Endothelial PAS domain-containing protein 1 (EPAS1) gene polymorphisms and response to anti-VEGF therapy in the comparison of AMD treatments trials (CATT).

Figure 1. Mean value standard deviation change of total retinal thickness (microns) from baseline in the Comparison of AMD Treatments Trials (CATT). The efficacy of the intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents bevacizumab and ranibizumab has revolutionized the treatment of neovascular age-related macular degeneration. Results from the Comparison of AMD Treatments Trials (CATT), the Alternative Treatments to Inhibit VEGF in Patients with Age-Related Choroidal Neovascularisation (IVAN) trial, and other multicenter randomized clinical trials that compared bevacizumab and ranibizumab indicate that both drugs provide dramatic and lasting visual improvements for patients. However, results from these trials also make clear that there is individual variation in the initial response to therapy and in the durability of the clinical effect. Genetic assessment of participants in these trials provides an ideal opportunity to investigate pharmacogenetic associations using rigorously defined phenotypic data. A recent report from the IVAN Study Group evaluated 509 participants across 494 single nucleotide polymorphisms (SNPs) for evidence of a genetic association with response to anti-VEGF therapy asmeasured by change in total retinal thickness (TRT) in 1 year. Eyes in the highest quartile of change in TRT (n 1⁄4 126) were designated as responders whereas those in the lowest quartile (n 1⁄4 128) were designated as nonresponders. The strongest association observed was for rs9679290 in the endothelial PAS domaincontaining protein 1 (EPAS1) gene (unadjusted P 1⁄4 0.002); however, the association was not significant after Bonferroni correction for multiple comparisons (P 1⁄4 0.84). Interestingly, 4 of the top 10 strongest associations from the IVAN study were in this gene, although none of them were significant after Bonferroni correction. The EPAS1 gene represents a plausible gene for influencing anti-VEGF treatment response. It is a transcription factor expressed predominantly in highly vascularized tissues and likely regulates vascularization. Mice that are Epas1 / demonstrate severe retinopathy at a young age, including photoreceptor loss, retinal thinning, and abnormal retinal vasculature. In an effort to replicate the pharmacogenetic association between EPAS1 SNPs and response to anti-VEGF therapy, we evaluated the top 4 EPAS1 SNPs from the IVAN study (rs6726454, rs7589621, rs9679290, and rs12712973) in 831 CATT participants. Similar to IVAN, we classified participants as responders or nonresponders to anti-VEGF therapy based on TRT as determined by optical coherence tomography. We calculated the change in TRT from baseline at the latest time point for which optical coherence tomography data were available through 1 year (4, 8, 12, 24, or 52 weeks). Eyes with changes in TRT greater than or equal to the 75th percentile were classified as responders, and those with changes less than or equal to the 25th percentile were classified as nonresponders. We classified 211 participants as responders and 210 classified as nonresponders. The distribution of change in TRT in CATT was remarkably similar to that seen in IVAN (Fig 1). The genotypic frequencies of all 4 SNPs in CATT were also similar to that seen in IVAN (Table 1; available at www.aaojournal.org). In the CATT patient cohort, no significant association was observed for any of the genotypes at the 4 EPAS1 SNPs. Similar to the IVAN result, the strongest association was at rs9679290 (P 1⁄4 0.21); however, the odds ratio was in the opposite direction (0.84 for CATT, 1.87 for IVAN). The other 3 EPAS1 SNPs (rs6726454, rs12712973, rs7589621) were also not associated with response to therapy in CATT, also with odds ratios in the opposite direction as seen in IVAN. The CATT data do not support a pharmacogenetic association between the 4 SNPs tested in EPAS1 and response to anti-VEGF therapy in patients with neovascular age-related macular degeneration.