The VEGF-A 165 isoform is important in ocular angiogenic control and is elevated in AMD patients [54]. Genetic variations in the VEGF gene confer increased susceptibility to AMD. Churchill et al. found that those homozygous for the C risk allele of variant SNP rs1413711 were at an increased risk of AMD (OR 2.4, 95% CI 1.09–5.26) [55]. As more data becomes available, we may be able to predict how well AMD patients will respond to current anti-VEGF therapies based upon genetic modifiers.

Genetic Variants on Chromosome 10q26

Although ARMD1 was the first confirmed susceptibility locus, chromosome 10q26 harbors the locus most significantly associated with AMD [24]. This region contains three genes: a hypothetical gene LOC387715/ARMS2, and two known genes: PLEKHA1 and HTRA1 (Fig. 1.3).

LOC387715/ARMS2

The LOC387715/ Age-Related Maculopathy Susceptibility 2 (ARMS2) region lies between PLEKHA1 and HTRA1 on chromosome 10q26. In multiple association studies, this gene has been implicated in AMD susceptibility [57–59]. Using two separate German cohorts, researchers identified SNP rs10490924, which results in an alanine to serine (A69S) change, as a high-risk variant for AMD. Pooled data showed that cases heterozygous or homozygous for the T risk allele of rs10490924 had a 2.69-fold (95% CI 2.22– 3.27) or 8.21-fold (95% CI 5.79–11.65) increased risk of AMD, respectively, compared with the homozygous non-risk genotype (GG) [59]. This association was independent of the Y402H

variant of CFH. A meta-analysis comprising five datasets showed similar results (TG heterozygous OR 2.48, 95% CI 1.67–3.70; TT homozygous OR 7.3, 95% CI 4.33–12.42) [58]. Phenotypically, the A69S variant was associated with a younger age of CNV onset [57, 60]. Although numbers vary by study, the population attributable risk for the A69S variant has been estimated between 34% and 57%, indicating that possibly over 50% of the AMD risk can be attributed to this variant [61–63].

Recently, an insertion-deletion (in/del) variant in LOC387715 was found that exists in perfect LD with the researched A69S variant. This in-del variant specifically removes the mRNA’s polyadenylated tail, leading to rapid mRNA turnover and a decreased LOC387715 mRNA expression. The in/del variant was highly correlated with AMD risk (p value: 4.1 × 10–29, OR 2.85, 95% CI 2.37–3.43) [64]. In contrast to the loss of function role of the in/del in LOC387715, the T allele of SNP rs2736911, a nonsynonymous coding SNP leading to a predicted premature stop (R38X) in LOC387715, is associated with a protective haplotype. These findings present a paradox. The in/del causes destabilization of LOC387715, suggesting that loss of function at that locus might confer risk to AMD. However, the introduction of the R38X mutation, which is also predicted to give rise to loss of the LOC387715 message, is protective [65]. Yang et al. showed that both the R38X and in/del have the same mode of action, which decreases expression of LOC387715. Therefore, the loss of LOC387715 is insufficient to explain AMD susceptibility.

Another criticism of the LOC387715/ ARMS2 gene is that it encodes a hypothetical gene with an unknown function. Present only in