Progression of Geographic Atrophy in Age-related Macular Degeneration

Abstract

Analyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning.

Risk factors for progression of age‐related macular degeneration

“…Multifocal lesions may have increased GA growth since they have a larger border of the active disease process. The location of the lesion is also found to be associated with the progression of the GA. Extrafoveal lesions seem to have faster growth rates (0.31–0.33 mm year −1 or 2.05 mm 2 year −1 ) when compared to foveal lesions (0.22–0.27 mm year −1 or 1.28 mm 2 year −1 ) …”

“…This common variant is in perfect LD ( R 2 = 1.0) with the rs3750846 variant in the original discovery GWAS of 2016. Several prospective studies have confirmed that the minor allele of this variant is a risk factor for the incidence of early AMD (OR 1.36), and progression to nAMD (HR 1.4–2.8) and GA (HR 1.4–3.3), and increased GA growth (the wildtype, heterozygous and homozygous combination had progression rates of 0.23, 0.30 and 0.32 mm year −1 , respectively) . Functional studies suggest that the ARMS2 gene may encode a protein which has a function in the mitochondrial outer membrane of the retina, while other reports suggest that it encodes an extracellular protein .…”

“…Natural history studies show that the GA enlargement is dependent on the baseline GA area, showing an exponential increase in GA area over time. Of note, some studies suggest that this acceleration is dependent on the GA lesion at a specific time point, showing an acceleration of the GA growth in earlier stages of GA and deacceleration of GA growth at later stages of GA when there are no remaining RPE cells in the macula . However, when the GA enlargement is adjusted for the baseline lesion size by using a square root transformation, the lesion itself seems to have less influence on the GA growth.…”

“…The minor allele of the rs116503776 variant in C2/CFB is a protective allele for disease progression to late stage AMD (HR 0.56); the minor allele of the rs10033900 variant in CFI is a risk allele for AMD, but has only been confirmed to be associated with disease progression to GA (HR 1.19); and the minor allele of the rs2230199 variant in C3 is a risk allele for AMD and confirmed to be a risk factor for the incidence of early AMD (HR 1.22), and progression to nAMD (HR 1.25) and GA (HR 1.26) . Interestingly, when GA had developed, the minor allele of the rs2230199 variant in C3 was a protective factor for GA growth (the wildtype, heterozygous and homozygous combination had progression rates of 0.30, 0.27 and 0.15 mm year −1 , respectively), which was later confirmed in another cohort . The authors hypothesised that AMD‐associated variants may have differential effects at different disease stages.…”

A Deep Learning Model for Segmentation of Geographic Atrophy to Study Its Long-Term Natural History

“…For example, Domalpally et al observed 0.30 mm/year, 29 and Keenan et al observed 0.28 mm/year. 41 A reason for this may be the dependence of growth rate on baseline area. When we split the dataset on baseline lesion size, we observed that small lesions have larger square root growth rates (see Table 2).…”