Genome-Wide Association Study for Glucocorticoid-Induced Ocular Hypertension

Area of Science:

• Ophthalmology
• Genetics
• Pharmacogenomics

Background:

• Glucocorticoids (GCs) are widely used to treat ocular inflammation but can induce significant intraocular pressure (IOP) elevation.
• Identifying genetic factors influencing this response is crucial for personalized treatment strategies and managing glaucoma risk.

Purpose of the Study:

• To discover genetic variants associated with changes in intraocular pressure (IOP) following glucocorticoid (GC) exposure.
• Utilizing genome-wide association study (GWAS) and whole exome sequencing (WES) to analyze genetic contributions to GC-induced IOP.
• To identify specific genes and variants that may modulate the ocular hypertensive response to GCs.

Main Methods:

• Analysis of 530 participants from the FAME trials and 588 from the MEE/RHC cohort, all exposed to GCs, primarily via intravitreal injection.
• Serial IOP measurements were taken within six months of GC exposure.
• Genome-wide association study (GWAS) and rare variant gene burden analyses were performed, adjusting for relevant covariates.

Main Results:

• A genome-wide significant variant, rs13425173 in the UBE2E3 locus, was identified for maximal IOP change in the FAME cohort (P=2.88 X 10^-8).
• Meta-analysis of FAME and MEE/RHC cohorts confirmed rs1040227 in UBE2E3 as genome-wide significant (P=2.88 X 10^-8).
• Colocalization analysis linked the UBE2E3 locus to gene expression regulation, and gene-level analysis showed UBE2E3 significance (P=6 X 10^-6). The gene MSTO1 passed FDR correction in WES analysis.

Conclusions:

• Genome-wide significant common variants associated with GC-induced IOP change have been identified.
• Specific genes and rare variants potentially influencing GC-induced IOP elevation were discovered.
• These findings contribute to understanding the genetic basis of ocular hypertensive responses to GCs.