April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
Pharmacogenomics Of Steroid Response In The Eye
Author Affiliations & Notes
  • M. Elizabeth Fini
    USC Institute for Genetic Medicine,
    Keck School of Medicine of USC, Los Angeles, California
  • Stephen G. Schwartz
    Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida
  • Nitin Patel
    USC Institute for Genetic Medicine,
    Keck School of Medicine of USC, Los Angeles, California
  • David V. Conti
    Zilkha Neurogenetic Institute,
    Keck School of Medicine of USC, Los Angeles, California
  • Mathew T. Pletcher
    The Scripps Research Institute, Jupiter, Florida
  • Carmen A. Puliafito
    Office of the Dean,
    Keck School of Medicine of USC, Los Angeles, California
  • Miami/USC Pharmacogenomics Team
    Keck School of Medicine of USC, Los Angeles, California
  • Footnotes
    Commercial Relationships  M. Elizabeth Fini, Co-inventor designated on a patent application for technology licensed to IC Labs, LLC (P); Stephen G. Schwartz, Bausch and Lomb (R), Co-inventor designated on a patent application for technology licensed to IC Labs, LLC (P); Nitin Patel, None; David V. Conti, None; Mathew T. Pletcher, None; Carmen A. Puliafito, None
  • Footnotes
    Support  American Health Assistance Foundation, Prevent Blindness America, Prevent Blindness Florida, NIH grant P30-EY014801, Research to Prevent Blindness, Keck School of Medicine of USC, NIH grant UL1 RR0319
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 2403. doi:https://doi.org/
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      M. Elizabeth Fini, Stephen G. Schwartz, Nitin Patel, David V. Conti, Mathew T. Pletcher, Carmen A. Puliafito, Miami/USC Pharmacogenomics Team; Pharmacogenomics Of Steroid Response In The Eye. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2403. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Glucocorticoids cause elevation of intraocular pressure (IOP) in a high percentage of patients. We performed a genome-wide association study to discover single nucleotide polymorphisms (SNPs) that predict individual response, as well as novel genes that control IOP.

Methods: : Fifty-four patients were enrolled that received intravitreal triamcinolone acetonide (IVTA) for any indication and at least 1 follow-up visit within 3 months. The maximum IOP and the maximum change in IOP (delta IOP) were determined. Patient DNA was used to interrogate the Affymetrix GeneChip® Human Mapping 500K Array Set. Statistical analysis was performed using HelixTree software with correction for multiple comparisons. Delta IOP was treated as a continuous variable. Fast track replication was performed by Taqman genotyping and the results analyzed statistically by standard ANOVA. Bioinformatics analysis was done using data available on public websites. A racial admixture analysis to control for population structure is in progress.

Results: : Statistical analysis of the raw microarray "calls" identified 48 SNPs in 41 genes that associate with steroid response at corrected P-values better than 10-2. Fast track replication identified 6 SNPs that associate at genome-wide significance (10-8 to better than 10-10) and 5 more SNPs that are highly significant (P-value better than 10-6). The 10 genes in which these SNPs are found are all involved with signal transduction; 6 are involved specifically with neuronal signaling. Three genes control levels of endogenous IOP regulators (serotonin, glutamate, endocannabinoid). Two others are orphan G-protein coupled receptors (GPCRs) of unknown function, both expressed in the eye. A 7th gene is a receptor in the TGF-beta superfamily, a signaling pathway connected to aqueous outflow deficiency.

Conclusions: : Because pharmacogenomic effects can be quite large, a small cohort may provide sufficient statistical power. Preliminary results are compelling because of functional correlation, suggesting that response to steroids may be determined by individual genetic variation in IOP regulatory pathways. The GPCRs are candidate drug targets for IOP regulation in glaucoma; structure/function studies are in progress.

Keywords: genetics • intraocular pressure • corticosteroids 
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