CFH and ARMS2 genetic risk determines progression to neovascular age-related macular degeneration after antioxidant and zinc supplementation

Significance Age-related macular degeneration (AMD) is the leading cause of severe vision loss in the elderly and has major economic and quality-of-life impact. Prophylactic high-dose zinc and antioxidant supplements treatments are typically recommended with the assumption of homogeneously distributed benefit and risk of developing neovascular AMD. We show that individual variation at complement factor H and age-related maculopathy susceptibility 2, genes which predispose to AMD, also determines the effectiveness of nutritional prophylaxis. Some individuals paradoxically experience worsening disease with treatment, while others experience greater than average benefit. These divergent responses are difficult to identify when treatment effects have long latency. Understanding individual variations in prophylactic treatment response should inform future research and optimize health outcomes. We evaluated the influence of an antioxidant and zinc nutritional supplement [the Age-Related Eye Disease Study (AREDS) formulation] on delaying or preventing progression to neovascular AMD (NV) in persons with age-related macular degeneration (AMD). AREDS subjects (n = 802) with category 3 or 4 AMD at baseline who had been treated with placebo or the AREDS formulation were evaluated for differences in the risk of progression to NV as a function of complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genotype groups. We used published genetic grouping: a two-SNP haplotype risk-calling algorithm to assess CFH, and either the single SNP rs10490924 or 372_815del443ins54 to mark ARMS2 risk. Progression risk was determined using the Cox proportional hazard model. Genetics–treatment interaction on NV risk was assessed using a multiiterative bootstrap validation analysis. We identified strong interaction of genetics with AREDS formulation treatment on the development of NV. Individuals with high CFH and no ARMS2 risk alleles and taking the AREDS formulation had increased progression to NV compared with placebo. Those with low CFH risk and high ARMS2 risk had decreased progression risk. Analysis of CFH and ARMS2 genotype groups from a validation dataset reinforces this conclusion. Bootstrapping analysis confirms the presence of a genetics–treatment interaction and suggests that individual treatment response to the AREDS formulation is largely determined by genetics. The AREDS formulation modifies the risk of progression to NV based on individual genetics. Its use should be based on patient-specific genotype.