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.
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ABSTRACT: OBJECTIVE: Risk factors for susceptibility to bacterial meningitis have been identified, but basic causes of inter-individual differences in susceptibility are largely unknown. METHODS: To determine the effect of genetic variation in the complement system on susceptibility to bacterial meningitis we performed a prospective nationwide genetic association study in patients with community-acquired bacterial meningitis. We genotyped 17 common SNPs (minor allele frequencies >5%) in genes coding for complement components and evaluated functional consequences by measuring complement levels in the cerebrospinal fluid. RESULTS: From March 2006 to June 2009 we included 636 adults with community-acquired bacterial meningitis. DNA was available for 439 patients and 302 controls. Rs1047286 (Pro314Leu) in complement component 3 was associated with reduced susceptibility to bacterial meningitis after correction for multiple testing: the protective Leu/Leu genotype was found in 5 of 435 patients (1%) compared to 15 of 302 controls (5%; odds ratio [OR] 4.50, 95% confidence interval [CI] 1.62-12.50, p = 0.0017). Rs1047286 is in strong linkage disequilibrium with Rs2230199 (C3 Arg102Gly), of which the Arg/Arg genotype was associated with higher CSF levels of C3 and lower levels of C5a and terminal complement complex (TCC; soluble C5b-9), indicating decreased consumption of C3 and less activation of the complement system. Rs1047286 was associated with susceptibility albeit not significantly after Bonferroni correction (OR 1.37, 95% CI 1.01-1.87; p = 0.04). CONCLUSIONS: This study shows an association between a common single nucleotide polymorphism in C3 and susceptibility for community-acquired bacterial meningitis.The Journal of infection 10/2012; · 4.13 Impact Factor