CFH, C3 and ARMS2 are significant risk loci for age‐related macular degeneration but not for late stage disease progression

Abstract

Abstract Purpose Variants in the genes encoding complement factor H (CFH), complement component 3 (C3) and age‐related maculopathy susceptibility 2 (ARMS2) have repeatedly been shown to confer significant risks for age‐related macular degeneration (AMD). However, their role in disease progression and thus their relevance for the design of targeted therapeutic intervention remains unknown. Methods Association between variants in CFH, C3 and ARMS2 and disease progression of late atrophic AMD was analyzed. Patients were selected from the multicenter FAM study cohort (n=619) and compared with 612 matched controls. A quantitative phenotype of disease progression was computed based on longitudinal observations by fundus autofluorescence imaging. Results In a subset of 99 cases with pure bilateral geographic atrophy (GA), variants in CFH (Y402H), C3 (R102G), and ARMS2 (A69S) are associated with disease (P=1.6×10‐9, 3.2×10‐3, and P=2.6×10‐12, respectively). Median progression rate of GA over a mean follow‐up period of 3.0 years was 1.61 mm2/year with high concordance between fellow eyes. No association between the quantitative progression variable and any of the genetic risk variants at the three loci was observed (P>0.13). Conclusion Variants at CFH, C3, and ARMS2 confer significant risks for atrophic AMD; however there is no association with disease progression. Consequently, treatment options targeted at ameliorating pathogenic effects mediated by any one of the three susceptibility factors are likely to fail once atrophic manifestations of AMD have developed. Other, as yet unknown susceptibilities may influence disease progression.