Abstract
Purpose :
The two most common genetic contributors to age-related macular degeneration (AMD) are variants associated with the CFH-CFHR5 locus on chromosome 1q32 (Chr1 locus) and the ARMS2/HTRA1 genes on chromosome 10q26 (Chr10 locus). We sought to evaluate associations between first manifestation of complete retinal pigment epithelium and outer retinal atrophy (cRORA) and genetic risk at the Chr1 and Chr10 loci.
Methods :
Subjects recruited and followed as part of a large observational case series at the Steele Center for Translational Medicine, John A. Moran Eye Center, University of Utah were stratified based on risk, neutral or protective diplotypes at the Chr1 and Chr10 loci. Serial retinal imaging data were reviewed for the presence of cRORA in the absence of any signs of active or regressed exudation. Associations between genetic groups and first presentation of cRORA were analyzed.
Results :
At total of 307 eyes of 235 subjects (median age at first visit 75.9 IQR 11.0 years) from six diplotype groups were included. The median initial absolute size of cRORA (p = 0.7) and the median time interval between the last visit before conversion and the visit with first recorded conversion (p = 0.6) did not differ between the six groups. At the earliest timepoint of cRORA manifestation, individuals (n = 19) homozygous risk at both Chr1 and Chr10 were the youngest (median 73.4 [68.3; 74.4]), as compared to individuals (n=20) homozygous at Chr10 only (77.0 [72.5; 85.2]) or (n=79) homozygous at Chr1 only (78.4 [71.9; 83.9]). Comparing individuals heterozygous risk at Chr1 who had different genetic risk at Chr10, the median age of first cRORA manifestation was youngest with concomitant homozygous risk at Chr10 (n=12, 75.7 [71.2; 83.3]), followed by concomitant heterozygous risk at Chr10 (n=72, 78.4 [73.6; 84.2]) followed by no risk at Chr10 (n= 36, 81.5 [75.8; 86.5]).
Conclusions :
Increasing genetic risk and particularly risk at Chr10 appears to be associated with younger presentation of cRORA. Understanding the differential effects of ARMS2/HTRA1 and CFH-CFHR5 risk alleles on the impact of retinal atrophy and degeneration in AMD will likely have important implications for patient management and upcoming treatment strategies.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.