title: Peripheral blood gene expression as a novel genomic biomarker in complicated sarcoidosis.
abstract: Sarcoidosis, a systemic granulomatous syndrome invariably affecting the lung, typically spontaneously remits but in ~20% of cases progresses with severe lung dysfunction or cardiac and neurologic involvement (complicated sarcoidosis). Unfortunately, current biomarkers fail to distinguish patients with remitting (uncomplicated) sarcoidosis from other fibrotic lung disorders, and fail to identify individuals at risk for complicated sarcoidosis. We utilized genome-wide peripheral blood gene expression analysis to identify a 20-gene sarcoidosis biomarker signature distinguishing sarcoidosis (n = 39) from healthy controls (n = 35, 86% classification accuracy) and which served as a molecular signature for complicated sarcoidosis (n = 17). As aberrancies in T cell receptor (TCR) signaling, JAK-STAT (JS) signaling, and cytokine-cytokine receptor (CCR) signaling are implicated in sarcoidosis pathogenesis, a 31-gene signature comprised of T cell signaling pathway genes associated with sarcoidosis (TCR/JS/CCR) was compared to the unbiased 20-gene biomarker signature but proved inferior in prediction accuracy in distinguishing complicated from uncomplicated sarcoidosis. Additional validation strategies included significant association of single nucleotide polymorphisms (SNPs) in signature genes with sarcoidosis susceptibility and severity (unbiased signature genes - CX3CR1, FKBP1A, NOG, RBM12B, SENS3, TSHZ2; T cell/JAK-STAT pathway genes such as AKT3, CBLB, DLG1, IFNG, IL2RA, IL7R, ITK, JUN, MALT1, NFATC2, PLCG1, SPRED1). In summary, this validated peripheral blood molecular gene signature appears to be a valuable biomarker in identifying cases with sarcoidoisis and predicting risk for complicated sarcoidosis.
authors.affiliation: Institute for Personalized Respiratory Medicine, The University of Illinois at Chicago, Chicago, Illinois, United States of America.
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Nadera J
authors.initials: NJ
authors.lastname: Sweiss
authors.forename: Edward S
authors.initials: ES
authors.lastname: Chen
authors.forename: David R
authors.initials: DR
authors.lastname: Moller
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Knox
authors.forename: Shwu-Fan
authors.initials: SF
authors.lastname: Ma
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wade
authors.forename: Imre
authors.initials: I
authors.lastname: Noth
authors.forename: Roberto F
authors.initials: RF
authors.lastname: Machado
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012507:Sarcoidosis / Q000097:blood* / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D011948:Receptors, Antigen, T-Cell