Common and rare genetic risk variants for Age-related Macular Degeneration progression in the Coimbra Eye Study.

Abstract

Purpose : To analyze the effect of common and rare genetic risk variants in AMD development in the Epidemiologic Coimbra Eye Study (CES).

Methods : Population-based cohort study. Participants underwent standardized interviews and ophthalmologic examination in the CES for AMD prevalence and incidence in central Portugal(NCT01298674,NCT02748824). Staging at both visits was performed with Rotterdam classification in a centralized reading center. Genomic DNA was isolated from blood samples. The genotyping assay was based on single-molecule molecular inversion probes for target selection and used next-generation sequencing to sequence 87 single nucleotide polymorphisms (SNPs). A total of 792 samples and 69 successfully genotyped SNPs were tested for association under an additive model, using the progression/no progression to AMD as a binary outcome. A logistic regression analysis was performed to assess allelic odds ratio (ORs) at 95% CI for each variant, adjusted for age and sex, significance level was set to 0.05.

Results : We included 142 participants who developed AMD (stages 2,3,4) during the 6.5-year follow-up and 650 controls (no AMD). Both common and rare variants were found to be associated with increased risk of developing AMD: CFH rs35292876 (OR,3.07;95%CI 1.19,7.43;P=0.015); ARMS2 rs10490924 (OR,1.51;95%CI 1.08,2.1;P=0.016); CFHR5 rs10922153 (OR,1.42;95%CI 1.09,1.85;P=0.010); and ARMS2-HTRA1 rs3750846 (OR,1.52;95%CI 1.08,2.12;P=0.015). Protective variants associated to reduced risk of progression to AMD were also identified: CFH rs10922109 (OR,0.68;95%CI 0.51,0.90;P=0.007); CFH rs1410996 (OR,0.66;95%CI 0.49,0.86;P=0.003); CNN2 rs10422209 (OR,0.63;95%CI 0.40,0.95;P=0.035); C2-CFB-SKIV2L rs429608 (OR,0.43;95%CI 0.24,0.71;P=0.002); COL10A1 rs3812111 (OR,0.76;95%CI 0.58,0.99;P=0.045); and SYN3-TIMP3 rs5754227 (OR,0.56;95%CI 0.33,0.91;P=0.026).

Conclusions : Both common and rare variants were found to be associated with the development of AMD in our epidemiological longitudinal study, while others were protective. Genetic characterization is important to pursue in different populations, as the identification of potential genetic therapeutic targets is of major interest. We will also explore the correlation between genetics, clinical and phenotypic features in risk assessment.

This is a 2021 ARVO Annual Meeting abstract.