gms | German Medical Science

Background: To study the levels of complement activation in different disease stages of age-related macular degeneration (AMD) and the influence of genetic polymorphisms in complement genes.

Methods: We included 797 AMD patients and 945 controls from the European Genetic Database. Patients were grouped into five AMD stages: early AMD, intermediate AMD, geographic atrophy (GA), active choroidal neovascularization (CNV) or inactive CNV. Differences in complement activation, as defined by the systemic C3d/C3 ratio, between AMD stages were evaluated using general linear modeling. In addition, we evaluated the influence of eighteen genetic AMD polymorphisms in complement genes and their effect on complement activation. Differences in complement activation were evaluated stratifying by complement associated haplotypes.

Results: Complement activation levels differed significantly between AMD disease stages. As compared to controls, the C3d/C3 ratio was higher in patients with intermediate AMD(P<0.001) and highest in GA(P=0.002). Two polymorphisms in CFH (rs10922109 and rs570618) and one in CFB (rs116503776) were significantly associated with complement activation. The association between AMD disease stage and complement activation was more pronounced in patients with a high genetic risk for complement activation.

Conclusion: Systemic complement activation levels differ between AMD disease stages, especially in individuals with high risk variants in complement genes. In general, consecutive AMD disease stages showed increasing levels of complement activation, except for active and inactive CNV. These findings contribute to the discussion on the pathogenesis of AMD in relation to complement activation and suggest refinement in the treatment with complement inhibitors with regard to patient selection and the optimum window of treatment.