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.RNA sequencing by Ion Torrent Proton was performed on BAL cells obtained from 215 well characterised patients with pulmonary sarcoidosis enrolled in the multicenter Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) study. Weighted Gene Co-expression Network Analysis (WGCNA) and non-parametric statistics were used to analyse genome wide BAL transcriptome. Validation of results was performed using a microarray expression data set of an independent sarcoidosis cohort (Freiburg, Germany (n=50)).Our supervised analysis found associations between distinct transcriptional programs and major pulmonary phenotypic manifestations of sarcoidosis including TH1 and TH17 pathways associated with hilar lymphadenopathy, TGFB1 and MTOR signaling with parenchymal involvement, and IL7 and IL2 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 PI3 K activation pathways; chronic and multiorgan disease with increased immune response pathways; and multiorgan 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. Taken together our results identify BAL gene expression programs that characterise major pulmonary sarcoidosis phenotypes and suggest the presence of distinct disease molecular endotypes.
Milica Vukmirovic, Xiting Yan, Kevin F Gibson, Mridu Gulati, Jonas C Schupp, Giuseppe DeIuliis, Taylor S Adams, Buqu Hu, Antun Mihaljinec, Tony N Woolard, Heather Lynn, Nkiruka Emeagwali, Erica L Herzog, Edward S Chen, Alison Morris, Joseph K Leader, Yingze Zhang, Joe G N Garcia, Lisa A Maier, Ronald G Collman, Wonder P Drake, Michael J Becich, Harry Hochheiser, Steven R Wisniewski, Panayiotis V Benos, David R Moller, Antje Prasse, Laura L Koth, Naftali Kaminski, GRADS Investigators