Genetic Polymorphisms of CFH and ARMS2 Do Not Predict Response to Antioxidants and Zinc in Patients with Age-Related Macular Degeneration: Independent Statistical Evaluations of Data from the Age-Related Eye Disease Study

Abstract

Purpose: Considerable controversy has erupted in recent years regarding whether genotyping should be part of standard care for patients with age-related macular degeneration (AMD) who are being considered for treatment with antioxidants and zinc. We aimed to determine whether genotype predicts response to supplements in AMD.

Design: Three separate statistical teams reanalyzed data derived from the Age-Related Eye Disease Study (AREDS), receiving data prepared by the AREDS investigators and, separately, data from investigators reporting findings that support the use of genotyping.

Participants: The population of interest was AREDS participants with AMD worse than category 1 and genotyping data available. Data from the 2 groups overlap imperfectly with respect to measurements made: the largest common set involved 879 participants for whom the same CFH and ARMS2 single nucleotide polymorphisms were measured by both groups.

Methods: Each team took a separate but complementary approach. One team focused on data concordance between conflicting studies. A second team focused on replicating the key claim of an interaction between genotype and treatment. The third team took a blank slate approach in attempting to find baseline predictors of treatment response.

Main outcome measures: Progression to advanced AMD.

Results: We found errors in the data used to support the initial claim of genotype-treatment interaction. Although we found evidence that high-risk patients had more to gain from treatment, we were unable to replicate any genotype-treatment interactions after adjusting for multiple testing. We tested 1 genotype claim on an independent set of data, with negative results. Even if we assumed that interactions in fact did exist, we did not find evidence to support the claim that supplementation leads to a large increase in the risk of advanced AMD in some genotype subgroups.

Conclusions: Patients who meet criteria for supplements to prevent AMD progression should be offered zinc and antioxidants without consideration of genotype.