Abstract
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.
Footnotes
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Conflict of interest: Dr. Vukmirovic has nothing to disclose.
Conflict of interest: Dr. Yan has nothing to disclose.
Conflict of interest: Dr. Gibson has nothing to disclose.
Conflict of interest: Dr. Gulati reports grants from NIH, during the conduct of the study; personal fees and other from Boehringer Ingelheim, other from ßrance Foundation, other from Pulmonary Fibrosis Foundation, grants from NIH, grants from Sarcoidosis Research Foundation, outside the submitted work; .
Conflict of interest: Dr. Schupp has nothing to disclose.
Conflict of interest: DeIuliis: I have none.
Conflict of interest: Dr. Adams has nothing to disclose.
Conflict of interest: Mr. Hu has nothing to disclose.
Conflict of interest: Dr. Mihaljinec has nothing to disclose.
Conflict of interest: Dr. Woolard has nothing to disclose.
Conflict of interest: Dr. Lynn has nothing to disclose.
Conflict of interest: Dr. Emeagwali has nothing to disclose.
Conflict of interest: Dr. Herzog reports grants from NIH, grants from Sanofi, grants from Bristol Myers, grants from Promedior, personal fees from Boehringer Ingelheim, personal fees from Pfizer, outside the submitted work; .
Conflict of interest: Dr. Chen has nothing to disclose.
Conflict of interest: Dr. Morris reports grants from NIH, during the conduct of the study; .
Conflict of interest: Dr. Leader has nothing to disclose.
Conflict of interest: Dr. Zhang has nothing to disclose.
Conflict of interest: Garcia.
Conflict of interest: Dr. Maier is a member of the FSR Scientific Advisory Board. She does not receive any compensation for this activity.Conflict of interest: Dr. Collman reports grants from National Institutes of Health, during the conduct of the study; .
Conflict of interest: Dr. Drake has nothing to disclose.
Conflict of interest: Dr. Becich reports grants from NCATS, grants from NCI, grants from PCORI, grants from NHLBI, grants from CDC NIOSH, other from SpIntellx, during the conduct of the study; other from SpIntellx, outside the submitted work; In addition, Dr. Becich has a patents SpIntellx (multiple) pending.
Conflict of interest: Dr. Hochheiser has nothing to disclose.
Conflict of interest: Dr. Wisniewski has nothing to disclose.
Conflict of interest: Dr. Benos has nothing to disclose.
Conflict of interest: Dr. Moller reports grants from NHLBI, during the conduct of the study; personal fees from Merck, personal fees from aTYR, personal fees from Roivant, personal fees from SarcoMed , personal fees from Legal expert, other from Hodder Education, other from Taylor & Francis Group, outside the submitted work; In addition, Dr. Moller has a patent Patent No.: 9,683,999 B2 issued, and a patent Patent No.: 9,977,029 B2 issued and DMoller is Chairman and Chief Technical Officer of Sarcoidosis Diagnostic Testing, LLC (a company whose goal is to develop a diagnostic blood test for sarcoidosis) and has received funding including past salary support under the NHLBI STTR program, grant R41 HL129728 over 3 yrs ago; former member of the Scientific Advisory Board of the Foundation for Sarcoidosis Research.
Conflict of interest: Dr. Prasse reports personal fees and non-financial support from Boehringer Ingelheim, personal fees and non-financial support from Roche, personal fees from Novartis, personal fees from AstraZeneca, personal fees from Amgen, personal fees from Pliant, personal fees from Nitto Denko, outside the submitted work; .
Conflict of interest: Dr. Koth has nothing to disclose.
Conflict of interest: Dr. Kaminski reports personal fees from Biogen Idec, Boehringer Ingelheim, Third Rock, Samumed, NuMedii, Indaloo, Theravance, LifeMax, Three Lake Partners, RohBar, Pliant, non-financial support from Miragen , equity with Pliant and miRagen, a grant from Veracyte. All outside the submitted work; In addition, Dr. Kaminski has a patent New Threapies in Pulmonary Fibrosis and on Peripheral Blood Gene Expression that have been licensed to Biotech.
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- Received July 28, 2020.
- Accepted April 20, 2021.
- Copyright ©The authors 2021. For reproduction rights and permissions contact permissions{at}ersnet.org
