Complement Activation Levels Are Related to Disease Stage in AMD

Abstract

Purpose: To study the levels of complement activation in different disease stages of AMD and the influence of genetic polymorphisms in complement genes.

Methods: We included 797 patients with AMD and 945 controls from the European Genetic Database. Patients were grouped into five AMD stages: early AMD, intermediate AMD, central geographic atrophy, active choroidal neovascularization or inactive choroidal neovascularization. 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 18 genetic AMD polymorphisms in complement genes and their effect on complement activation. Differences in complement activation between stages were evaluated stratifying by complement associated haplotypes.

Results: Complement activation levels differed significantly between AMD disease stages. As compared with controls, the C3d/C3 ratio was higher in patients with intermediate AMD (P < 0.001) and central geographic atrophy (P = 0.001). 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 haplotypes associated with the highest complement activation.

Conclusions: In general, consecutive AMD disease stages showed increasing levels of complement activation, especially in individuals with a genetic burden in complement genes. These findings contribute to the discussion on the pathogenesis of AMD in relation to complement activation and might suggest refinement in patient selection and the optimum window of treatment with complement inhibitors. Prospective studies are needed to confirm these results.

Figure 1.

Association between systemic complement activation and AMD disease stage in (A) total study population, (B) participants with CFH haplotype CG, and (C) participants with other CFH haplotypes. Analysis is based on multivariate general linear modeling. P values are based on a least significant difference post hoc test between the patient groups and adjusted for the following covariates: age, sex, smoking status, BMI, and triglycerides. Overall P value of the association between AMD disease stage and systemic complement activation is P < 0.001. Red lines represent mean levels of log C3d/C3 ratio per subgroup. *Including noncentral GA. BMI, body mass index; C3, complement component 3; C3d, complement component 3d; CFH, complement factor H.

Figure 2.

Hypothetical overview of potential underlying mechanisms between genetics, complement activation and AMD. We hypothesize that, in the presence of a genetic burden and other inflammatory stimuli, complement activation levels increase. The increased complement activation may contribute directly to the onset and progression of AMD, eventually toward advanced stage central GA (arrow 1). One might speculate that the active macular disease process also elicits an inflammatory signal, especially in those with a high genetic burden, resulting in a self-perpetuating amplification loop of increasing complement activation in a proinflammatory environment (arrow 2). Progression to CNV may also involve alternative mechanisms in a VEGF-driven environment, explaining the relatively lower levels of complement activation in this patient group (arrow 3). *Including noncentral GA.