021

Volume: 12

Issue: 1

Online publication date: 07/12/2021

Acceptance date: 15/11/2021

Date deposited: 13/01/2022

ISSN (electronic): 2041-1723

Publisher: Nature Research


DOI: 10.1038/s41467-021-27326-0


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