Levels of Complement Activation Differ Between Stages of Age-related Macular Degeneration.

Abstract

 

Purpose

 

It has been well established that overactivation of the complement system plays an important role in the development of age-related macular degeneration (AMD). We have conducted this retrospective case-control study to learn about levels of complement activation (CA) in different stages of the disease and how this may be influenced by genes and treatment.

 

Methods

 

We included 887 patients and 1004 controls from the European Genetic Database (EUGENDA). Patients were classified as early, intermediate or advanced AMD, the latter subdivided in geographic atrophy (GA), active choroidal neovascularization (CNV) or inactive CNV.<br /> Serum CA (defined as the C3d/C3 ratio) was measured in all participants.<br /> General linear models were used to evaluate the differences in CA between AMD stages. In the same way we evaluated the effect of anti-VEGF treatment in the past three months before examination and single nucleotide polymorphisms (SNPs) involved in the complement system.

 

Results

 

Significant differences in CA were observed between AMD stages. Mean CA was lowest in controls (P<0.05 compared to all AMD groups except for inactive CNV). The highest levels of CA were observed in cases with GA and intermediate AMD.<br /> Three SNPs in CFH, CFB and C3 were significantly associated with CA. After dividing the participants in two groups based on genetic risk (>4 risk alleles or ≤3 risk alleles) we could only replicate the association between AMD stage and CA in the high risk group.<br /> In addition to a genetic influence we also observed an effect of treatment on CA. Patients with anti-VEGF treatment in the last three months had lower CA levels (P = 0.036).

 

Conclusions

 

Our findings show that CA varies among the AMD stages and is highest in patients with intermediate AMD and GA. These differences seem most prominent in cases with a high genetic predisposition Next to this, patients who received anti-VEGF were found to have lower CA levels, suggesting that anti-VEGF lowers CA. Our results suggest that CA in AMD is a dynamic process. These data may have important implications for determining at what stage of the disease complement inhibitors may play a role in AMD treatment and who should benefit from treatment: is there a role for genetic testing?<br /> Our results shed new light on the relation between CA and AMD, but these findings need to be replicated in longitudinal data in order to evaluate the dynamics of CA in AMD in more detail.