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Identification of a Novel Mucin Gene HCG22 Associated With Steroid-Induced Ocular Hypertension. | LitMetric

Identification of a Novel Mucin Gene HCG22 Associated With Steroid-Induced Ocular Hypertension.

Invest Ophthalmol Vis Sci

USC Institute for Genetic Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, California, United States 2USC Eye Institute/Department of Ophthalmology, Keck School of Medicine of USC, University of Southern California.

Published: April 2015

AI Article Synopsis

Article Abstract

Purpose: The pathophysiology of ocular hypertension (OH) leading to primary open-angle glaucoma shares many features with a secondary form of OH caused by treatment with glucocorticoids, but also exhibits distinct differences. In this study, a pharmacogenomics approach was taken to discover candidate genes for this disorder.

Methods: A genome-wide association study was performed, followed by an independent candidate gene study, using a cohort enrolled from patients treated with off-label intravitreal triamcinolone, and handling change in IOP as a quantitative trait.

Results: An intergenic quantitative trait locus (QTL) was identified at chromosome 6p21.33 near the 5' end of HCG22 that attained the accepted statistical threshold for genome-level significance. The HCG22 transcript, encoding a novel mucin protein, was expressed in trabecular meshwork cells, and expression was stimulated by IL-1, and inhibited by triamcinolone acetate and TGF-β. Bioinformatic analysis defined the QTL as an approximately 4 kilobase (kb) linkage disequilibrium block containing 10 common single nucleotide polymorphisms (SNPs). Four of these SNPs were identified in the National Center for Biotechnology Information (NCBI) GTEx eQTL browser as modifiers of HCG22 expression. Most are predicted to disrupt or improve motifs for transcription factor binding, the most relevant being disruption of the glucocorticoid receptor binding motif. A second QTL was identified within the predicted signal peptide of the HCG22 encoded protein that could affect its secretion. Translation, O-glycosylation, and secretion of the predicted HCG22 protein was verified in cultured trabecular meshwork cells.

Conclusions: Identification of two independent QTLs that could affect expression of the HCG22 mucin gene product via two different mechanisms (transcription or secretion) is highly suggestive of a role in steroid-induced OH.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416661PMC
http://dx.doi.org/10.1167/iovs.14-14803DOI Listing

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