Abstract
Purpose :
Several genes have been shown to be associated with rate of progression to advanced age-related macular degeneration (AMD). Lifestyle factors are also related to this transition. However, associations of many of these predictors with age of progression have not been evaluated.
Methods :
Progression to advanced AMD was based on the severity scale in the Age-Related Eye Disease Study database. An eye that progressed was defined as a transition from non-advanced dry AMD without any evidence of geographic atrophy (GA) (scales 1-8) to any GA or evidence of neovascularization (NV) or both (scales ≥9) during 12 years follow up. Genotyping was performed by our study labs. A stepwise selection of genetic variants related to age of progression using PROC PHREG of SAS with the eye as the unit of analysis and using age as the time scale yielded 11 genetic variants associated with progression, adjusting for sex, education, smoking history, BMI, baseline severity scale, and AREDS treatment. Multivariate analysis was performed to calculate the effect of each variant and each covariate on age of progression using PROC MIXED of SAS.
Results :
A total of 5327 eyes with complete data were analyzed and 1169 eyes progressed to advanced AMD. The genetic variants associated with progression to advanced AMD selected from the stepwise model included genes in several pathways: complement, immune, inflammatory, lipid, extracellular matrix, DNA repair and protein binding. Among these, 3 variants showed a significant association with earlier age of progression adjusting for other covariates: CFH R1210C (P=0.022) with 4.6 years earlier age at progression among carriers of this mutation, C3 K155Q (P=0.016) with 2.35 years earlier age at progression for carriers, and ARMS2/HTRA1 A69S (P=0.025) with 0.61 years earlier age of progression per allele. Subjects who were smokers (P<0.001) or had higher BMI (P=0.014) also had an earlier age at progression to advanced disease (4 years and 1.3 years, respectively).
Conclusions :
Genetics and some modifiable factors are associated with age at time of progression to GA and NV. Carriers of rare variants in the complement pathway and subjects with a common risk allele in ARMS2/HTRA1 have an earlier age of onset to advanced disease. Furthermore, unhealthy behavioral factors confer risk of earlier age of progression from non-advanced to advanced stages of AMD.
This is a 2020 ARVO Annual Meeting abstract.