Transcriptomics of bronchoalveolar lavage cells identifies new molecular endotypes of sarcoidosis

Details

• Alternative Title:
  Eur Respir J
• Personal Author:
  Vukmirovic, Milica ; Yan, Xiting ; Gibson, Kevin F. ; Gulati, Mridu ; Schupp, Jonas C. ; DeIuliis, Giuseppe ; Adams, Taylor S. ; Hu, Buqu ; Mihaljinec, Antun ; Woolard, Tony N. ; Lynn, Heather ; Emeagwali, Nkiruka ; Herzog, Erica L. ; Chen, Edward S. ; Morris, Alison ; Leader, Joseph K. ; Zhang, Yingze ; Garcia, Joe G.N. ; Maier, Lisa A. ; Collman, Ronald G. ; Drake, Wonder P. ; Becich, Michael J. ; Hochheiser, Harry ; Wisniewski, Steven R. ; Benos, Panayiotis V. ; Moller, David R. ; Prasse, Antje ; Koth, Laura L. ; Kaminski, Naftali
• Description:
  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.
  
  
• Subjects:
  Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid Humans Sarcoidosis Sarcoidosis, Pulmonary Transcriptome
• Source:
  Eur Respir J. 58(6)
• Pubmed ID:
  34083402
• Pubmed Central ID:
  PMC9759791
• Document Type:
  Journal Article
• Funding:
  U01 HL112694/HL/NHLBI NIH HHSUnited States/ ; R01 HL140357/HL/NHLBI NIH HHSUnited States/ ; U01 HL112711/HL/NHLBI NIH HHSUnited States/ ; R01 HL127349/HL/NHLBI NIH HHSUnited States/ ; UL1 RR025780/RR/NCRR NIH HHSUnited States/ ; R01 HL110883/HL/NHLBI NIH HHSUnited States/ ; U01 HL112707/HL/NHLBI NIH HHSUnited States/ ; U01 HL112702/HL/NHLBI NIH HHSUnited States/ ; U01 HL112695/HL/NHLBI NIH HHSUnited States/ ; U24 OH009077/OH/NIOSH CDC HHSUnited States/ ; UL1 RR029882/RR/NCRR NIH HHSUnited States/ ; R56 HL149129/HL/NHLBI NIH HHSUnited States/ ; U01 HL112696/HL/NHLBI NIH HHSUnited States/ ; U01 HL112712/HL/NHLBI NIH HHSUnited States/ ; U01 HL137159/HL/NHLBI NIH HHSUnited States/ ; R01 HL127461/HL/NHLBI NIH HHSUnited States/ ; UL1 TR000005/TR/NCATS NIH HHSUnited States/ ; U01 HL112708/HL/NHLBI NIH HHSUnited States/ ; R21 LM012884/LM/NLM NIH HHSUnited States/ ; R01 HL136681/HL/NHLBI NIH HHSUnited States/ ; R41 HL129728/HL/NHLBI NIH HHSUnited States/ ; UL1 TR002535/TR/NCATS NIH HHSUnited States/ ; R01 HL114587/HL/NHLBI NIH HHSUnited States/ ; R01 HL117074/HL/NHLBI NIH HHSUnited States/ ; K24 HL127301/HL/NHLBI NIH HHSUnited States/
• Volume:
  58
• Issue:
  6
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:70f0baeb8a17182ebbb316f4e0ba2a021174324a9d462ab03c4f48932fd3b0e6
• Download URL:
  https://stacks.cdc.gov/view/cdc/154412/cdc_154412_DS1.pdf
• File Type:
  [PDF - 1.92 MB ]