Genotype at four loci associated with risk of advanced AMD does not predict progression rate from intermediate to advanced disease

Abstract

 

Purpose

 

Risk of developing advanced age-related macular degeneration (AMD) is associated with both environmental factors, such as age, gender and smoking history, and common and rare genetic variants at several loci. However, disease risk is just one facet of AMD disease architecture; disease progression rate is a second important component that can vary substantially among individuals. Whether genetic variants also affect progression rate from early/intermediate stages to advanced disease is largely unknown. We test whether genetic risk at 4 major AMD risk-associated loci (CFH, ARMS2, C2 and C3) also predicts disease progression.

 

Methods

 

We recruited AMD cases and monitored disease progression via regular clinical exams. Individuals were graded using the modified AREDS system. We tested whether time to disease progression from intermediate dry AMD to geographic atrophy (GA) or choroidal neovascularization (CNV) was correlated with the number of risk alleles at CFH, ARMS2, C2 and C3 using an additive disease model (0, 1 or 2 risk alleles), accounting for age at first diagnosis of intermediate dry AMD and gender. Cox proportional-hazards models were fit to allow for right censoring (some eyes had not progressed by the most recent exam), and for repeated measures (both left and right eyes may be monitored).

 

Results

 

Over the study period (max. 13 years), 184 (of 591) eyes from 401 individuals progressed from intermediate dry AMD to GA or CNV. The number of risk alleles at each of the 4 loci did not predict progression rate: CFH (HR=1.16, 95%CI=0.87-1.55, p=0.32); ARMS2 (hazard ratio (HR)=0.98, 95% CI=0.77-1.26, p=0.90); C2 (HR=0.87, 95%CI=0.66-1.15, p=0.34); C3 (HR=0.85, 95% CI=0.66-1.10, p=0.22), but older individuals had higher hazard ratios (HR= 1.06, 95% CI=1.03-1.08, p<0.01). Gender was not significant in any model.

 

Conclusions

 

The absence of a correlation between progression rate and genotype at 4 major variants known to predict AMD risk suggests that alternative genetic or environmental factors are the main cause of variation in AMD progression. These results indicate the need to test for association with novel loci and other potential environmental predictors.