Genetic Risk Score Predicts of Severity of Age-related Macular Degeneration

Abstract

Purpose: Impact of a genetic risk score based on 16 AMD risk loci on asymmetric AMD severity & progression. We hypothesized that a genetic risk score would contribute significantly to differences between AMD progressors & non-progressors and severity of AMD.

Methods: Clinical & genotype risk factor data on two sets of patients were evaluated. Patients who entered the study with nonexudative AMD (Grades 1, 2, 3 or 4) in both eyes and followed annually were in group 1. Group 2 contained patients who had exudative AMD (grade 5) in one or both eyes when they entered the study. Evidence of progression or non-progression of AMD grade in eyes with grade 4 or less was analyzed by evaluating serial fundus photographs. Progressors were defined as those who advanced by one or more grade or whose condition within a grade worsened clinically. Of 50 group 1 patients, 32 were progressors & 18 non-progressors. We tested progression of AMD against a weighted genetic risk score calculated based on 16 AMD risk variants. Age at initial exam, smoking & gender were included as covariates and analyzed using logistic regression. In group 2, 482 patients with grade 5 AMD in both eyes were compared to 491 patients with grade 5 in one eye only. An additional subset analysis was done on patients with Grade 5 in one eye & Grades 2, 3, or 4 in the fellow eye for determining the influence of genetic risk score against disease severity.

Results: No significant association was detected when progressors and non-progressors were compared in this small sample (group 1). When group 2 patients with grade 5 AMD were stratified based on unilateral (n=491) or bilateral disease (n=482), we detected a significant effect from the risk score (P<0.0003; OR=4.85; 95% CI 2.69-8.76) when included along with gender & age at exam. Including smoking as a covariate decreased our sample size to 726, & significance remained trending. Comparing the unilateral grade 5 patients with grades 1, 2, 3 or 4 in the fellow eye and bilateral grade 5, the LSMEANS of the risk score trended significantly higher as the AMD severity rose in the fellow eye - 1.06710658, 1.17629142, 1.20540778, 1.26111358 respectively, with the highest in bilateral grade 5 patients - 1.28466396.

Conclusions: Cumulative genetic risk appears to predict severity of AMD in a subset of individuals with Grade 5 in one versus both eyes, and trended upwards as the severity of AMD grade increased in the fellow eye.

Keywords: 412 age-related macular degeneration • 539 genetics • 464 clinical (human) or epidemiologic studies: risk factor assessment