Genetic biomarkers predicting response to anti-vascular endothelial growth factor injections in diabetic macular edema, a pilot study

Abstract

Purpose : Intraocular anti-vascular endothelial growth factor (anti-VEGF) therapies are the front-line treatment for diabetic macular edema (DME), however, treatment response varies widely. This study aims to identify genetic determinants associated with anti-VEGF treatment response in DME patients.

Methods : We performed a genome-wide association study on 220 DME patients treated with anti-VEGF therapy, genotyped on Illumina Global Screening Array. Changes in central macular thickness (CMT) and best-corrected visual acuity (BCVA) after 12 months were our primary outcome measures. Association between single nucleotide polymorhphism (SNP) genotypes and DME outcomes were evaluated by linear regression (additive model) using PLINK2.0, adjusting for the first three principal components, age, baseline CMT/BCVA, duration of diabetic retinopathy, and HbA1c.

Results : In the GWAS for CMT change, a single SNP on chromosome 6 (rs78466540, P=1.16E-09) and a locus on chromosome 12 (top SNP rs11614480, P=2.69E-08) reached genome-wide significance (Figure 1A). The chromosome 12 locus was supported by four nearby SNPs rs11615848, rs11614887, rs11615870, rs11615833 in linkage disequilibrium which also showed genome-wide significance (P≤5E-08). For BCVA change we found five SNPs reaching genome-wide significance(Figure 1B), three on chromosome 11, (rs148980760, P=5.30E-09; rs117744949, P= P=6.57E-09 and rs57801753, P= P=1.71E-08), and a SNP each on chromosome 5 (rs187876551, P=1.52E-08) and chromosome 6 (rs118074968, P=4.94E-08). In silico investigations of each locus identify multiple eQTLs and potentially relevant candidate genes warranting further analysis.

Conclusions : Multiple genetic loci predicting treatment outcomes for anti-VEGF therapies in DME have been identified. This work will potentially lead to personalized medicine approaches for managing DME.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.

 

Figure 1. Association analyses on response to Anti–Vascular Endothelial Growth Factor therapy in diabetic macular edema. The x-axis represents the chromosomal position of each SNP, and the y-axis shows the −log10 (P value) for association with A: change in central macular thickness over 12 months of treatment and B: change in best-corrected visual acuity over 12 months. Red and blue horizontal lines correspond to the thresholds for genome-wide significant (P≤5E-08) and suggestive association (P≤5E-07), respectively.