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Clara Castillejo Becerra, Amr Sabbagh, Jihad Aljabban, Samuel Frank, Ali Tahboub, Dexter Hadley; Meta-Analysis of Genetic Expression Profiles in Glaucoma. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6068.
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Glaucoma is the second leading cause of blindness worldwide, associated with irreversible optic nerve damage and progressive visual loss. Although elevated intraocular pressure is a well-established risk factor, we have not identified all the factors that contribute to its pathogenesis. In this study, we performed a meta-analysis of expression profiles of tissues from optic nerve heads from glaucoma and healthy patients to better characterize the mechanisms involved in the development of glaucoma and identify potential therapeutic targets.
Human microarray expression profiles were obtained from Gene Expression Omnibus (GEO). The Search Tag Analyze Resource for GEO (STARGEO) platform was then used to annotate individual samples across different studies with our disease status. We tagged 39 optic nerve head samples from glaucoma patients and compared them to 60 healthy controls, we then analyzed the genetic signature from the STARGEO analysis using Ingenuity Pathway Analysis. We limited our results to genes that showed statistical significance disease and control samples (p<0.05) and an absolute experimental log ratio of at least 0.1.
Meta-analysis revealed axonal guidance signaling (p= 6.70E-05), interferon signaling (p= 2.79E-03) and complement system (p= 3.01E-03) as top canonical pathways in glaucoma. TGFB1 (p= 1.33E-09), OSM (p= 5.53E-08), IL1B (p= 1.72E-07) and PDGF BB (p= 3.81E-07) were found to be top upstream regulators. We also observed upregulation of a number of genes, SELENOP, FGF7, and FOXF2; and downregulation of BCL-2L1. The overexpression of the anti-oxidant, SELENOP is likely a response to inflammation induced oxidative stress. Upregulation of FGF7 and downregulation of BCL-2L1 suggests a fine balance between the proliferation and apoptosis of optic nerve cells. While the overexpression of FOXF2, a transcription factor implicated in the normal development of the anterior segment, might contribute to the structural abnormalities seen in glaucoma.
Our analysis highlights several mechanisms involved in glaucoma pathogenesis including oxidative stress, immune system dysregulation, and disrupted cell proliferation and apoptosis. We isolated TGFB1, OSM, IL1B, and PDGF BB as key regulators of glaucoma pathogenesis. Their role in cell proliferation, differentiation, and inflammation account for the expression profile in the downstream genes and point to their potential use as therapeutic targets.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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