Objective: To investigate associations between dietary omega-3 fatty acids and other fat intake, genes related to age-related macular degeneration (AMD), and progression to geographic atrophy (GA).

Design: Observational analysis of a prospective cohort.

Participants: A total of 2531 individuals from the Age-Related Eye Disease Study, among which 525 eyes progressed to GA and 4165 eyes did not.

Methods: Eyes without advanced AMD at baseline were evaluated for progression to GA. Behavioral data, including smoking and body mass index measurements, were collected at baseline using questionnaires. Dietary data were collected from food frequency questionnaires (FFQs) at baseline. Omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]), omega-6 fatty acids, monounsaturated, saturated, polyunsaturated, and total fat were adjusted for sex and calories and divided into quintiles (Q). Eight single nucleotide polymorphisms in 7 genes (CFH, ARMS2/HTRA1, CFB, C2, C3, CFI, and LIPC) were genotyped. Cox proportional hazards models were used to test for associations between incident GA and intake of dietary lipids and interaction effects between dietary fat intake and genetic variation on risk of GA.

Main Outcome Measures: Associations between dietary fat intake reported from FFQs, genetic variants, and incident GA.

Results: Increased intake of DHA was significantly associated with reduced risk of progression to GA in models with behavioral factors (model A) plus genetic variants (model B) (P trend = 0.01 and 0.03, respectively). Total omega-3 long chain polyunsaturated (DHA + EPA) fatty acid intake was significantly associated with reduced risk of progression in model B (Ptrend = 0.02). Monounsaturated fat was associated with increased risk in model A (P trend = 0.05). DHA intake was significantly associated with reduced risk of incident GA among those with theARMS2/HTRA1 homozygous risk genotype (hazard ratio [HR] Q5 vs Q1, 0.4; P = 0.002;P for interaction between gene and fat intake = 0.05). DHA was not associated with reduced risk of GA among those with the homozygous ARMS2/HTRA1 nonrisk genotype (HR, 1.0; P = 0.90).

Conclusions: Increased self-reported dietary intake of omega-3 fatty acids is associated with reduced risk of GA and may modify genetic susceptibility for progression to GA.