Pharmacogenomics of steroid-induced ocular hypertension: relationship to high-tension glaucomas and new pathophysiologic insight

Adverse drug reactions are a frequent cause of worldwide morbidity and mortality. Glucocorticoids (GCs), commonly used to treat inflammatory diseases, alter gene expression with both beneficial and adverse consequences. When used in the eye, GCs cause steroid-induced ocular hypertension (SIOH) in 30-50% of patients, leading to steroid-induced glaucoma. Evidence suggests that predisposition to SIOH is genetically determined. Here we took a pharmacogenomic approach to discover DNA variants associated with SIOH. We identified 44 SNPs of genome-wide significance (p<5E-08) located at 26 risk loci out of a total of 531 SNPs of suggestive significance (p<5E-06) at 262 risk loci. Unlike SNPs identified in complex disease which are overwhelmingly common in frequency, most SNPs found here were rare or of low frequency, likely discoverable because of their large effect sizes. Follow-up analyses provide insight into the pathogenetic relationship of SIOH to high-tension glaucomas and suggest a new mechanistic paradigm for SIOH pathophysiology.