James T Rosenbaum1, Christina A Harrington2, Robert P Searles3, Suzanne S Fei4, Amr Zaki5, Sruthi Arepalli5, Michael A Paley6, Lynn M Hassman7, Albert T Vitale8, Christopher D Conrady8, Puthyda Keath5, Claire Mitchell5, Lindsey Watson5, Stephen R Planck9, Tammy M Martin10, Dongseok Choi11. 1. From the Department of Ophthalmology/Casey Eye Institute (J.T.R., A.Z., S.A., P.K, C.M., L.W., S.R.P., T.M.M., D.C.); Department of Medicine (J.T.R., D.C.), and; Department of Cell Biology (J.T.R., S.R.P.), Oregon Health & Science University; Legacy Devers Eye Institute (J.T.R.). Electronic address: rosenbaj@ohsu.edu. 2. Integrated Genomics Laboratory (C.A.H., R.P.S.) and; Department of Molecular and Medical Genetics (C.A.H.), Oregon Health & Science University, Portland. 3. Integrated Genomics Laboratory (C.A.H., R.P.S.) and. 4. Bioinformatics and Biostatistics Core, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton (S.S.F.), Oregon. 5. From the Department of Ophthalmology/Casey Eye Institute (J.T.R., A.Z., S.A., P.K, C.M., L.W., S.R.P., T.M.M., D.C.). 6. Department of Medicine, Division of Rheumatology, Washington University School of Medicine (M.A.P.). 7. Department of Ophthalmology, Washington University (L.M.H.), St. Louis, Missouri. 8. Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah, Salt Lake City, Utah (A.T.V., C.D.C.). 9. From the Department of Ophthalmology/Casey Eye Institute (J.T.R., A.Z., S.A., P.K, C.M., L.W., S.R.P., T.M.M., D.C.); Department of Cell Biology (J.T.R., S.R.P.), Oregon Health & Science University. 10. From the Department of Ophthalmology/Casey Eye Institute (J.T.R., A.Z., S.A., P.K, C.M., L.W., S.R.P., T.M.M., D.C.); Department of Molecular Microbiology and Immunology (T.M.M.) and. 11. From the Department of Ophthalmology/Casey Eye Institute (J.T.R., A.Z., S.A., P.K, C.M., L.W., S.R.P., T.M.M., D.C.); Department of Medicine (J.T.R., D.C.), and; OHSU-PSU School of Public Health (D.C.), Oregon Health & Science University, Portland, Oregon, USA; and; Graduate School of Dentistry, Kyung Hee University, Seoul, Korea (D.C.).
Abstract
PURPOSE: Uveitis is a heterogeneous collection of diseases. We tested the hypothesis that despite the diversity of uveitides, there could be common mechanisms shared by multiple subtypes, and that evidence of these common mechanisms may be detected as gene expression profiles in whole blood. DESIGN: Cohort study. METHODS: Ninety subjects with uveitis including axial spondyloarthritis (n = 17), sarcoidosis (n = 13), inflammatory bowel disease (n = 12), tubulointerstitial nephritis with uveitis (n = 10), or idiopathic uveitis (n = 38) as well as 18 healthy controls were enrolled, predominantly at Oregon Health & Science University. RNA-Seq data generated from peripheral, whole blood identified 19,859 unique transcripts. We analyzed gene expression pathways via Kyoto Encyclopedia of Genes and Genomes and Gene Ontology (GO). We validated our list of upregulated genes by comparison to a previously published study on peripheral blood gene expression among 50 subjects with diverse forms of uveitis. RESULTS: Both the Kyoto Encyclopedia of Genes and Genomes and GO analysis identified multiple shared pathways or GO terms with a P value of <.0001. Almost all pathways related to the immune response and/or response to an infection. A total of 119 individual transcripts were upregulated by at least 1.5-fold and false discovery rate <.05, and 61 were downregulated by similar criteria. Comparing mRNA from our study with a false discovery rate <.05 and the prior report, we identified 10 common gene transcripts: ICAM1, IL15RA, IL15, IRF1, IL10RB, GSK3A, TYK2, MEF2A, MEF2B, and MEF2D. CONCLUSIONS: Many forms of uveitis share overlapping mechanisms. These data support the concept that a single therapeutic approach could benefit diverse forms of this disease.
PURPOSE: Uveitis is a heterogeneous collection of diseases. We tested the hypothesis that despite the diversity of uveitides, there could be common mechanisms shared by multiple subtypes, and that evidence of these common mechanisms may be detected as gene expression profiles in whole blood. DESIGN: Cohort study. METHODS: Ninety subjects with uveitis including axial spondyloarthritis (n = 17), sarcoidosis (n = 13), inflammatory bowel disease (n = 12), tubulointerstitial nephritis with uveitis (n = 10), or idiopathic uveitis (n = 38) as well as 18 healthy controls were enrolled, predominantly at Oregon Health & Science University. RNA-Seq data generated from peripheral, whole blood identified 19,859 unique transcripts. We analyzed gene expression pathways via Kyoto Encyclopedia of Genes and Genomes and Gene Ontology (GO). We validated our list of upregulated genes by comparison to a previously published study on peripheral blood gene expression among 50 subjects with diverse forms of uveitis. RESULTS: Both the Kyoto Encyclopedia of Genes and Genomes and GO analysis identified multiple shared pathways or GO terms with a P value of <.0001. Almost all pathways related to the immune response and/or response to an infection. A total of 119 individual transcripts were upregulated by at least 1.5-fold and false discovery rate <.05, and 61 were downregulated by similar criteria. Comparing mRNA from our study with a false discovery rate <.05 and the prior report, we identified 10 common gene transcripts: ICAM1, IL15RA, IL15, IRF1, IL10RB, GSK3A, TYK2, MEF2A, MEF2B, and MEF2D. CONCLUSIONS: Many forms of uveitis share overlapping mechanisms. These data support the concept that a single therapeutic approach could benefit diverse forms of this disease.
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