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Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk

AuthorsHeurich, Meike; Martínez-Barricarte, Rubén ; Francis, Nigel J.; Roberts, Dawn L.; Rodríguez de Córdoba, Santiago ; Morgan, B. Paul; Harris, Claire L.
Issue Date9-May-2011
PublisherNational Academy of Sciences (U.S.)
CitationProceedings of the National Academy of Sciences of the USA
AbstractCommon polymorphisms in complement alternative pathway (AP) proteins C3 (C3R102G), factor B (fBR32Q), and factor H (fHV62I) are associated with age-related macular degeneration (AMD) and other pathologies. Our published work showed that fBR32Q influences C3 convertase formation, whereas fHV62I affects factor I cofactor activity. Here we show how C3R102G (C3S/F) influences AP activity. In hemolysis assays, C3102G activated AP more efficiently (EC50 C3102G: 157 nM; C3102R: 191 nM; P < 0.0001). fB binding kinetics and convertase stability were identical, but native and recombinant fH bound more strongly to C3b102R (KD C3b102R: 1.0 ìM; C3b102G: 1.4 ìM; P < 0.0001). Accelerated decay was unaltered, but fH cofactor activity was reduced for C3b102G, favoring AP amplification. Combining disease “risk” variants (C3102G, fB32R, and fH62V) in add-back assays yielded sixfold higher hemolytic activity compared with “protective” variants (C3102R, fB32Q, and fH62I; P < 0.0001). These data introduce the concept of a functional complotype (combination of polymorphisms) defining complement activity in an individual, thereby influencing susceptibility to AP-driven disease.r_
Publisher version (URL)http://dx.doi.org/10.1073/pnas.1019338108
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