title: Longitudinal analysis of sarcoidosis blood transcriptomic signatures and disease outcomes.
abstract: Previously, we demonstrated concordance in differentially expressed genes in sarcoidosis blood and lung, implicating shared dysfunction of specific immune pathways. In the present study, we hypothesised that expression levels of candidate genes in sarcoidosis blood could predict and track with disease outcomes longitudinally. We applied Ingenuity Pathway Analysis to a cross-sectional derivation microarray dataset (n=38) to identify canonical pathways and candidate genes associated with sarcoidosis. In a separate longitudinal sarcoidosis cohort (n=103), we serially measured 48 candidate gene transcripts, and assessed their relation to disease chronicity and severity. In the cross-sectional derivation study, pathway analysis showed upregulation of genes related to interferon signalling and the role of pattern recognition receptors, and downregulation of T-cell receptor (TCR) signalling pathways in sarcoidosis. In the longitudinal cohort, factor analysis confirmed coregulation of genes marking these pathways and identified CXCL9 as an additional candidate pathway. CXCL9 and TCR factors discriminated between chronic versus nonprogressive disease, and CXCL9 predicted disease outcomes longitudinally. Interferon factor was similarly increased in both disease phenotypes. Factors associated with lung function decline included decreased TCR factor and increased CXCL9. These findings demonstrate blood transcriptomic signatures reflecting TCR signalling and CXCL9 predict sarcoidosis chronicity and correlate with disease severity longitudinally.
authors.affiliation: Division of Rheumatology, University of California, San Francisco, CA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Su
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy, Dept of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Li
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy, Dept of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Nirav R
authors.initials: NR
authors.lastname: Bhakta
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy, Dept of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Owen D
authors.initials: OD
authors.lastname: Solberg
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy, Dept of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Eli P B
authors.initials: EP
authors.lastname: Darnell
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy, Dept of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Joris
authors.initials: J
authors.lastname: Ramstein
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy, Dept of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Garudadri
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy, Dept of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Ho
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy, Dept of Medicine, University of California, San Francisco, CA, USA Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
authors.forename: Prescott G
authors.initials: PG
authors.lastname: Woodruff
authors.affiliation: Division of Pulmonary, Critical Care, Sleep and Allergy, Dept of Medicine, University of California, San Francisco, CA, USA laura.koth@ucsf.edu.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Koth
mesh_terms: D000328:Adult; D000368:Aged; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D012507:Sarcoidosis / Q000097:blood* / Q000235:genetics*; D059467:Transcriptome