Identifying Genetic Biomarkers Predicting Response to Anti-Vascular Endothelial Growth Factor Injections in Diabetic Macular Edema

Abstract

Intraocular anti-vascular endothelial growth factor (VEGF) therapies are the front-line treatment for diabetic macular edema (DME); however, treatment response varies widely. This study aimed to identify genetic determinants associated with anti-VEGF treatment response in DME. We performed a genome-wide association study on 220 Australian patients with DME treated with anti-VEGF therapy, genotyped on the Illumina Global Screening Array, and imputed to the Haplotype Reference Consortium panel. The primary outcome measures were changes in central macular thickness (CMT in microns) and best-corrected visual acuity (BCVA in ETDRS letters) after 12 months. Association between single nucleotide polymorphism (SNP) genotypes and DME outcomes were evaluated by linear regression, adjusting for the first three principal components, age, baseline CMT/BCVA, duration of diabetic retinopathy, and HbA1c. Two loci reached genome-wide significance (p < 5 × 10−8) for association with increased CMT: a single SNP on chromosome 6 near CASC15 (rs78466540, p = 1.16 × 10−9) and a locus on chromosome 12 near RP11-116D17.1 (top SNP rs11614480, p = 2.69 × 10−8). Four loci were significantly associated with reduction in BCVA: two loci on chromosome 11, downstream of NTM (top SNP rs148980760, p = 5.30 × 10−9) and intronic in RP11-744N12.3 (top SNP rs57801753, p = 1.71 × 10−8); one near PGAM1P1 on chromosome 5 (rs187876551, p = 1.52 × 10−8); and one near TBC1D32 on chromosome 6 (rs118074968, p = 4.94 × 10−8). In silico investigations of each locus identified multiple expression quantitative trait loci and potentially relevant candidate genes warranting further analysis. Thus, we identified multiple genetic loci predicting treatment outcomes for anti-VEGF therapies in DME. This work may potentially lead to managing DME using personalized treatment approaches.

Factors Affecting Intensive Aflibercept Treatment Response in Diabetic Macular Edema: A Real-World Study

“…Previous epidemiological studies established that the prevalence of DME increases along with the duration of diabetes [13,23]. Similar to our study results, DM duration has been reported as a negative predictor of anti-VEGF treatment response in DME [18,36]. Eyes with a longer duration of DM are more likely to be chronically exposed to a DME- [37] and a transition from an acute inflammatory phase to a more treatment-resistant chronic inflammatory phase [38,39].…”

Predictive factors for treatment outcomes with intravitreal anti-vascular endothelial growth factor injections in diabetic macular edema in clinical practice

“…It is therefore clear that other clinical, demographic, genetic and/or epigenetic factors are involved. Studies exploring such potential risk factors are required and are beginning to emerge [ 78 , 79 ]. Further, less than a third of DME patients (31.85%) showed combined response (functional and anatomical) with a weak negative correlation (Correlation coefficient =-0.30) observed between the two outcome categories.…”

Genome-Wide Associations and Confirmatory Meta-Analyses in Diabetic Retinopathy

“…It is worth noting that there have been exciting developments in the field of DR genetics in recent years. These advancements include exome sequencing for rare and functional variants [ 15 ], and a more in-depth analysis of DR GWAS datasets has provided further understanding of the underlying pathological pathways [ 52 ], causal factors for DR [ 53 , 54 , 55 ], ability to predict DR using polygenic risk scores [ 56 ], and pharmacogenetic responses to treatment [ 57 ].…”