Complement C3 Variant and the Risk of Age-Related Macular Degeneration

Abstract

Background Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in the pathogenesis. Methods We tested for an association between age-related macular degeneration and 13 singlenucleotide polymorphisms (SNPs) spanning the complement genes C3 and C5 in case subjects and control subjects from the southeastern region of England. All subjects were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. To test for replication of the most significant findings, we genotyped a set of Scottish cases and controls. Results The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P = 5.9×10-5) and the Scottish group (244 cases and 351 controls, P = 5.0×10-5). The odds ratio for age-related macular degeneration in C3 S/F heterozygotes as compared with S/S homozygotes was 1.7 (95% confidence interval [CI], 1.3 to 2.1); for F/F homozygotes, the odds ratio was 2.6 (95% CI, 1.6 to 4.1). The estimated population attributable risk for C3F was 22%. Conclusions Complement C3 is important in the pathogenesis of age-related macular degeneration. This finding further underscores the influence of the complement pathway in the pathogenesis of this disease.

The association between macular pigment optical density and CFH, ARMS2, C2/BF, and C3 genotype

“…Subsequently, other genes associated with the complement system, namely C2/BF and C3, were also found to play a lesser role in the genetic predisposition to this condition (Gold et al, 2006;Maller et al, 2007;Yates et al, 2007). The association of the variant CFH Y402H haplotype with increased risk for AMD, and the subsequent association of certain haplotypes of C2/BF and C3 with increased risk for AMD, represents evidence that inflammation is important in the pathogenesis of AMD.…”

“…We genotyped six single nucleotide polymorphisms (SNPs) in CFH (rs419137, rs6677604, rs2284664, rs3753396, rs1061170, rs800292) and three in ARMS2 (rs10490924, rs10490923, rs2736911) enabling determination of risk and protective haplotypes across both loci in the current cohort, as described previously using multiplex PCR and primer extension methodology (ABI Snapshot, ABI Warrington, UK) (Hughes et al, 2006(Hughes et al, , 2007. In a separate Snapshot assay, two tag SNPs (rs1042663, rs2072632) identifying protective and risk haplotypes respectively across the C2/BF locus, (McKay et al, 2009) and rs2230199 identifying increased risk at C3, (Maller et al, 2007;Yates et al, 2007) were also genotyped. All primer and probe sequences are available upon request.…”

“…The strong association of the CFH Y402H variant allele with increased risk for AMD suggested an important role for the alternative complement pathway and the involvement of inflammation in the pathogenesis of AMD (Anderson et al, 2002;Hageman et al, 2005). The role of the complement system was further emphasized with the discovery of amended risk of AMD associated with the paralogous complement component 2 (C2) and complement factor B (BF) genes, and the complement component 3 (C3) gene (Gold et al, 2006;Maller et al, 2007;Yates et al, 2007). In late 2005, a second major risk allele was reported, the hypothetical LOC387715, within the locus of the age-related maculopathy susceptibility 2 (ARMS2) gene, localized to chromosome 10q26 (Rivera et al, 2005).…”

The role of the alternative pathway of complement activation in glomerular diseases

“…Although the CFH binding sites and the common C3 SNPs are situated in two different chains (α and β, respectively) of the C3 molecule ( Fig. 1), the 3D model of C3 places the MG1 (C3S/F; rs2230199) and C3d region (CFH binding site) in a close proximity [14,47]. This implicates the possibility that the presence of many different risks variants of C3 and CFH [50] + (DDD) --c.C1775T/p.R592Q (rs121909583) [101] + --V619 M (rs146613648) [64] + --R1303H [64] + --R13200Q [64] + --C1518R [64] + --D1625H [64] + --ΔDG3923 [64] + (DDD) + -c.131_146del; p.Leu44Argfs*19 [73] - [12,34,62,65,68] + (DDD, C3GN) + (SLE) -V62I (rs800292) [34,[63][64][65] + (DDD) [75] + − − Duplication in CFHR1 gene [39] + − − CFHR3-1 hybrid gene [76] + --CFHR2-CFHR5 hybrid gene [40] + --CFHR5-CFHR2 hybrid gene [77] + − − CFHR1-5 hybrid gene [80] + − − rs16840639 [69] - [34] + (DDD) --−20T/C (rs9427662) [34] + (DDD) --IVS1 + 75T/A [34] + (DDD) --IVS2 + 58C/T [34] + (DDD) --in a single individual may have a more potent effect on AP regulation and may increase the risk of GN development.…”

“…Three positively charged amino acids in the MG1 domain (Arg80, Arg72, and Lys82) form the thioester bond with four negative amino acids in the TED domain (Asp1007, Glu1008, Glu1010, Glu1013). The C3F variant, containing neutral glycine (instead of positively charged arginine), has a weaker ability to bind to CFH, which may impair the downregulation of the AP convertase, thus altering the C3 function [14,46,47]. The frequency of F allele varies among different populations, and it is the highest in Caucasian (18%) and the lowest in Asian (1%) [6,48].…”