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Response to AREDS supplements according to genetic factors: survival analysis approach using the eye as the unit of analysis
  1. Johanna M Seddon1,2,3,
  2. Rachel E Silver1,
  3. Bernard Rosner4
  1. 1Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, Massachusetts, USA
  2. 2Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts, USA
  3. 3Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA
  4. 4Channing Division of Network Medicine, Harvard Medical School, Harvard University, Boston, Massachusetts, USA
  1. Correspondence to Johanna M Seddon, Ophthalmic Epidemiology and Genetics Service, Tufts Medical Center, 800 Washington St. #450, Boston, MA 02111, USA; jseddon{at}


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.

  • Epidemiology
  • Treatment other
  • Genetics
  • Macula

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  • Contributors The authors' responsibilities were as follows—JMS and BR: designed and conducted the research; BR: analysed the data or performed the statistical analysis; and all authors wrote the manuscript and have primary responsibility for the final content.

  • Funding This work is supported by R01-EY11309 and R01-EY022445 from the National Institutes of Health; the Massachusetts Lions Eye Research Fund, New Bedford, MA; unrestricted grants from Research to Prevent Blindness, New York, NY and the Age-Related Macular Degeneration Research Fund, Ophthalmic Epidemiology and Genetics Service, Tufts Medical Center, Tufts University School of Medicine, Boston, MA.

  • Competing interests JMS: research grant – Novartis. BR: statistical critique of one article – ArcticDx.

  • Ethics approval Institutional Review Boards at participating centres approved the original AREDS. This manuscript only involves secondary data analysis using de-identified data.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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