Ophthalmology science · 2026
Genome-Wide Association Study for Glucocorticoid-Induced Ocular Hypertension.
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Lama Jyoti, Liu Renee, Huerta-Chagoya Alicia, Li Ashley, Huynh Katie, Stanwyck Lynn K, Han Samuel, Zhao Yan, Chan Weilin, Chen Liyin, Mukundan Ananya, Meng Da, Yang Janine Y, Susarla Gayatri, Sang Delia, Papaliodis George N, Shen Lucy Q, Rossin Elizabeth, Elkins Christine, Benavides Irma, Wafapoor Hussein, Cutino Antonio, Wiggs Janey L, Eaton Alexander M, Segrè Ayellet V, Sobrin Lucia
Аннотация
PURPOSE: To identify genetic variants associated with glucocorticoid (GC)-induced intraocular pressure (IOP) change using genome-wide association study (GWAS) and whole exome sequencing (WES) analyses.
DESIGN: A pharmacogenetic study within a clinical trial and cohort study.
PARTICIPANTS: Five hundred thirty discovery cohort participants were included from the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) trials. Replication was performed in an independent cohort of 588 Mass Eye and Ear/Retina Health Center (MEE/RHC) participants. Participants were exposed to GC, primarily by intravitreal injection.
METHODS: Intraocular pressure was measured at baseline and serially within the first 6 months after GC exposure. Participants' DNA underwent genome-wide genotyping and WES. Genome-wide association study and WES rare variant gene burden analyses were applied to all ancestries and the European participants separately, adjusting for covariates. Expression and splicing quantitative trait loci colocalization analysis using eCAVIAR, and gene-level and pathway analyses using Multi-marker Analysis of GenoMic Annotation were performed.
MAIN OUTCOME MEASURES: Genetic associations with the maximal change in IOP within 6 months after GC exposure.
RESULTS: Genetic associations for maximal IOP change within 6 months after GC exposure were evaluated. For the primary outcome across all ancestries in FAME, 1 variant, rs13425173 within the UBE2E3 locus, reached genome-wide significance (P = 2.88 × 10-8). In the FAME and MEE/RHC meta-analysis, variant rs1040227, also in the UBE2E3 locus, was significantly associated at the genome-wide level (P = 1.23 × 10-8). In the colocalization analyses, the significant FAME GWAS UBE2E3 locus was linked to expression regulation of this gene in 6 tissues including artery aorta. In gene-level analysis, UBE2E3 also demonstrated subthreshold significance (P = 6.6 × 10-6). Five hundred thirty-two FAME and 586 MEE/RHC participants were included in the WES gene burden analysis. One gene, MSTO1, passed false discovery rate correction for the primary outcome in FAME.
CONCLUSIONS: We have identified genome-wide significant common variants associated with GC-IOP change, as well as genes and rare variants that may influence GC-induced IOP change.
FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
DESIGN: A pharmacogenetic study within a clinical trial and cohort study.
PARTICIPANTS: Five hundred thirty discovery cohort participants were included from the Fluocinolone Acetonide in Diabetic Macular Edema (FAME) trials. Replication was performed in an independent cohort of 588 Mass Eye and Ear/Retina Health Center (MEE/RHC) participants. Participants were exposed to GC, primarily by intravitreal injection.
METHODS: Intraocular pressure was measured at baseline and serially within the first 6 months after GC exposure. Participants' DNA underwent genome-wide genotyping and WES. Genome-wide association study and WES rare variant gene burden analyses were applied to all ancestries and the European participants separately, adjusting for covariates. Expression and splicing quantitative trait loci colocalization analysis using eCAVIAR, and gene-level and pathway analyses using Multi-marker Analysis of GenoMic Annotation were performed.
MAIN OUTCOME MEASURES: Genetic associations with the maximal change in IOP within 6 months after GC exposure.
RESULTS: Genetic associations for maximal IOP change within 6 months after GC exposure were evaluated. For the primary outcome across all ancestries in FAME, 1 variant, rs13425173 within the UBE2E3 locus, reached genome-wide significance (P = 2.88 × 10-8). In the FAME and MEE/RHC meta-analysis, variant rs1040227, also in the UBE2E3 locus, was significantly associated at the genome-wide level (P = 1.23 × 10-8). In the colocalization analyses, the significant FAME GWAS UBE2E3 locus was linked to expression regulation of this gene in 6 tissues including artery aorta. In gene-level analysis, UBE2E3 also demonstrated subthreshold significance (P = 6.6 × 10-6). Five hundred thirty-two FAME and 586 MEE/RHC participants were included in the WES gene burden analysis. One gene, MSTO1, passed false discovery rate correction for the primary outcome in FAME.
CONCLUSIONS: We have identified genome-wide significant common variants associated with GC-IOP change, as well as genes and rare variants that may influence GC-induced IOP change.
FINANCIAL DISCLOSURES: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.