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

ABSTRACT: 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.

SUBMITTER: Fini ME

PROVIDER: S-EPMC5237612 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Fini M Elizabeth ME Schwartz Stephen G SG Gao Xiaoyi X Jeong Shinwu S Patel Nitin N Itakura Tatsuo T Price Marianne O MO Price Francis W FW Varma Rohit R Stamer W Daniel WD

Progress in retinal and eye research 20160922

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 av ...[more]

PMID: 27666015

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Project description:AimTo access the association of forty-eight single nucleotide polymorphisms (SNPs) identified from Caucasian population with steroid-induced ocular hypertension (OHT) in India population.MethodsFifty-four triamcinolone-acetonide (TA) and forty-seven dexamethasone (Dex) administered subjects were enrolled in the study after a written consent. Intraocular pressure (IOP) values were recorded for a period of 6-month post steroid injections and patients were grouped as steroid-responders (SR: IOP≥21 mm Hg) and non-responders (NR: IOP≤20 mm Hg). Genomic DNA was isolated from peripheral venous blood. Forty-eight SNPs identified in TA treated Caucasian patients by genome wide association study (GWAS) were genotyped using iPLEX™ MassARRAY among TA as well as Dex administered Indian patients. Genotyping data of 48 general subjects from a previous study were considered as reference controls for statistical analysis. Genotypic frequencies were calculated and P-value, Chi-square and odds ratio at 95% confidence-interval of group A (steroid treated vs controls), group B (SR vs NR), group C (phenotype correlation: influence of time, severity and gender on IOP rise), were calculated. P<0.05 was considered to be statistically significant.ResultsOHT was observed in 50% of TA and 26% of Dex administered patients, respectively. IOP rise was mostly severe (>30 mm Hg) and immediate (<1wk) among TA-SR patients while it was noticed to be mild (<30 mm Hg) and between 1-2mo among Dex-SR patients. Logistic regression for risk factor correlation with OHT remained non-significant, hence these factors were not considered as confounding parameters for further analysis. rs133, rs34016742, rs274554, rs10936746, rs274547, rs804854, rs7751500, rs359498, and rs7547448 SNPs significantly varied even after Bonferroni corrections (P<0.0025; group A). rs1879370 (TA) and rs6559662 (Dex) were significantly (P<0.05) associated with OHT (group B). rs133 (severe IOP rise), rs11047639 and rs1879370 (male gender), and rs11171569 (immediate IOP rise) significantly (P<0.05) influenced the phenotype correlation only among TA-OHT patients. However, the significance of these SNPs in group B and phenotype analysis (group C) was lost upon Bonferroni corrections (P<0.0025).ConclusionPrevalence of OHT in study population is observed to be similar to other studies both in TA and Dex treated patients. We can correlate rs34016742 involved in diabetes signaling pathway to the occurrence of ocular edematous and inflammatory conditions. Except rs133 that is involved in neuro-degeneration and myopia occurrence, none of the other SNPs identified in Caucasian population possess any correlation with OHT incidence in TA and Dex administered Indian subjects.

Dataset Information

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

Publications

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

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