title: Common polymorphisms in C3, factor B, and factor H collaborate to determine systemic complement activity and disease risk.
abstract: Common polymorphisms in complement alternative pathway (AP) proteins C3 (C3(R102G)), factor B (fB(R32Q)), and factor H (fH(V62I)) are associated with age-related macular degeneration (AMD) and other pathologies. Our published work showed that fB(R32Q) influences C3 convertase formation, whereas fH(V62I) affects factor I cofactor activity. Here we show how C3(R102G) (C3S/F) influences AP activity. In hemolysis assays, C3(102G) activated AP more efficiently (EC(50) C3(102G): 157 nM; C3(102R): 191 nM; P < 0.0001). fB binding kinetics and convertase stability were identical, but native and recombinant fH bound more strongly to C3b(102R) (K(D) C3b(102R): 1.0 μM; C3b(102G): 1.4 μM; P < 0.0001). Accelerated decay was unaltered, but fH cofactor activity was reduced for C3b(102G), favoring AP amplification. Combining disease "risk" variants (C3(102G), fB(32R), and fH(62V)) in add-back assays yielded sixfold higher hemolytic activity compared with "protective" variants (C3(102R), fB(32Q), and fH(62I); 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.
authors.affiliation: Department of Infection, Immunity and Biochemistry, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom.
authors.forename: Meike
authors.initials: M
authors.lastname: Heurich
authors.forename: Ruben
authors.initials: R
authors.lastname: Martínez-Barricarte
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Francis
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Roberts
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodríguez de Córdoba
authors.forename: B Paul
authors.initials: BP
authors.lastname: Morgan
authors.forename: Claire L
authors.initials: CL
authors.lastname: Harris
mesh_terms: D003167:Complement Activation / Q000235:genetics*; D003176:Complement C3 / Q000235:genetics*; D050577:Complement C3-C5 Convertases / Q000378:metabolism; D011415:Complement Factor B / Q000235:genetics*; D017242:Complement Factor H / Q000235:genetics*; D004198:Disease Susceptibility / Q000276:immunology*; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D008268:Macular Degeneration; D011110:Polymorphism, Genetic / Q000276:immunology*; D011485:Protein Binding; D012307:Risk Factors
chemical_list: C038245:C3 protein, human; D003176:Complement C3; D017242:Complement Factor H; D005340:Fibrinogen; D050577:Complement C3-C5 Convertases; D011415:Complement Factor B