title: Response to AREDS supplements according to genetic factors: survival analysis approach using the eye as the unit of analysis.
abstract: OBJECTIVE
  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.
  
  
  BACKGROUND
  NCT00594672, pre-results.
authors.affiliation: Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, Massachusetts, USA.|Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts, USA.|Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts, USA.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Seddon
authors.affiliation: Ophthalmic Epidemiology and Genetics Service, New England Eye Center, Tufts Medical Center, Boston, Massachusetts, USA.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Silver
authors.affiliation: Channing Division of Network Medicine, Harvard Medical School, Harvard University, Boston, Massachusetts, USA.
authors.forename: Bernard
authors.initials: B
authors.lastname: Rosner
mesh_terms: D000368:Aged; D000483:Alleles; D000975:Antioxidants / Q000008:administration & dosage*; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D019587:Dietary Supplements; D018450:Disease Progression; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D057092:Geographic Atrophy / Q000235:genetics* / Q000628:therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D016019:Survival Analysis; D017967:Zinc Compounds / Q000008:administration & dosage*
chemical_list: C514392:ARMS2 protein, human; D000975:Antioxidants; C493495:CFH protein, human; D011506:Proteins; D017967:Zinc Compounds; D017242:Complement Factor H; D004247:DNA
keywords: Epidemiology; Genetics; Macula; Treatment other