Genetic Testing in Persons with Age-Related Macular Degeneration and the Use of the AREDS Supplements: To Test or Not to Test?

Abstract

The controversy surrounding the use of genetic testing to guide the treatment of persons with age-related macular degeneration (AMD) continues. In 2001, the results of the Age-Related Eye Disease Study (AREDS), a placebo-controlled trial, demonstrated that oral supplementation with a combination of antioxidant vitamins and zinc reduced the risk of progression to late AMD by 25% in persons with intermediate AMD in at least one eye.1 Klein et al evaluated the influence of the genotypes complement factor H (CFH) (Y402H, rs1061170) and LOC387715/age-related maculopathy susceptibility 2 (ARMS2) (A69S, rs10490924) on the response to treatment with AREDS supplements (combination of antioxidants and zinc), zinc alone, or antioxidants alone in 876 AREDS participants who had available DNA and who were at high risk of developing advanced AMD.2 Although there was a possible interaction between CFH genotype and treatment, Klein et al concluded that the AREDS supplements were associated with a general reduction in the risk of developing late AMD in all genotype groups compared with placebo, and neither antioxidant alone nor zinc alone was superior to the antioxidant and zinc combination in any of the genetic groups examined. Awh and his colleagues created a genetic test to evaluate CFH and ARMS2 genes, and performed retrospective analyses of AREDS subgroups (n=989).3 They claimed that treatment with the AREDS supplements should be tailored according to the patient’s genotype, suggesting the need to genotype all patients taking the AREDS supplements. The AREDS investigators compared response to treatment in individuals with different genotype configurations in a larger group of AREDS participants (n=1,237) and failed to find statistically significant differences in response to treatment with AREDS supplement.4 In this current issue, Awh et al have further refined their genetic subgroups based on outcome, and furthered their claim that AREDS supplements can be harmful to individuals with certain genotypes.5 Are these findings by Awh et al true associations or are they the result of chance, selection bias, or some other confounder? Our request for the identification codes of the AREDS participants in their analyses was turned down. Since the DNA and data used by Awh et al. originated from our AREDS dataset, we have reconstructed their sample – which represents only a subset of AREDS participants for whom genetic information is available. Based on when and how the DNA were requested, we are confident of the identification codes for 893 (90%) of the 989 participants used in their analyses, which we verified by finding similar progression rates to late AMD and similar risk ratios for each of the supplements in each of their genetic risk groups. We agree with Awh et al, that the ultimate test of the validity of their study is a replication sample.5 Thus, it is fortuitous that Awh and colleagues had access to only a portion of the AREDS patients with available DNA. We were able to assemble a validation cohort from the remaining patients (n=526) and this cohort is referred here as the “residual cohort”. If the findings from Awh’s recent report are correct, the results of the analysis from this residual cohort will likely be in the same direction (either beneficial or harmful), and on average, of the same magnitude as those published by Awh et al, validating their analysis. However, if Awh’s results were generated by selection bias and not true associations, the results would be different, likely regressing to the overall mean differences observed in the AREDS primary study results.