Interleukin-20 Receptor Expression in the Trabecular Meshwork and Its Implication in Glaucoma

Keller, Kate E.; Yang, Yong; Sun, Ying; Sykes, Renee; Gaudette, N. Donna; Samples, John R.; Acott, Ted S.; Wirtz, Mary K.

doi:10.1089/jop.2013.0187

Cited by 23 publications

(22 citation statements)

References 44 publications

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“…Significance was recently extended to inflammatory cytokine IL20 and signaling through Jak/Stat, identified as causal in an inherited form of POAG (Keller et al, 2014; Wirtz and Keller, 2016). …”

Section: Intracellular Signalingmentioning

confidence: 99%

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

Fini

Schwartz

Gao

et al. 2017

Progress in Retinal and Eye Research

120

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Elevation of intraocular pressure (IOP) due to therapeutic use of glucocorticoids is called steroid-induced ocular hypertension (SIOH); this can lead to steroid-induced glaucoma (SIG). Glucocorticoids initiate signaling cascades ultimately affecting expression of hundreds of genes; this provides the potential for a highly personalized pharmacological response. Studies attempting to define genetic risk factors were undertaken early in the history of glucocorticoid use, however scientific tools available at that time were limited and progress stalled. In contrast, significant advances were made over the ensuing years in defining disease pathophysiology. As the genomics age emerged, it appeared the time was right to renew investigation into genetics. Pharmacogenomics is an unbiased discovery approach, not requiring an underlying hypothesis, and provides a way to pinpoint clinically significant genes and pathways that could not have been discovered any other way. Results of the first genome-wide association study to identify polymorphisms associated with SIOH, and follow-up on two novel genes linked to the disorder, GPR158 and HCG22, is discussed in the second half of the article. However, knowledge of genetic variants determining response to steroids in the eye also has value in its own right as a predictive and diagnostic tool. This article concludes with a discussion of how the Precision Medicine Initiative®, announced by U.S. President Obama in his 2015 State of the Union address, is beginning to touch the practice of ophthalmology. It is argued that SIOH/SIG may provide one of the next opportunities for effective application of precision medicine.

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Section: Intracellular Signalingmentioning

confidence: 99%

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

Fini

Schwartz

Gao

et al. 2017

Progress in Retinal and Eye Research

120

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“…However, IL20RB diseasing-causing variants are exceedingly rare, with none identified in the 230 random POAG cases screened in the American study. 7 In this study, we report the presence of one novel nonsynonymous variant, p.(Arg140Ter), in 1 HTG case and no rare nonsynonymous variants in 1096 controls. Our results support the involvement of IL20RB in IOP regulation.…”

Section: 57mentioning

confidence: 65%

“…62 It was not until 2014 that the culprit variant for the original linkage signal was identified in IL20RB, p.(Thr104Met), via Sanger sequencing. 7 The variant was reported to reduce receptor function in primary dermal fibroblasts from patients. Human trabecular meshwork cells expressed the IL20RB protein and demonstrated its upregulation in response to cytokine treatment, indicating its role in aqueous outflow resistance in POAG.…”

Section: 57mentioning

confidence: 99%

“…Additionally, the GLC1C locus has since been linked to the gene IL20RB (interleukin 20 receptor subunit beta) via Sanger sequencing. 7 Family-based linkage studies on large affected pedigrees have revealed a number of genes linked to POAG with Mendelian inheritance. Only three genes (MYOC, OPTN, CYP1B1) with disease-causing single nucleotide variants (SNV) and one with copy number variants (TBK1) have been unequivocally replicated in discrete glaucoma cohorts.…”

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confidence: 99%

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Contribution of Mutations in Known Mendelian Glaucoma Genes to Advanced Early-Onset Primary Open-Angle Glaucoma

Zhou

Souzeau

Siggs

et al. 2017

Invest. Ophthalmol. Vis. Sci.

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Citation: Zhou T, Souzeau E, Siggs OM, et al. Contribution of mutations in known Mendelian glaucoma genes to advanced early-onset primary openangle glaucoma. Invest Ophthalmol Vis Sci. 2017;58:153758: -154458: . DOI: 10.1167 PURPOSE. Primary open-angle glaucoma (POAG) and primary congenital glaucoma (PCG) with Mendelian inheritance are caused by mutations in at least nine genes. Utilizing whole-exome sequencing, we examined the disease burden accounted for by these known Mendelian glaucoma genes in a cohort of individuals with advanced early-onset POAG. METHODS.The cases exhibited advanced POAG with young age of diagnosis. Cases and examined local controls were subjected to whole-exome sequencing. Nine hundred ninetythree previously sequenced exomes of Australian controls were called jointly with our dataset. Qualifying variants were selected based on predicted pathogenicity and rarity in public domain gene variant databases. Case-control mutational burdens were calculated for glaucoma-linked genes.RESULTS. Two hundred eighteen unrelated POAG participants and 103 nonglaucomatous controls were included in addition to 993 unexamined controls. Fifty-eight participants (26.6%) harbored rare potentially pathogenic variants in known glaucoma genes. Enrichment of qualifying variants toward glaucoma was present in all genes except WDR36, in which controls harbored more variants, and TBK1, in which no qualifying variants were detected in cases or controls. After multiple testing correction, only MYOC showed statistically significant enrichment of qualifying variants (odds ratio [OR] ¼ 16.62, P ¼ 6.31310 À16 ).CONCLUSIONS. Rare, potentially disease-causing variants in Mendelian POAG genes that showed enrichment in our dataset were found in 22.9% of advanced early-onset POAG cases. MYOC variants represented the largest monogenic cause in POAG. The association between WDR36 and POAG was not supported, and the majority of POAG cases did not harbor a potentially disease-causing variant in the remaining Mendelian genes.

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“…A specific IL20RB mutation T104M (rs367923973) has been identified in a large POAG family (Keller et al, 2014). Although the mutation was not present in all affected family members, there is supportive evidence that suggests its role in POAG pathogenesis.…”

Section: Genetic Linkage Analyses Of Poagmentioning

confidence: 99%

Major review: Molecular genetics of primary open-angle glaucoma

Liu

Allingham

2017

Experimental Eye Research

124

106

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Glaucoma is a leading cause of irreversible blindness worldwide. Primary open-angle glaucoma (POAG), the most common type, is a complex inherited disorder that is characterized by progressive retinal ganglion cell death, optic nerve head excavation, and visual field loss. The discovery of a large, and growing, number of genetic and chromosomal loci has been shown to contribute to POAG risk, which carry implications for disease pathogenesis. Differential gene expression analyses in glaucoma-affected tissues as well as animal models of POAG are enhancing our mechanistic understanding in this common, blinding disorder. In this review we summarize recent developments in POAG genetics and molecular genetics research.

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Interleukin-20 Receptor Expression in the Trabecular Meshwork and Its Implication in Glaucoma

Cited by 23 publications

References 44 publications

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

Steroid-induced ocular hypertension/glaucoma: Focus on pharmacogenomics and implications for precision medicine

Contribution of Mutations in Known Mendelian Glaucoma Genes to Advanced Early-Onset Primary Open-Angle Glaucoma

Major review: Molecular genetics of primary open-angle glaucoma

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