Abstract
Dysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112) and controls (n = 67). Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (p<0.001), were significantly elevated in AMD patients compared to controls. Similar alterations were observed in factor D, but not in C3, C4 or factor H. Logistic regression analysis revealed better discriminative accuracy of a model that is based only on complement activation markers Ba, C3d and factor D compared to a model based on genetic markers of the complement system within our study population. In both the controls' and AMD patients' group, the protein markers of complement activation were correlated with CFH haplotypes.This study is the first to show systemic complement activation in AMD patients. This suggests that AMD is a systemic disease with local disease manifestation at the ageing macula. Furthermore, the data provide evidence for an association of systemic activation of the alternative complement pathway with genetic variants of CFH that were previously linked to AMD susceptibility.
Highlights
Age-related macular degeneration (AMD) is the leading cause of blindness in all populations of European origin [1]
Strong evidence for a role of complement in this disease derives from an independent line of research which showed that variants in the complement factor H (CFH) gene are significantly associated with an increased risk for AMD in Caucasian populations [4,5,6,7]
These genetic studies were recently extended by the observation that polymorphisms in other complement genes, notably those coding for factor B-complement component C2 (BF-C2) and complement C3 (C3), are associated with AMD [8,9,10,11]
Summary
Age-related macular degeneration (AMD) is the leading cause of blindness in all populations of European origin [1]. Strong evidence for a role of complement in this disease derives from an independent line of research which showed that variants in the complement factor H (CFH) gene are significantly associated with an increased risk for AMD in Caucasian populations [4,5,6,7]. These genetic studies were recently extended by the observation that polymorphisms in other complement genes, notably those coding for factor B-complement component C2 (BF-C2) and complement C3 (C3), are associated with AMD [8,9,10,11]. Multiple haplotypes in the CFH and BF genes appear to modulate the AMD disease risk and both diseasepredisposing and protective gene variants were identified [7,8,12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
