Response to AREDS Supplements According to Genetic Factors

Survival Analysis Approach Using the Eye as the Unit of Analysis

Johanna M Seddon; Rachel E Silver; Bernard Rosner


Br J Ophthalmol. 2016;100(12):1731-1737. 

In This Article

Abstract and Introduction


Background/aims The Age-Related Eye Disease Study (AREDS) reported the beneficial impact of antioxidant and zinc supplements on the risk of progression to advanced stages of age-related macular degeneration (AMD). We evaluated the role of genetic variants in modifying the relationship between supplementation and progression to advanced AMD.

Methods Among 4124 eyes (2317 subjects with a genetic specimen), 882 progressed from no AMD, early or intermediate AMD to overall advanced disease, including geographic atrophy (GA) and neovascular disease (NV) over the course of the clinical trial. Survival analysis using individual eyes as the unit of analysis was used to assess the effect of supplementation on AMD outcomes, with adjustment for demographic, environmental, ocular and genetic covariates. Interaction effects between supplement groups and individual complement factor H (CFH) Y402H and age-related maculopathy susceptibility 2 (ARMS2) genotypes, and composite genetic risk groups combining the number of risk alleles for both loci, were evaluated for their association with progression.

Results Among antioxidant and zinc supplement users compared with the placebo group, subjects with a non-risk genotype for CFH (TT) had a lower risk of progression to advanced AMD (HR: 0.55, 95% CI 0.32 to 0.95, p=0.033). No significant treatment effect was apparent among subjects who were homozygous for the CFH risk allele (CC). A protective effect was observed among high-risk ARMS2 (TT) carriers (HR: 0.52, 95% CI 0.33 to 0.82, p=0.005). Similar results were seen for the NV subtype but not GA.

Conclusions The effectiveness of antioxidant and zinc supplementation appears to differ by genotype. Further study is needed to determine the biological basis for this interaction.


Age-related macular degeneration (AMD) is the leading cause of blindness, irreversible vision loss and reduced quality of life among adults over age 65. The multifactorial aetiology of AMD is encompassed by a complex web of risk factors, both heritable and modifiable, that influence progression to advanced stages of disease.[1] Combined demographic, behavioural and genetic factors have been incorporated into validated, comprehensive risk models for progression.[2–5] Subsequent inclusion of newly identified genetic variants has enhanced the predictability of these models over time,[6,7] and increasing evidence has emerged that supports plausible interactions between these genetic and modifiable factors.[8,9] Understanding this interplay is of utmost importance when considering the preventive and therapeutic strategies involved in patient care.

The impact of nutritional supplements on rate of progression to advanced AMD for patients within specific genotype groups has been a subject of debate. The controversy surrounding whether genetic testing should be required prior to selecting specific supplements has been particularly noteworthy, and complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) have been of primary interest as genes associated with AMD and its progression.[10] The Age-Related Eye Disease Study (AREDS) originally evaluated the impact of supplements consisting of antioxidants (vitamin E, vitamin C and beta-carotene) and zinc and reported a 25% reduced risk of progression to advanced AMD over 5 years.[11] The first evidence of a differential treatment effect on progression according to genotype demonstrated that the odds ratio of progression for the combined antioxidant and zinc group versus the placebo group was lower for non-risk CFH subjects compared with high-risk subjects.[2,12] More recent publications evaluated similar relationships between treatment and genotype; however, these studies revealed conflicting results.[13–16]

Given the emergence of personalised medicine and targeted therapies, it is important to consider the utility of evaluating individual genotypes in order to inform the selection of patient-specific strategies.[7] We therefore aimed to further evaluate the specific genotypes for CFH Y402H and ARMS2 that modify the relationship between supplementation and progression. Our study differs from previous publications by the analytic method selected, namely the use of survival analysis that evaluates individual eyes, and includes a larger component of the AREDS population with a genetic specimen.