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