Genetic variants in ANO2 may be predictive for treatment response to anti-VEGF in neovascular age-related macular degeneration

Abstract

Purpose : Genetic predisposition can contribute to treatment response, and predictive variants may explain response direction and/or magnitude. In the VIEW 1 and 2 Phase 3 randomized controlled trials (RCTs), intravitreal aflibercept (IVT-AFL) provided rapid and robust gains in visual acuity (VA) in patients (n=2419) with neovascular age-related macular degeneration (nAMD). This analysis aimed to identify any associations between gene variants and clinical endpoints in VIEW 1 and 2.

Methods : A genome-wide association study (GWAS), utilizing the Illumina HumanOmniExpress Exome v1.3 platform, was conducted on a subgroup of patients from VIEW 1 and 2 (NCT00509795/NCT00637377) consenting to the optional pharmacogenetic analysis.

Results : Data were pooled from 780 patients (VIEW 1, n=362; VIEW 2, n=418), who were representative of the overall VIEW 1 and 2 population. After Bonferroni correction for multiplicity and statistical adjustment for baseline risk factors, there were no significant associations between known gene variants and treatment response according to the pre-specified VIEW 1 and 2 endpoints. Genome wide there were no significant genetic associations in participants experiencing gains ≥15 ETDRS letters after 1 or 2 years of treatment. Investigating participants with VA loss ≥5 letters, a cluster of variants in the ANO2 gene on Chromosome 12 reached p<5x10^-8. Exploring VA scores at Year 1 and 2, the ANO2 rs2110166 single-nucleotide polymorphism (SNP) also reached p<5x10^-8. Carriers of the rs2110166 TC genotype showed a smaller improvement in VA score in response to IVT-AFL or ranibizumab (effect size 2.19) compared to those without. The minor allele frequency was 3% in VIEW; these participants lost, on average, ≥5 letters at 1 year.

Conclusions : Based on data from two large, robust RCTs, preliminary analyses suggest an association of ANO2 with retinal function, with a potential impact on VA of ~1 line over 1–2 years. Typical associations between known and potential target candidate AMD variants and clinical endpoints were not found. ANO2 encodes anoctamin 2, a calcium-activated chloride channel expressed on photoreceptor cells and is a gene meriting further investigation of its function in retinal pathophysiology. Further studies may elucidate whether the variants identified are predictive or prognostic in nAMD.

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