A Human Pharmacogenomics Approach Provides Insight Into the Pathogenesis and Pathophysiology of Steroid-Induced...

To identify single nucleotide polymorphisms (SNPs) and their likely target genes associated with steroid-induced ocular hypertension (SI-OHT), and to conduct functional annotation analyses.

Genome-wide association study (GWAS).

Patients with Fuchs endothelial corneal dystrophy were enrolled after corneal transplantation at a single clinical practice (N = 439). Patients self-administered 1% prednisolone acetate eyedrops after surgery. Intraocular pressure (IOP) was measured at baseline and at 1, 3, 6, and 12 months postsurgery.

Saliva samples were collected, and DNA was extracted and genotyped. A GWAS was then conducted, with maximum change in IOP serving as the quantitative trait (QT). Replication analysis employed 4 independent cohorts (N = 49-103) with participants that had been previously genotyped.

Linear regression analysis was performed to determine association between QT and genotype using the Haplotype Reference Consortium reference panel for imputation.

A total of 46 SNPs of genome-wide significance (P < 5E-08) clustered at 29 different risk loci in a total of 623 SNPs of suggestive significance (P < 5E-06) clustered at 323 risk loci. Most SNPs are rare or of low frequency with large effect sizes. A list of 441 prioritized target genes was validated by comparison to gene profiling study results and by annotation analyses. Of the top 29 risk loci, 31% colocalize with those for other high-tension OHT phenotypes, and 2 more are linked to OHT by biological evidence for a total of 38% overlap. Three of the discovered SNPs were independently replicated. Many of the prioritized target genes are not expressed in trabecular meshwork or juxtacanalicular tissue, contrary to the current disease paradigm. Annotation analyses suggest novel pathophysiologic mechanisms.

Why some individuals develop SI-OHT, but others do not, has remained unknown since glucocorticoids were first used to treat eye disease in the early 1950s. Results of this study demonstrate a genetic basis for SI-OHT, support a relationship with other high-tension OHT phenotypes, and provide hypothesis-generating information for laboratory follow-up. Discovered and replicated SNPs may be valuable for SI-OHT risk prediction and prioritized target genes might be targeted for SI-OHT management.

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