Genome-wide association study (GWAS) of anti-VEGF treatment response in diabetic macular edema identifies genetic associations with retina central subfield thickness and visual acuity improvement

Abstract

Purpose : Intravitreous vascular endothelial growth factor (VEGF) inhibitors are the preferred therapy for diabetic macular edema (DME). However, only ~60% of patients respond completely to anti-VEGF treatment. This study aimed to identify common genetic variants associated with treatment response to anti-VEGF agents in DME patients.

Methods : We conducted GWAS on 863 or 585 DME patients treated with 1 of 3 anti-VEGF agents from 5 randomized clinical trials (DRCRnet Protocols I, S, T, U, V) for 6 or 12 Months, respectively. Quality controlled genotypes from Illumina’s Infinium Global Screening Array were imputed using TOPMed reference panel. Phenotypes tested were change of retinal central subfield thickness (CSTChg6Mo/1Yr) and visual acuity (Early Treatment Diabetic Retinopathy scale; ETDRSChg6Mo/1Yr) at 6/12 months compared to baseline. Linear regression was applied (PLINK2.0) to all samples and subpopulations, adjusting for 10 genotype PCs, age, sex, HbA1c, diabetes type and duration, hypertension, prior DME treatment, prior panretinal photocoagulation, diabetic retinopathy severity, baseline ETDRS and CST, type and number of anti-VEGF agents received within 6/12 months. A cross-ancestry (EUR, AFR, AMR) meta-analysis was performed using METAL. To prioritize causal genes and pathways, we performed gene and gene-set level association testing using MAGMA.

Results : At 6 months, for CST change, 2 loci reached genome-wide significance (P<5E-08) in the EUR GWAS (rs111635965, rs138380412) and 4 loci (3 more frequent in EUR, 1 in AFR) in the METAL analysis. For ETDRSChg6Mo, 1 locus was significant with METAL (rs188125847, AFR and AMR). Eleven other loci were significant for CSTChg1Yr in GWAS or METAL, 2 of which were found in both (EUR: rs146280264, rs1371051), and 13 loci for ETDRSChg1Yr, 4 of which were found in GWAS and METAL (AFR-specific: rs115221338, more frequent in EUR: rs75017948, rs149196597, rs62208905). No overlap was detected between CST and ETDRS change GWAS hits. IPO8 and PRSS12 were associated with CSTChg1Yr, and PTBP2 and CTAGE6 with ETDRSChg1Yr (MAGMA P<3E-06).

Conclusions : Our findings of genetic association with anti-VEGF response in DME eyes may shed light on underlying biological processes. Future replication may inform personalized treatment of DME patients.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.