C3 R102G polymorphism increases risk of age-related macular degeneration

Abstract

Inflammation has long been suspected to play a role in the pathogenesis of age-related macular degeneration (AMD). Association of variants in the complement factor H (CFH) and complement factor B (CFB) genes has targeted the search for additional loci to the alternative complement cascade, of which C3 is a major component. Two non-synonymous coding polymorphisms within C3, R102G and L314P, have previously been strongly associated with increased risk. These variants are in strong linkage disequilibrium (LD), making the contribution of this locus to AMD even more difficult to ascertain. We sought to determine whether the C3 association resulted primarily from only one of these two variants or from a combined effect of both in 223 families and an independent dataset of 701 cases and 286 unrelated controls. The C3 polymorphisms were in strong LD (r(2) = 0.85), and both were associated in the family-based and case-control datasets (R102G genoPDT P = 0.02, case-control genotypic P = 0.004; L314P genoPDT P = 0.001, case-control genotypic P = 0.04). In conditional analyses in the case-control dataset, R102G remained associated with disease in the L314P risk allele carriers (P = 0.01), but there was no effect of L314P in the R102G risk allele carriers (P = 0.2). After adjusting for age, smoking, CFH Y402H, LOC387715 A69S, and CFB R32Q, the effect of R102G remained strong [P = 0.015, odds ratio = 1.55, 95% confidence interval 1.09 to 2.21, adjusted PAR(population attributable risk) = 0.17]. Therefore, while the strong LD between R102G and L314P makes it difficult to disentangle their individual effects on disease risk, the R102G polymorphism acting alone provides the best model for disease in our data.

Association between a functional genetic polymorphism (rs2230199) and age-related macular degeneration risk: a meta-analysis

“…The association between SNPs in the C3 gene and AMD susceptibility has been established in multiple studies (Maller et al, 2007;Spencer et al, 2008;Park et al, 2009;Liu et al, 2010). Rs2230199 is a SNP in the C3 gene, which is a central component of all three pathways of complement activation -the alternative, classical, and mannose binding lectin pathways.…”

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

“…A common polymorphism in C3, originally identified from electrophoretic mobility and dubbed C3S/F for slow/fast migration (17) (18,19). Each polymorphism also links to other disorders.…”

Genome-Wide Association Studies: Getting to Pathogenesis, the Role of Inflammation/Complement in Age-Related Macular Degeneration

“…The encoded proteins were absent from the serum of individuals homozygous for the protective haplotype 5 (Hughes et al 2006). Further analyses confirmed this protective effect and the independence of this effect from the Y402H variant (e.g., Spencer et al 2008a;Fritsche et al 2010;Sawitzke et al 2011), although results for the level of significance the deletion contributes to protection from AMD varied (e.g., Spencer et al 2008b). Further exploring CFH, Spencer and colleagues evaluated previously reported (Hageman et al 2005) CFH haplotypes and the interaction of smoking status with these in a sample of 584 AMD cases and 248 controls and an additional analysis of 201 families (Spencer et al 2007).…”

“…Major risk-modifying loci include variants in the CFH gene on chromosome 1 (e.g., Edwards et al 2005;Hageman et al 2005;Haines et al 2005;Klein et al 2005;Souied et al 2005;Zareparsi et al 2005;Baird et al 2006;Conley et al 2006;Hughes et al 2006) and the ARMS2-HTRA1 locus on chromosome 10 (e.g., Jakobsdottir et al 2005;Rivera et al 2005;Maller et al 2006;Schmidt et al 2006;Yang et al 2006;Shuler Jr. et al 2007;Fritsche et al 2008). Additional AMD-associated variants are located in several other complement genes including C3 (Maller et al 2007;Yates et al 2007;Spencer et al 2008b), CFI (Fagerness et al 2009), and two genes located in the major histocompatibility complex class III region (C2 and CFB) (Gold et al 2006;Spencer et al 2007). The two major genetic contributors to AMD are variants in the CFH and ARMS2/HTRA1 genes.…”