From: AMD and the alternative complement pathway: genetics and functional implications
Gene | Variant | Position | OR | Common/Rare | Domain | Variant domain effect | Effect on AP | Ref |
---|---|---|---|---|---|---|---|---|
C3 | R102G | 19:6718387 | 1.7–2.6 | Common | Macroglobulin 1 | Decreased binding efficiency of C3b to its inhibitor CFH decreasing CFH’s cofactor activity | Increased AP | |
C3 | P314L | 19:6713262 | 1.5 | Common | Macroglobulin 3 | Decreased binding efficiency of C3b to its inhibitor CFH decreasing CFH’s cofactor activity | Increased AP | [65] |
C3 | K155Q | 19:6718146 | 2.8–3.8 | Rare | Macroglobulin 2 | Reduces binding to FH and C3b proteolytic cleavage by CFI | Increase C3 convertase production | |
CFB | R32Q | 6:31914180 | 0.32 | Common | Ba | Reduced affinity for C3b and reduced hemolytic activity | Decrease formation of C3 convertase; reduced AP | [130] |
CFB | L9H | 6:31914024 | 0.37 | Common | Signal peptide | Affects secretion of CFB | Decrease formation of C3 convertase; reduced AP | [12] |
CFH | Y402H | 1:196659291 | 2.45–5.57 | Common | Complement control protein 7 | Affects binding to GAG heparin sulfate, sialic acid, and C-reactive protein | Reduces ability of CFH to degrade C3: increased AP | [131] |
CFH | R1210C | 1:196716375 | 23.11 | Rare | Complement control protein 20 | Defective binding to C3b, C3d, and heparin | Impaired CFH attachment to host surfaces; reduces AP regulation | [58] |
CFH | R53C | 1:196642206 | Â | Rare | Complement control protein 1 | Reduced accelerating activity for AP C3 convertase | Altered CFH-mediated cofactor activity or decay-accelerating activity; increased AP | [63] |
CFH | D90G | 1:196643011 | Â | Rare | Complement control protein 2 | Alters CFI cofactor activity | Decreased cofactor-mediated inactivation; increased AP | [63] |
CFH | I62V | 1:196642233 | 1.95–2.79 | Common | Complement control protein 2 | Binds more efficiently to C3b | Enhanced cofactor activity and increased formation of iC3b; reduced AP | [63] |
CFH | N1050Y | 1:196712596 | 0.4 | Common | Complement control protein 18 | Possibly affects GAG and sialic acid binding | Increased AP | [62] |
CFHR1/3 | CFHR1/3del | Â | 0.29 | Common | n/a | n/a | Reduces cofactor activity for CFI and inhibits C5 convertase; reduced AP | |
CFI | G119R | 4:110685820 | 22.2 | Rare | Scavenger receptor cysteine-rich | Perturbs interdomain packing and stability of CFI | Diminished ability to degrade C3b; increased formation of C5 convertase; increased AP | [19] |
CFI | G188A | 4:110682768 | Â | Rare | Scavenger receptor cysteine-rich | Perturbs interdomain packing and stability of CFI | Diminished ability to degrade C3b; increased formation of C5 convertase; increased AP | [19] |
C9 | P167S | 5:39331894 | 2.2 | Rare | Membrane attack complex/perforin | Alters oligomerization and possibly inhibits C9's lytic activity | Affects binding with CD59; alters pore formation | [59] |