Transcriptomics of Bronchoalveolar Lavage Cells Identifies New Molecular Endotypes of Sarcoidosis

Details

• Personal Author:
  Adams TS ; Becich MJ ; Benos PV ; Chen ES ; Collman RG ; DeIuliis G ; Drake WP ; Emeagwali N ; Garcia JGN ; Gibson KF ; Gulati M ; Herzog EL ; Hochheiser H ; Hu B ; Kaminski N ; Koth LL ; Leader JK ; Lynn H ; Maier LA ; Mihaljinec A ; Moller DR ; Morris A ; Prasse A ; Schupp JC ; Vukmirovic M ; Wisniewski SR ; Woolard TN ; Yan X ; Zhang Y
• Corporate Authors:
  Genomic Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis
• 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-beta1 (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. [Description provided by NIOSH]
• Subjects:
  Cohort Studies Immune System Lung Lung Diseases Occupational Health Pathology Respiratory System Respiratory Tract Diseases Safety
• Keywords:
  Alveolar Cells Cell Signaling Cohort Studies DNA Microarrays Gene Expression Genomics Immune Reaction Pulmonary System Disorders Sarcoidosis
• ISSN:
  0903-1936
• Document Type:
  Text
• Funding:
  Cooperative Agreement
• Genre:
  Journal Article
• Place as Subject:
  Arizona ; California ; Colorado ; Connecticut ; Maryland ; OSHA Region 1 ; OSHA Region 3 ; OSHA Region 4 ; OSHA Region 8 ; OSHA Region 9 ; Pennsylvania ; Tennessee
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  58
• Issue:
  6
• NIOSHTIC Number:
  nn:20064206
• Citation:
  Eur Respir J 2021 Dec; 58(6):2002950
• Contact Point Address:
  Naftali Kaminski, Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
• Email:
  naftali.kaminski@yale.edu
• Federal Fiscal Year:
  2022
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  True
• Start Date:
  20060901
• Source Full Name:
  European Respiratory Journal
• End Date:
  20260831
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:e0a6df39edf9531e43bbd6451859e2390e776552216069f8e322058d0c119912bb20676fc9ae900708200f6d20229d106514ad682e2c627ac3b63adf37b98525
• Download URL:
  https://stacks.cdc.gov/view/cdc/222711/cdc_222711_DS1.pdf
• File Type:
  [PDF - 1.21 MB ]