Identification of a rare coding variant in complement 3 associated with age-related macular degeneration

Abstract

Macular degeneration is a common cause of blindness in the elderly. To identify rare coding variants associated with a large increase in risk of age-related macular degeneration (AMD), we sequenced 2,335 cases and 789 controls in 10 candidate loci (57 genes). To increase power, we augmented our control set with ancestry-matched exome-sequenced controls. An analysis of coding variation in 2,268 AMD cases and 2,268 ancestry-matched controls identified 2 large-effect rare variants: previously described p.Arg1210Cys encoded in the CFH gene (case frequency (fcase) = 0.51%; control frequency (fcontrol) = 0.02%; odds ratio (OR) = 23.11) and newly identified p.Lys155Gln encoded in the C3 gene (fcase = 1.06%; fcontrol = 0.39%; OR = 2.68). The variants suggest decreased inhibition of C3 by complement factor H, resulting in increased activation of the alternative complement pathway, as a key component of disease biology.

Figure 1

C3 variants R102G and K155Q and CFH variant R1210C are in the interaction domains of the first alpha-macro-globular domain of C3b and CFH, respectively. The fragment of the crystal structure of the four Sushi domains (purple in figure, one not shown for clarity) of CFH in a complex with complement fragment C3b (PDB file: 2wii) was used to explore the effect of disease associated nonsynonymous changes. The CFH residues 987–1230 were used to generate the structure using the first four Sushi domains from 2wii as a structural template (shown in pink, with cysteine residue side chains in yellow). The C-terminal Sushi domains were docked to the binding site in C3b. The first two alpha-macro-globulin domains of C3b, MG-1 and MG-2, are shown in green and cyan, respectively. The location of mutations R102G, K155Q, and R1210C are marked in red.