TY - JOUR T1 - Transcriptomics of bronchoalveolar lavage cells identifies new molecular endotypes of sarcoidosis JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.02950-2020 VL - 58 IS - 6 SP - 2002950 AU - Milica Vukmirovic AU - Xiting Yan AU - Kevin F. Gibson AU - Mridu Gulati AU - Jonas C. Schupp AU - Giuseppe DeIuliis AU - Taylor S. Adams AU - Buqu Hu AU - Antun Mihaljinec AU - Tony N. Woolard AU - Heather Lynn AU - Nkiruka Emeagwali AU - Erica L. Herzog AU - Edward S. Chen AU - Alison Morris AU - Joseph K. Leader AU - Yingze Zhang AU - Joe G.N. Garcia AU - Lisa A. Maier AU - Ronald G. Collman AU - Wonder P. Drake AU - Michael J. Becich AU - Harry Hochheiser AU - Steven R. Wisniewski AU - Panayiotis V. Benos AU - David R. Moller AU - Antje Prasse AU - Laura L. Koth AU - Naftali Kaminski A2 - , Y1 - 2021/12/01 UR - http://erj.ersjournals.com/content/58/6/2002950.abstract N2 - Background Sarcoidosis is a multisystem granulomatous disease of unknown origin with a variable and often unpredictable course and pattern of organ involvement. In this study we sought to identify specific bronchoalveolar lavage (BAL) cell gene expression patterns indicative of distinct disease phenotypic traits.Methods RNA sequencing by Ion Torrent Proton was performed on BAL cells obtained from 215 well-characterised patients with pulmonary sarcoidosis enrolled in the multicentre Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Weighted gene co-expression network analysis and nonparametric statistics were used to analyse genome-wide BAL transcriptome. Validation of results was performed using a microarray expression dataset of an independent sarcoidosis cohort (Freiburg, Germany; n=50).Results Our supervised analysis found associations between distinct transcriptional programmes and major pulmonary phenotypic manifestations of sarcoidosis including T-helper type 1 (Th1) and Th17 pathways associated with hilar lymphadenopathy, transforming growth factor-β1 (TGFB1) and mechanistic target of rapamycin (MTOR) signalling with parenchymal involvement, and interleukin (IL)-7 and IL-2 with airway involvement. Our unsupervised analysis revealed gene modules that uncovered four potential sarcoidosis endotypes including hilar lymphadenopathy with increased acute T-cell immune response; extraocular organ involvement with PI3K activation pathways; chronic and multiorgan disease with increased immune response pathways; and multiorgan involvement, with increased IL-1 and IL-18 immune and inflammatory responses. We validated the occurrence of these endotypes using gene expression, pulmonary function tests and cell differentials from Freiburg.Conclusion Taken together, our results identify BAL gene expression programmes that characterise major pulmonary sarcoidosis phenotypes and suggest the presence of distinct disease molecular endotypes.Genome-wide BAL transcriptomics identified novel gene expression profiles associated with distinct phenotypic traits in sarcoidosis and is suggestive of the presence of novel molecular and clinical sarcoidosis endotypes https://bit.ly/3vf7VfT ER -