Dietary folate, B vitamins, genetic susceptibility and progression to advanced nonexudative age-related macular degeneration with geographic atrophy: a prospective cohort study

Am J Clin Nutr. 2016 Apr;103(4):1135-44. doi: 10.3945/ajcn.115.117606.


Background: There is growing evidence of the importance of nutrition in age-related macular degeneration (AMD), but few studies have explored associations with folate and B vitamins. No effective therapeutic strategy for geographic atrophy (GA) is available, and prevention could be of great value.

Objective: We investigated associations between dietary folate, B vitamins, and progression to GA and whether these associations might be modified by genetic susceptibility.

Design: Among 2525 subjects (4663 eyes) in the Age-Related Eye Disease Study, 405 subjects (528 eyes) progressed to GA over 13 y. Folate and B vitamins were log transformed and calorie adjusted separately for men and women. Ten loci in 7 AMD genes [complement factor H, age-related maculopathy susceptibility 2/high-temperature requirement A serine peptidase 1, complement component 2, complement component 3, complement factor B, collagen type VIII α 1, and RAD51 paralog B] were examined. Survival analysis was used to assess associations between incident GA and dietary intake of folate and B vitamins. Interaction effects between these nutrients and genetic variation on AMD risk were also evaluated. Subjects with at least one eye free of advanced AMD at baseline were included in these analyses.

Results: There was a reduced risk of progression to GA with increasing intake of thiamin, riboflavin, and folate after adjusting for age, sex, and total energy intake (P-trend = 0.01, 0.03, and 0.001, respectively). After adjustment for demographic, behavioral, ocular, and genetic covariates, trends remained statistically significant for folate (P-trend = 0.007) and were borderline for thiamin (P-trend = 0.05). Riboflavin did not retain statistical significance (P-trend = 0.20). Folate was significantly associated with lower risk of incident GA among subjects homozygous for the complement component 3 (C3) R102G rs2230199 nonrisk genotype (CC) (HR = 0.43; 95% CI: 0.27, 0.70; P = 0.0005) but not subjects carrying the risk allele (G) (P = 0.76). Neither folate nor any B vitamin was significantly associated with neovascular AMD.

Conclusions: High folate intake was associated with a reduced risk of progression to GA. This relation could be modified by genetic susceptibility, particularly related to the C3 genotype. This trial was registered at as NCT00594672.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Body Mass Index
  • Collagen Type VIII / genetics
  • Collagen Type VIII / metabolism
  • Complement C2 / genetics
  • Complement C2 / metabolism
  • Complement C3 / genetics
  • Complement C3 / metabolism
  • Complement Factor B / genetics
  • Complement Factor B / metabolism
  • Complement Factor H / genetics
  • Complement Factor H / metabolism
  • Disease Progression
  • Female
  • Folic Acid / administration & dosage*
  • Genetic Predisposition to Disease*
  • Geographic Atrophy / genetics*
  • High-Temperature Requirement A Serine Peptidase 1
  • Humans
  • Macular Degeneration / genetics*
  • Male
  • Middle Aged
  • Prospective Studies
  • Proteins / genetics
  • Proteins / metabolism
  • Riboflavin / administration & dosage
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism
  • Thiamine / administration & dosage
  • Vitamin B Complex / administration & dosage*


  • ARMS2 protein, human
  • Collagen Type VIII
  • Complement C2
  • Complement C3
  • Proteins
  • Vitamin B Complex
  • Complement Factor H
  • Folic Acid
  • High-Temperature Requirement A Serine Peptidase 1
  • HtrA1 protein, human
  • Serine Endopeptidases
  • Complement Factor B
  • Riboflavin
  • Thiamine

Associated data