Abstract
Purpose: :
Sarcoidosis is an immune-mediated disease that has the potential to affect multiple organs. Uveitis is the most common sight-threatening ocular manifestation. Although both genetic and environmental factors are implicated, the etiology remains unknown. This study tested the hypothesis that patients with sarcoidosis have a characteristic peripheral blood mRNA profile.
Methods: :
Blood samples were analyzed using high-density human GeneChip® probe arrays (HG-U133 plus 2.0, Affymetrix) for mRNA expression profiling of peripheral blood leukocytes from 12 patients with sarcoidosis (7 with uveitis, and 5 without uveitis) and 12 healthy controls. Differential gene expression between groups was assessed by Significance Analysis of Microarrays (SAM) after normalization. Genes were studied based on gene ontology function, pathway information, and cluster analyses. Validation was obtained by analysis of gene expression in lymph node or lung biopsy (6 sarcoidosis vs 6 controls).
Results: :
1187 genes were upregulated and 1281 were downregulated among patients with sarcoidosis compared to controls with selection criteria of ≥ 1.5 fold ratio and q value ≤ 0.05. There were no significantly upregulated and downregulated genes detected in sarcoidosis with uveitis compared to sarcoidosis without uveitis. A significant upregulation (> 1.5 fold ratio and q value < 0.001) of the gene transcript for the major transcription factor, STAT1, was validated by similar results from various probe sets that detect different segments of the sequence. In addition, 13 out of 18 genes that are known to be directly downstream of STAT1 were significantly upregulated in patients with sarcoidosis; these include CDKN1A, Pim-1, CXCL9, TRH, MT-1, OPRM1, MHC2TA, IRF-1, WARS, PSMB9, CD64, A2M and CCND1. Gene expression in lung and lymph node confirmed upregulation of STAT1 related genes.
Conclusions: :
Gene expression in peripheral blood leukocytes from patients with sarcoidosis differs from that of controls. While sarcoidosis markedly affects gene expression in peripheral blood, the clinical manifestation, uveitis, has less of an effect. STAT1, which is regulated by interferons, appears to have an important role in sarcoidosis. This hypothesis is novel, supported by blood and tissue data, and consistent with other reports that indicate that interferons can cause granulomatous disease.
Keywords: gene microarray • gene/expression • uveitis-clinical/animal model