Systemic Complement Activation in Age-Related Macular Degeneration

• Published in: PloS one Vol. 3; no. 7; p. e2593
• Main Authors: Scholl, Hendrik P. N., Issa, Peter Charbel, Walier, Maja, Janzer, Stefanie, Pollok-Kopp, Beatrix, Börncke, Florian, Fritsche, Lars G., Chong, Ngaihang V., Fimmers, Rolf, Wienker, Thomas, Holz, Frank G., Weber, Bernhard H. F., Oppermann, Martin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.07.2008; Public Library of Science (PLoS)
• Subjects: Age; Age related diseases; Aged; Aged, 80 and over; Alternative pathway; Anticoagulants; Biometrics; Blindness; Blood plasma; Case-Control Studies; Complement; Complement Activation; Complement component C2; Complement component C3; Complement component C3d; Complement component C4; Complement component C5a; Complement factor B; Complement factor H; Complement Factor H - genetics; Complement Factor H - metabolism; Correlation analysis; Digitization; Enzymes; Epidemiology; Female; Genes; Genetic aspects; Genetic diversity; Genetic markers; Genetic variance; Genetic Variation; Genetics and Genomics/Genetics of Disease; Genotype; Geriatrics; Haplotypes; Humans; Immunoassay; Immunology; Immunology/Innate Immunity; Informatics; Macular degeneration; Macular Degeneration - genetics; Macular Degeneration - immunology; Male; Markers; Older people; Ophthalmology/Inherited Eye Disorders; Ophthalmology/Macular Disorders; Pathogenesis; Patients; Physiological aspects; Plasma; Polymorphism, Single Nucleotide; Population studies; Proteins; Regression analysis; Regulators; Risk Factors; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Studies; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0002593

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.