Risco Genético de Drusen Extramaculares e Degenerescência Macular Relacionada com a Idade no Coimbra Eye Study

INTRODUCTION: The genetic risk for age-related macular degeneration (AMD) was previously evaluated in the AMD incidence study (Coimbra Eye Study, NCT02748824) including a genetic risk score (GRS) analysis. In AMD most genotype-phenotype associations rely on the phenotypic analysis of the macular area, with few analyzing extramacular drusen (EMD). Genetic associations between these peripheral changes and genotypes known to be associated with AMD were explored by few groups and with conflicting results. Our purpose was to evaluate the relationship between GRS for AMD and the presence of EMD in the participants from AMD incidence study with and without AMD, and to explore whether the EMD phenotype could represent another expression of genetic susceptibility. METHODS: Multimodal imaging with color fundus photography, optical coherence tomography, autofluorescence and near-infrared imaging was used to assess the presence and staging of AMD and EMD. To test for differences in the GRS between 4 groups: AMD only, AMD+EMD, EMD only and controls, an adjusted clustered Wilcoxon rank sum test was used. Associations of GRS with EMD and AMD were assessed using adjusted logistic regression models. RESULTS: A total of 1846 eyes (939 subjects) were included: 570 eyes had EMD only, 252 eyes had EMD+AMD, 122 eyes had AMD only, and 902 eyes were controls. For genetic analysis, the phenotype-genotype sample comprised 1612 eyes (829 subjects) – 346 eyes with AMD and 1266 eyes without AMD. The GRS from control eyes was inferior compared to AMD eyes with and without EMD (p=1.4e-07; p=0.0001), and the GRS from eyes with only EMD was also inferior compared with AMD eyes with and without EMD (p=2.5e-05, p=0.0019). There was a strong association between EMD and AMD (OR=3.118,95% CI 2.239-4.342, p<0.001). GRS was associated with AMD (OR=1.444,95% CI 1.248-1.670, p<0.001), but no association with EMD was found when adjusting for the coexistence of AMD (OR=1.092,95% CI 0.964-1.235, p=0.16). CONCLUSION: Our results highlight a strong relationship between AMD and EMD. However, GRS, calculated based on risk variants for AMD, was surprisingly not associated with EMD per se in our population. Further studies are required to understand the clinical relevance of genetic risk factors in EMD, with or without AMD.