Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood
Sokratis Kariotis, Emmanuel Jammeh, Emilia M. Swietlik, Josephine Pickworth, Christopher J. Rhodes, P. Morales Otero, John Wharton, James Iremonger, Mark Dunning, Divya Pandya, Thomas S. Mascarenhas, Niamh Errington, A. A. Roger Thompson, Casey E. Romanoski, Franz Rischard, Joe G. N. Garcia, Jason X.‐J. Yuan, Tae-Hwi Schwantes An, Ankit A. Desai, Gerry Coghlan, Jim Lordan, Paul A. Corris, Luke Howard, Robin Condliffe, David G. Kiely, Colin Church, Joanna Pepke‐Żaba, Mark Toshner, Stephen J. Wort, Stefan Gräf, Nicholas W. Morrell, Martin R. Wilkins, Allan Lawrie, Dennis Wang, Marta Bleda, Charaka Hadinnapola, Matthias Haimel, Kate Auckland, Tobias Tilly, Jennifer M. Martin, Katherine Yates, Carmen Treacy, Margaret Day, Alan Greenhalgh, Debbie Shipley, Andrew J. Peacock, Val Irvine, Fiona Kennedy, Shahin Moledina, Lynsay MacDonald, Eleni Tamvaki, Anabelle Barnes, Victoria Cookson, Latifa Chentouf, Souad Ali, Shokri Othman, Lavanya Ranganathan, J. Simon R. Gibbs, Rosa DaCosta, Joy Pinguel, Natalie Dormand, Alice Parker, Della Stokes, Dipa Ghedia, Yvonne Tan, Tanaka Ngcozana, Ivy Wanjiku, Gary Polwarth, Rob V. Mackenzie Ross, Jay Suntharalingam, Mark Grover, Ali Kirby, Ali Grove, Katie White, A Seatter, Amanda Creaser-Myers, Sara J. Walker, Stephen Roney, Charles Elliot, Athanasios Charalampopoulos, Ian Sabroe, Abdul Hameed, Iain Armstrong, Neil Hamilton, Alexander Rothman, Andrew J. Swift, James M. Wild, Florent Soubrier, Mélanie Eyries, Marc Humbert, David Montani, Barbara Girerd, Laura Scelsi, Stefano Ghio, Henning Gall, Ardi Ghofrani, Harm Jan Bogaard, Anton Vonk Noordegraaf, Arjan C. Houweling, Anna Huis in’t Veld
Abstract
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.