Association of Apolipoprotein E Alleles with Age-Related Macular Degeneration in a Large Cohort of Patients

Abstract

Abstract: : Purpose: Age-related macular degeneration (AMD), the leading cause of blindness in the elderly, represents an increasing international health burden, for which there are limited therapeutic interventions. Previous published studies have suggested that the APOE gene is important in the development of this disease; the ε4 allele is associated with a decreased incidence of disease and the ε2 allele with increased susceptibility. In order to determine how these results can be generalized to other study populations, we defined the genetic composition at the APOE locus for a large population of North American individuals with end-stage AMD. Methods: Study participants were identified from ophthalmic clinics in the Michigan Health System and blood samples were collected after obtaining informed consent. Retinal findings were determined by ophthalmic evaluation and graded in accordance with the AMD international grading system. Patient histories including age, sex, age at diagnosis, and family history of eye disorders were also collected. We analyzed a total of 422 unrelated Caucasian patients with either neovascularization (n=227), geographic atrophy (n=121), or bi-lateral large drusen (n=74). DNA was isolated from blood leukocytes and APOE genotypes were obtained following PCR amplification and restriction enzyme digestion. Results: APOE allele frequencies in AMD patients were 0.09 for ε2, 0.80 for ε3 and 0.11 for ε4 allele. The frequency of the ε4 allele was significantly reduced in AMD patients compared to controls (0.11 vs. 0.15, p<0.002). Although the frequency of the ε2 allele appeared higher in patients than controls (0.09 vs. 0.08), this difference is not significant. The frequency of ε4 allele was significantly decreased in both individuals with geographic atrophy (0.10 vs. 0.15, p<0.04) and individuals with neovascularization (0.10 vs. 0.15, p<0.01) compared to controls. However, the frequency of the ε2 allele was higher than controls only in individuals with neovascularization (0.10) and not in individuals with geographic atrophy (0.07). Conclusions: The frequency of the APOE-ε4 allele was significantly reduced in this large sample of patients with end-stage AMD, indicating a protective effect for AMD by the ε4 allele. Our results, based on the largest study to date, support the previous published reports of an association between APOE and AMD. Future studies are needed to determine the mechanism of action for APOE in AMD.

Keywords: age-related macular degeneration • genetics • lipids