and Complement Factor B (BF, CFB, alternative pathway) genes have been associated with AMD. Gold et al. investigated haplotypes involving these two genes. Although one haplotype conferred risk for AMD, two haplotypes did not. A haplotype involving the nearly complete linkage disequilibrium (LD) set of the L9H variant of BF and the E318D variant of C2 was highly protective against AMD (p value: 2×10−4, OR 0.37, 95% CI 0.18– 0.60). A haplotype combining the nearly complete LD set of the R32Q variant of BF with the rs547154 variant of C2 intron 10, was highly protective as well (p value: 6.43×10 −9, OR 0.32, 95% CI 0.21–0.48). Further analysis showed a codominant model for these two haplotypes [44]. Another study investigating similar SNPs in a Caucasian family-based data set hypothesized that rs547154 is the same as R32Q due to their high LD. It purported that BF R32Q may be the most significant protective variant of the C2-BF locus, after controlling for age, common risk variants on chromosome 1 and 10, and smoking (OR 0.21, 95% CI 0.11–0.39) [45]. Functional studies of the R32Q variant supported this claim by showing a fourfold decreased affinity for C3b, and subsequent decreased formation of activated convertase [46]. Future functional studies will continue to elucidate the protective effects of C2 and BF variants.

Complement Component 3

Unlike C2-BF, variants in the complement component 3 (C3) gene confer susceptibility to AMD [47–50]. Two SNPs in high LD with each other have been implicated: rs2230199 (R102G) and rs1047286 (P314L). Yates et al. and Maller et al. [48, 50] examined the rs2230199 SNP in different cohorts of Caucasian patients. Odds ratios for being homozygous or heterozygous for the G risk allele were 1.7 (95% CI 1.3–2.1) and 2.6 (95% CI 1.6–4.1), respectively [50]. The rs2230199 SNP encodes an arginine to glycine switch in the third exon of C3 (R120G). The normal arginine provides a positive charge that may help stabilize a thioester binding motif. A switch to a neutral glycine residue at this position could weaken the thioester motif –a motif implicated in CFH binding [50]. Weakening of a CFH-binding site would prevent proper inhibition of C3. This variant also

results in two separate allotypes based upon their electrophoretic characteristics (slow, C3S; fast C3F). The fast allotype has been implicated in renal diseases much like variants of CFH [49].

Although multiple researchers have indicated that rs2230199 is a stronger risk variant for AMD [49, 50], others contend that both SNPs have a role in AMD risk [48]. No functional explanation has been assigned to SNP rs1047286. However, a recent meta-analysis showed a pooled susceptibility odds ratio of 1.50 for the P314L allele (95% CI 1.31–1.71) and 1.61 for the R102G allele (95% CI 1.46–1.78). Further studies will help refine these associations.

Pearl

The Y402H Complement Factor H genetic variant accounts for over 50% of the risk associated with AMD. Most variants in C2/ BF are protective of AMD, while C3 variants confer AMD risk.

Other Inflammatory Factor Variants

Toll-Like Receptor

Some believe that underlying bacterial or viral infections instigate inflammatory ocular cascades that promote the propagation of AMD. Along this line of thinking, variant rs4986790 in the toll-like receptor (TLR) 4 gene (encodes a bacterial endotoxin receptor) was associated with AMD susceptibility [51]. Yang et al. investigated SNPs in both TLR3 and TLR4. Although they did not confirm the TLR4 variant associations, they showed that SNP rs3775291 of TLR3 conferred protection against geographic atrophy. Odds ratios for heterozygotes and homozygotes of this variant were 0.712 (95% CI 0.5–1.00) and 0.437 (95% CI 0.23–0.84), respectively [52].

VEGF-A

Vascular endothelial growth factor (VEGF) has been implicated in the pathogenesis of neovascular AMD (CNV) [53]. The VEGF-A protein can be alternatively spliced to create multiple isoforms.