Genetic risk score on select genes provides predictive tool for second eye involvement in AMD

Research, led by scientists at the Kyoto University Graduate School of Medicine, Japan, has demonstrated that the Genetic Risk Score (GRS), using five previously characterised risk genes, ARMS2, CFH, TNFRSF10A, VEGFA and CFI, show a significant association with second-eye involvement in AMD. While a number of genome wide association studies of AMD in the first eye have been conducted, the Japanese research group highlighted a scarcity of data on the extent to which known AMD susceptibility genes might contribute to second-eye involvement. As a result, the research team sought to assess survival analysis in relation to the genotypes of 11 of 19 reported AMD susceptibility genes.


The multicentre retrospective open cohort study consisted of 891 unilateral AMD patients recruited from Kyoto University Graduate School of Medicine, Fukushima Medical University and Kobe City General Hospital. The subjects were followed for a period of least 1 year and genotyping was performed using Illumina OmniExpress, HumanOmni2.5-8, and/or HumanExome. Survival analyses and Cox proportional hazard models were used to define the association between 11 AMD susceptibility genes and the duration of time until second-eye involvement occured. Results from the study showed that the ARMS2 rs10490924 recessive model (hazard ratio [HR]meta = 2.04; Pmeta = 3.4 X10^-3) and CFH rs800292 additive model (HRmeta =1.77; Pmeta = 0.013) showed significant associations with second-eye involvement. According to the published results, the dominant model of TNFRSF10A rs13278062, VEGFA rs943080, and CFI rs4698775 showed consistent effects across three datasets (I^2 = 0%; HRmeta = 1.46, 1.30, 1.51, respectively. The GRS of the five single nucleotide polymorphisms (SNPs) was also significantly associated (HRmeta [per score] = 2.42; P = 2.2 X 10^-5; I^2 = 0%). Analysis of the data showed that after 10 years from the first visit, the patients within the top 10% by GRS showed a 51% hazard rate, in contrast to 2.3% among patients within the lowest 10% by GRS.


According to the research team, a surprising outcome of the study was that 51% of patients with higher GRS values go on to develop AMD in their second eye within 10 years from their first clinical visit. More importantly, the low hazard rate among patients with lower GRS values will be of significant clinical interest. According to the study, patients with lower GRS scores rarely develop AMD in their second eye, having a hazard rate ranging from 1.7% to 2.3% within a 10-year period from their first clinical visit. As a result, the researchers estimated that “the predictive ability of GRS was considerably higher than that of any single SNP genotype.”