Joint Contribution of Genetic Susceptibility and Modifiable Factors to the Progression of Age-Related Macular Degeneration over 10 Years: The Three Continent AMD Consortium Report

PURPOSE:To assess joint effects of genetic and modifiable factors on the 10-year progression of age-related macular degeneration (AMD). DESIGN:Individual and pooled data analyses of 2 population-based cohorts. PARTICIPANTS:Blue Mountains Eye Study (BMES) and Rotterdam Study (RS) participants (n = 835). METHODS:Participants of the BMES and RS were followed up over 10 years or more. At baseline and follow-up visits, interviews using questionnaires and eye examinations with retinal photography were performed. Age-related macular degeneration was assessed by trained photographic graders and verified by retinal specialists. Genetic susceptibility to AMD meant carrying 2 or more risk alleles of the CFH or ARMS2 SNPs, or both (rs1061170 and rs10490924), relative to 0 or 1 risk allele. Discrete logistic regression models were used to investigate the joint associations of genetic susceptibility and either smoking, fish consumption, dietary intake of lutein-zeaxanthin, or combined environmental risk scores from the 3 modifiable factors with the risk of AMD progression. Odds ratios (ORs) with 95% confidence intervals (CIs) and synergy indexes are reported. MAIN OUTCOME MEASURE:Ten-year progression of AMD, categorized as any (≥1 step) or 2-step (≥2 steps) progression on the Three Continent AMD Consortium 5-step severity scale. RESULTS:Older age, the presence of AMD genetic susceptibility, and baseline AMD status were associated strongly with AMD progression (P < 0.0001). In analyses of pooled data, each additional score from the combined environmental risk scores was associated with an increased risk of 2-step progression over 10 years (OR, 1.26; 95% CI, 1.02-1.56). The copresence of AMD genetic susceptibility and combined risk score of 3 or more was associated with a substantially higher risk of 2-step progression compared with the presence of either factor alone. There was a significant synergistic effect (OR, 4.14; 95% CI, 1.07-15.95) and interaction (P = 0.025) between genetic susceptibility and environmental risk score of 3 or more. CONCLUSIONS:Among persons with AMD genetic susceptibility and pre-existing early AMD lesions, presenting with high environmental risk scores from 3 modifiable factors (smoking, infrequent consumption of fish, low lutein-zeaxanthin intake) were associated with an increased risk of 2-step progression over 10 years.