Genetic Variation in RRAGC Affects Progression Rate from Intermediate to Advanced Age-Related Macular Degeneration

Abstract

Purpose : Genome-wide association studies examining progression rate from intermediate to advanced age-related macular degeneration (AMD) are lacking. Most published studies on AMD progression rate feature known AMD risk loci, which may not fully explain progression rate variability among patients, and combine early and intermediate AMD cases together, introducing phenotypic heterogeneity. This study aims to identify novel progression loci with a focus on phenotypic subtypes that have drusen as prominent characteristics at baseline.

Methods : We studied 397 European-descended subjects (606 eyes with intermediate AMD at baseline, 178 of which progressed) with ≥ 2 examinations and a mean follow-up time of 2.5 years (range 0.05-13). Mean age at baseline was 76.5 years, and 58% of subjects were female. Genome-wide genotyping utilized the Illumina HumanCoreExome array and the dataset was imputed to 6.3 million single nucleotide polymorphisms (SNPs), with imputation quality (R²)>0.3 and minor allele frequency≥0.05, using IMPUTE2 and the 1000 Genomes Project Phase I reference panel. Cox proportional hazards regression models were used to assess association of imputed SNP dosage with time to progression in each eye from intermediate AMD (extensive intermediate-size drusen or any large drusen) to advanced AMD (geographic atrophy or choroidal neovascularization). Non-progressors were censored at time of last examination. Models included the top two principal components from population stratification analyses, sex, and age at baseline, and accounted for correlation between an individual’s eyes.

Results : Thirteen SNPs (in strong linkage disequilibrium) in the RRAGC gene on chromosome 1 had genome-wide significant main effects (at rs188028731, p=1.2x10^-9, hazard ratio=3.1, 95% CI=2.2-4.5). These SNPs were associated with a shorter time to progression. Two other intergenic regions on chromosomes 3 (p=3.2x10^-8) and 12 (p=8.5x10^-10) produced genome-wide significant results. The 52 known AMD risk variants were not statistically significant.

Conclusions : RRAGC regulates mTORC1 signaling. This pathway influences neovascularization in AMD and is a target for drug development. Thus, identification of RRAGC as a progression locus may facilitate development of strategies for slowing progression rate from intermediate AMD to advanced AMD, slowing vision loss, and improving management of the disease in patients.

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