Identification of a Novel Variant Associated with anti-VEGF Response in Age-related Macular Degeneration Using Exome Chip Analysis

Abstract

Purpose : The current treatment for neovascular age-related macular degeneration (nvAMD) is by intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents, however, a variable treatment outcome has been reported. We aimed to investigate pharmacogenetic associations that may underlie such a differential response.

Methods : The discovery cohort consisted of 678 anti-VEGF treated nvAMD patients (>50 years of age) from 5 different clinics. Patients were identified through the International AMD Genomics Consortium (IAMDGC) and genotyped with a custom exome chip. The main outcome measure was change in visual acuity at 3 months of anti-VEGF treatment (deltaVA). After imputation and quality control, variants with a minor allele frequency ≥0.05 were selected for the analysis. In each cohort, a linear model was performed, adjusted for the first two ancestry principle components, baseline VA and age using EPACTS software, and followed by a meta-analysis on METAL software. Among the top associated variants (p-value <10^-5) 6 independant variants were genotyped in 844 patients from five independent cohorts using either KASp or iplex genotyping platform. Finally, a meta-analysis of the top six variants was performed on 1522 patients from 10 cohorts (discovery and replication).

Results : A total of 6,089,769 variants were included in the analysis, and six loci showed a suggestive association with deltaVA at the 3 month time point in all five discovery cohorts (p<1x10^-5). After replication of the selected variants, and subsequent meta-analysis of the 10 cohorts (discovery+replication), the top signal which showed consistent association with visual outcome was identified in a locus in and near a chaperonin gene on chromosome 1 (p-value=1.8x10^-6, effect= -0.0454±0.0095).

Conclusions : For the first time, we performed a multi-center, large cohort pharmacogenetic GWAS on anti-VEGF treated nvAMD patients. A locus including a chaperonin gene was associated with change in VA following anti-VEGF treatment in nvAMD patients. The results of this study may be potentially used in prediction models for treatment response in nvAMD, and to stratify patients for the best therapeutic option.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.