Rare Dysfunctional Complement Factor I Genetic Variants and Progression to Advanced Age-Related Macular Degeneration

PURPOSE: To evaluate associations between rare dysfunctional Complement Factor I (CFI) genetic variant status and progression to advanced age-related macular degeneration (AAMD), geographic atrophy (GA) and neovascular disease (NV). DESIGN: Prospective, longitudinal study PARTICIPANTS: Patients aged 55-80 years at baseline identifying as white with non-advanced AMD in one or both eyes at baseline were included. Follow-up grades were assigned as early, intermediate, or AAMD (GA or NV). CFI variants were categorized using genotyping and sequencing platforms. METHODS: Analyses were performed using the Seddon Longitudinal Cohort Study (N = 2116 subjects, 3901 eyes, mean follow-up 8.3 years) and the Age-Related Eye Disease Study (N = 2837 subjects, 5200 eyes, mean follow-up 9.2 years). CFI rare variants associated with low serum factor I (FI) protein levels and decreased FI function (type 1), other AMD genetic variants, demographic, behavioral, and ocular factors were evaluated. Generalized Estimating Equations methods were used to assess the association between CFI rare variants and progression, independent of other genetic variants and covariates. MAIN OUTCOME: Progression to AAMD, GA, or NV. RESULTS: In the prospective cohort of 4953 subjects (9101 eyes with non-advanced AMD at baseline), 1% were type 1 rare CFI carriers. Over 12 years, progression to AAMD was 44% for carriers and 20% for non-carriers (P <0.001) while 30% of carriers versus 10% of non-carriers progressed to GA (P < 0.001); 18% of carriers compared to 11% of non-carriers progressed to NV (P = 0.049). CFI carriers were more likely to have a family history of AMD (P for trend = 0.035) and a higher baseline AMD grade (P<0.001). After adjusting for all covariates, CFI carrier status was associated with progression to GA (OR = 1.91; 95% CI = 1.03, 3.52) but not NV (OR = 0.96). Higher BMI was associated with progression among CFI carriers (BMI [≥]25 vs <25; OR = 5.8; 95% CI 1.5, 22.3), but not for non-carriers (OR = 1.1; 95% CI = 0.9, 1.3), with P_interaction = 0.011. CONCLUSIONS: Results suggest that carriers of rare dysfunctional type 1 CFI variants are at higher risk for progression to AAMD with GA.