title: Treatment response to antioxidants and zinc based on CFH and ARMS2 genetic risk allele number in the Age-Related Eye Disease Study.
abstract: OBJECTIVE
  To evaluate the impact of complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) risk alleles on the observed response to components of the Age-Related Eye Disease Study (AREDS) formulation.
  
  
  METHODS
  Genetic and statistical subgroup analysis of a randomized, prospective clinical trial.
  
  
  METHODS
  White patients from the AREDS with category 3 or 4 age-related macular degeneration (AMD) with available DNA (n = 989).
  
  
  METHODS
  Four genotype groups based on CFH and ARMS2 risk allele number were defined. Progression to advanced AMD was analyzed by genotype and treatment using Cox proportionate hazards estimates and 7-year events.
  
  
  METHODS
  The effect of predefined genotype group on treatment-specific progression to advanced AMD.
  
  
  RESULTS
  Patients with 2 CFH risk alleles and no ARMS2 risk alleles progressed more with zinc-containing treatment compared with placebo, with a hazard ratio (HR) of 3.07 (P = 0.0196) for zinc and 2.73 (P = 0.0418) for AREDS formulation (AF). Seven-year treatment-specific progression rates were: placebo, 17.0%; zinc, 43.2% (P = 0.023); and AF, 40.2% (P = 0.039). Patients with 0 or 1 CFH risk alleles and 1 or 2 ARMS2 risk alleles benefited from zinc-containing treatment compared with placebo, with an HR of 0.514 for zinc (P = 0.012) and 0.569 for AF (P = 0.0254). Seven-year treatment-specific AMD progression rates were as follows: placebo, 43.3%; zinc, 25.2% (P = 0.020); and AF, 27.3% (P = 0.011). Zinc and AF treatment each interacted statistically with these 2 genotype groups under a Cox model, with P values of 0.000999 and 0.00366, respectively. For patients with 0 or 1 CFH risk alleles and no ARMS2 risk alleles, neither zinc-containing treatment altered progression compared with placebo, but treatment with antioxidants decreased progression (HR, 0.380; P = 0.034). Seven-year progression with placebo was 22.6% and with antioxidants was 9.17% (P = 0.033). For patients with 2 CFH risk alleles and 1 or 2 ARMS2 risk alleles, no treatment was better than placebo (48.4%).
  
  
  CONCLUSIONS
  The benefit of the AREDS formulation seems the result of a favorable response by patients in only 1 genotype group, balanced by neutral or unfavorable responses in 3 genotype groups.
authors.affiliation: Tennessee Retina, PC, Nashville, Tennessee. Electronic address: carlawh@gmail.com.
authors.forename: Carl C
authors.initials: CC
authors.lastname: Awh
authors.affiliation: Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Hawken
authors.affiliation: Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Canada; Department of Epidemiology, Ottawa Hospital Research Institute and Division of Hematology, Department of Medicine, University of Ottawa, Ottawa, Canada; The Arctic Group of Companies, Toronto, Canada.
authors.forename: Brent W
authors.initials: BW
authors.lastname: Zanke
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000975:Antioxidants / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000627:therapeutic use; D017242:Complement Factor H / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D060005:Genotyping Techniques; D006801:Humans; D008268:Macular Degeneration / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011506:Proteins / Q000235:genetics*; D012307:Risk Factors; D014810:Vitamin E / Q000627:therapeutic use; D017967:Zinc Compounds / Q000627:therapeutic use*; D019207:beta Carotene / Q000627:therapeutic use
chemical_list: C514392:ARMS2 protein, human; D000975:Antioxidants; C493495:CFH protein, human; D011506:Proteins; D017967:Zinc Compounds; D019207:beta Carotene; D014810:Vitamin E; D017242:Complement Factor H; D001205:Ascorbic Acid