Abstract
Elevated intraocular pressure (IOP) is the only modifiable risk factor for primary open-angle glaucoma (POAG). Herein we sought to prioritize a set of previously identified IOP-associated genes using novel and previously published datasets. We identified several genes for future study, including several involved in cytoskeletal/extracellular matrix reorganization, cell adhesion, angiogenesis, and TGF-β signaling. Our differential correlation analysis of IOP-associated genes identified 295 pairs of 201 genes with differential correlation. Pathway analysis identified β-estradiol as the top upstream regulator of these genes with ESR1 mediating 25 interactions. Several genes (i.e., EFEMP1, FOXC1, and SPTBN1) regulated by β-estradiol/ESR1 were highly expressed in non-glaucomatous human trabecular meshwork (TM) or Schlemm’s canal (SC) cells and specifically expressed in TM/SC cell clusters defined by single-cell RNA-sequencing. We confirmed ESR1 gene and protein expression in human TM cells and TM/SC tissue with quantitative real-time PCR and immunofluorescence, respectively. 17β-estradiol was identified in bovine, porcine, and human aqueous humor (AH) using ELISA. In conclusion, we have identified estrogen receptor signaling as a key modulator of several IOP-associated genes. The expression of ESR1 and these IOP-associated genes in TM/SC tissue and the presence of 17β-estradiol in AH supports a role for estrogen signaling in IOP regulation.
Highlights
Like other forms of glaucoma, Primary open-angle glaucoma (POAG) is characterized by retinal ganglion cell death and optic nerve atrophy resulting in progressive visual field loss, but differs from other forms of glaucoma in that it lacks an identifiable cause [3,4,5,6,7]
By combining the data provided in the supplemental files from Khawaja, et al, and MacGregor, et al, we compiled a list of 191 lead single nucleotide polymorphisms (SNPs) associated with intraocular pressure (IOP)
We have prioritized a set of 157 genes containing/neighboring IOPassociated SNPs
Summary
By combining the data provided in the supplemental files from Khawaja, et al, and MacGregor, et al, we compiled a list of 191 lead SNPs associated with IOP These SNPs were located in or near 157 genes. SNPs were identified within a single gene (e.g., TMCO1, FNDC3B, AFAP1, GMDS, OXR1, ANGPT1, LMX1B, and GAS7). Some SNPs were located between genes; in such cases, genes on either side of the SNP were included. Many genes were identified by both studies. For this reason, the final list of IOP-associated genes included only 157 non-redundant genes (Supplemental Table S3)
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