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L. A. Hecker, A. O. Edwards, E. Ryu, K. H. Baratz, W. L. Brown, P. Charbel Issa, H. P. N. Scholl, B. Pollok-Kopp, K. E. Schmid-Kubista, M. Oppermann; Systemic Complement Activation Increases the Risk of Developing AMD. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3520.
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To determine if systemic complement activation increases the risk of having age-related macular degeneration (AMD) and to understand how established genetic variants for AMD combine with plasma biomarkers of complement activation to predict development of AMD.
Proteins in the alternative pathway of complement (substrate protein factor B, pathway regulators factors D and H, and activation products Ba, C3d, and C5a) were quantified in plasma from 125 AMD and 149 control subjects without AMD. Subjects were genotyped for polymorphisms in CFH (rs800292, rs1061170, rs1048663, rs2274700, rs412852, rs11582939), complement factor B (rs4151667), complement component C2 (rs9332739, rs547154), complement component C3 (rs2230199), and ARMS2 (rs10490924). The impact of covariates on protein levels in control subjects was determined and correction made for significant effects. Statistical analysis to compare protein medians (µg/ml) between cases and controls employed non-parametric quantile regression. For prediction of AMD status, stepwise logistic regression was performed and AUC values calculated.
The chronic activation products Ba (AMD = 1.07, control = 0.78, p = 0.007) and C3d (AMD = 40.73, control = 35.82, p= 0.002) were significantly elevated in plasma from AMD subjects demonstrating increased systemic activation of the alternative pathway of complement. Further, the regulatory protein factor D (AMD = 1.50, control = 1.16, p<0.0001) and factor B substrate (AMD = 1103.0, control = 984.8, p = 0.01) were significantly elevated in AMD subjects. Risk genotypes in the CFH and C2/BF loci were associated with increased plasma levels of chronic activation products (Ba, C3d), factor B substrate, and factor D. Models using combinations of both proteomic and genetic biomarkers predicted having AMD. Plasma complement levels remained as an independent risk for AMD in a combined proteogenomic model.
Systemic activation of the alternative pathway of complement is associated with increased risk of AMD and correlates with genetic variants in complement genes previously associated with AMD. Both plasma protein levels and genetic markers were predictive of having AMD. Plasma complement activation persisted as an independent risk, after adjusting for the genetic risks. Thus, non-genetic factors also appear to increase AMD risk through activation of the alternative pathway of complement.
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