Abstract
Purpose :
To evaluate the associations between dysfunctional CFI rare variant carrier status and progression to advanced age-related macular degeneration (AMD), geographic atrophy (GA) and neovascular disease (NV) in a prospective analysis.
Methods :
Analyses were performed using the Seddon Longitudinal Cohort Study (SLCS) of AMD (N=2116 subjects, 3901 eyes, mean follow-up 8.3 years, 22% progression rate to advanced AMD, PMID 30389371) and the Age-Related Eye Disease Study (N=2837 subjects, 5200 eyes, mean follow-up 9.2 years, 18% progression rate to advanced AMD). CFI rare variants with low serum factor I levels and decreased function in a serum based assay (PMID’s 24036952 and 32908800), and other common and rare genetic variants related to AMD, demographic and behavioral factors, and baseline and follow-up macular status were evaluated. To estimate the effect of rare dysfunctional CFI variant status on AMD progression, independent of other variants related to progression, odds ratios (OR) were calculated based on Generalized Estimating Equations. Interactions between CFI carrier status and other variants were determined.
Results :
Among the 4953 subjects (9101 eyes) in the combined cohort, 1% were rare CFI variant carriers and 44% of the carriers progressed to overall AMD compared with 20% of non-carriers (P < .0001). For advanced AMD subtypes, 30% of carriers versus 10% of non-carriers progressed to GA (P < .0001), and 18% of carriers and 11% of non-carriers progressed to NV (P=.049) over a 12-year follow-up period. CFI carriers were more likely to have a family history of AMD (CFI variant: 36% with 1 family member affected and 14% with 2+ family members affected; no CFI variant: 19% with 1 family member affected and 8% with 2+ family members affected; P for trend =.035). CFI variant carrier status was associated with progression to GA (OR 1.91, 1.03-3.52) but not with NV (OR 0.96, 0.54-1.71), after adjustment for demographic and ocular factors and other genetic variants (Figure). CFI rare variant carrier status was associated with the common CFI (PMID 18685559) and hepatic lipase C (LIPC, PMID 20385826) genetic variants, but no significant interactions between CFI carrier status and other genetic variants were noted for progression to advanced AMD, GA or NV.
Conclusions :
These new findings suggest that carriers of dysfunctional CFI rare variants are at higher risk for progression to GA.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.