Characterizing the “POAGome”: A bioinformatics-driven approach to primary open-angle glaucoma

Abstract

Primary open-angle glaucoma (POAG) is a genetically, physiologically, and phenotypically complex neurodegenerative disorder. This study addressed the expanding collection of genes associated with POAG, referred to as the “POAGome.” We used bioinformatics tools to perform an extensive, systematic literature search and compiled 542 genes with confirmed associations with POAG and its related phenotypes (normal tension glaucoma, ocular hypertension, juvenile open-angle glaucoma, and primary congenital glaucoma). The genes were classified according to their associated ocular tissues and phenotypes, and functional annotation and pathway analyses were subsequently performed. Our study reveals that no single molecular pathway can encompass the pathophysiology of POAG. The analyses suggested that inflammation and senescence may play pivotal roles in both the development and perpetuation of the retinal ganglion cell degeneration seen in POAG. The TGF-β signaling pathway was repeatedly implicated in our analyses, suggesting that it may be an important contributor to the manifestation of POAG in the anterior and posterior segments of the globe. We propose a molecular model of POAG revolving around TGF-β signaling, which incorporates the roles of inflammation and senescence in this disease. Finally, we highlight emerging molecular therapies that show promise for treating POAG.

Modeling Glaucoma: Retinal Ganglion Cells Generated from Induced Pluripotent Stem Cells of Patients with SIX6 Risk Allele Show Developmental Abnormalities

“…APC encodes adenomatous polyposis coli tumor suppressor gene, which regulates Wnt signaling and retinoic acid production for retinal development and differentiation . To identify POAG associated genes, beyond CDKN2A and CDKN2B, involved with RPCs and RGCs, we examined the presence of DEGs in the POAGome, a recent literature‐curated database of 542 genes associated with POAG . Twenty five of 47 POAGome genes in the “retina tissues and retinal progenitors cells” category were common with DEGs in SIX6 risk allele RPCs and RGCs.…”

Genome-wide Expression Profiling and Pathway Analysis in Cyclic Stretched Human Trabecular Meshwork Cells

“…Cyclic mechanical stress has been shown to potentially activate TGF-β/BMP pathway through the SMAD-mediated Runx2 pathway or the non-SMAD-mediated MAPK pathway (55, 56). TGF-β and its related pathways have been strongly implicated in the pathogenesis of glaucoma and IOP regulation (54, 57-60). TGF-β may increase outflow resistance by altering extracellular matrix homeostasis and cell contractility in the TM through interactions with other proteins and signaling molecules (54, 58, 60).…”

Early removal of senescent cells protects retinal ganglion cells loss in experimental ocular hypertension

“…TBK also caused RGC death in ischemic retina injury 4 . Of particular note, a recent bioinformatic meta-analysis of a published set of genes associated with primary open-angle glaucoma (POAG) pointed at senescence and inflammation as key factors in RGC degeneration in glaucoma 5 .…”