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Abstract #60703 Published in IGR 16-4
Identification of a Novel Mucin Gene HCG22 Associated with Steroid-Induced Ocular Hypertension
Jeong S; Patel N; Edlund CC; Hartiala J; Hazelett D; Itakura T; Wu PC; Avery RL; Davis J; Flynn HW; Lalwani G; Puliafito CA; Wafapoor H; Hijikata M; Keicho N; Gao XA; Argueso P; Allayee H; Coetzee GA; Pletcher MT; Conti DV; Schwartz SG; Eaton AM; Fini MEInvestigative Ophthalmology and Visual Science 2015; 0:
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 intraocular pressure 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-beta. Bioinformatic analysis defined the QTL as an ~4 kilobase linkage disequilibrium block containing ten common single nucleotide polymorphisms (SNPs). Four of these SNPs were identified in NCBI's 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.
USC Institute for Genetic Medicine, University of Southern California, 2250 Alcazar Street, Los Angeles, California, 90033, United States of America.
Full articleClassification:
9.4.1 Steroid-induced glaucoma (Part of: 9 Clinical forms of glaucomas > 9.4 Glaucomas associated with other ocular and systemic disorders)
3.4.2 Gene studies (Part of: 3 Laboratory methods > 3.4 Molecular genetics)
