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

Abstract

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 clinicaltrials.gov as NCT00594672.

FIGURE 1

Flowchart illustrating the selection of subjects for this study who are at risk of progression to geographic atrophy from the AREDS cohort. AMD, age-related macular degeneration; AREDS, Age-Related Eye Disease Study.

FIGURE 2

Effect of dietary folate on progression to geographic atrophy according to C3 R102G genotype. HRs, 95% CIs, and P-trend were calculated by using Cox proportional hazards models adjusted for age, sex, education, smoking, BMI, AREDS treatment, multivitamin supplement use, AMD grade at baseline for both eyes, TEI, and 9 genetic variants [CFH: rs1061170 (Y402H), CFH: rs1410996, CFH: rs121913059 (R1210C), ARMS2/HTRA1: rs10490924, C2: rs9332739 (E318D), CFB: rs641153 (R32Q), C3: rs147859257 (K155Q), COL8A1: rs13095226, RAD51B: rs8017304]. AMD, age-related macular degeneration; AREDS, Age-Related Eye Disease Study; ARMS2, age-related maculopathy susceptibility 2; CFB, complement factor B; CFH, complement factor H; COL8A1, collagen type VIII α 1; C2, complement component 2; C3, complement component 3; HTRA1, high-temperature requirement A serine peptidase 1; Q, quintile; RAD51B, RAD51 paralog B; TEI, total energy intake.