Response to AREDS supplements according to genetic factors: survival analysis approach using the eye as the unit of analysis

Br J Ophthalmol. 2016 Dec;100(12):1731-1737. doi: 10.1136/bjophthalmol-2016-308624. Epub 2016 Jul 28.


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.

Trial registration number: NCT00594672, pre-results.

Keywords: Epidemiology; Genetics; Macula; Treatment other.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Alleles
  • Antioxidants / administration & dosage*
  • Complement Factor H / genetics
  • Complement Factor H / metabolism
  • DNA / genetics*
  • Dietary Supplements
  • Disease Progression
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Genotype
  • Geographic Atrophy / genetics*
  • Geographic Atrophy / therapy
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Prospective Studies
  • Proteins / genetics*
  • Proteins / metabolism
  • Risk Factors
  • Survival Analysis
  • Zinc Compounds / administration & dosage*


  • ARMS2 protein, human
  • Antioxidants
  • CFH protein, human
  • Proteins
  • Zinc Compounds
  • Complement Factor H
  • DNA

Associated data