An update on the genetics of age-related macular degeneration

Abstract

Age-related macular degeneration (AMD) is a genetically complex disorder of the photoreceptor-RPE-Bruch's membrane-choriocapillaris complex. Family and twin studies have shown that the susceptibility for this disease is genetically influenced. The heritability has been estimated to be up to 71%. Linkage and association studies have identified several chromosomal regions that are likely to contain susceptibility loci with strongest evidence found on chromosome 1q31 and 10q26. Variants in the complement factor H (CFH) gene have been shown by several independent studies to be associated with an increased risk for AMD in Caucasian populations. These findings imply that the innate immune system may play a significant role in AMD pathogenesis. The LOC387715/HTRA1 locus within 10q26 has been identified as a second major locus contributing to AMD pathogenesis. The two late forms of AMD, choroidal neovascularization and geographic atrophy, have not been found to be different in risk allele distribution. Variants within CFH and LOC387715/HTRA1 may contribute to the increased risk of late AMD largely through their impact on precursors, such as drusen and/or other RPE/Bruch's membrane changes. Considering variants at CFH, LOC387715/HTRA1 and complement component 2-complement factor B (C2-FB), high-risk homozygotes at all three loci may have a 250-fold increased risk compared to baseline. However, the identification of genetic factors has not resulted in therapeutic strategies to modify the disease so far and additional genetic and environmental factors are yet to be discovered in order to influence the onset and the progression of AMD.

Figure 1

Phenotyping by means of fundus autofluorescence imaging. Fundus autofluorescence images obtained with a cSLO (Heidelberg retina angiograph, HRA 2, Heidelberg Engineering, Dossenheim, Germany) according to a standard operating procedure. Left: Patient diagnosed with Stargardt's macular dystrophy (age, 17 years); right: patient diagnosed with atrophic AMD (GA) and a fundus autofluorescence pattern "diffuse-fine granular with peripheral punctate spots" according to Bindewald et al. [34] (age: 71 years).

Figure 2

Two-locus (LOC387715 and CFH) genotype specific disease risks. Two-locus genotype specific disease risks for the two variants: LOC387715 (A69S) and CFH (Y402H) according to Rivera et al. [57].

Figure 3

Progression of geographic atrophy imaged by fundus autofluorescence. Fundus autofluorescence images obtained in 12-month intervals in an AMD patient with a cSLO (Heidelberg retina angiograph, HRA classic and HRA 2, Heidelberg Engineering, Dossenheim, Germany). A large kidney-shaped area of GA was present at baseline (left) corresponding to decreased fundus autofluorescence (dark area). Recovered in yearly intervals, the area of the central atrophic area increased [80].