Pharmacogenetic Associations with VEGF Inhibition in Participants with Neovascular AMD
Researchers designed this cohort study, which combines information about patients' genotypes with information from a randomized controlled trial about responsiveness to anti-vascular endothelial growth factor (VEGF) therapy for neovascular age-related macular degeneration (AMD) to determine if prespecified genetic polymorphisms influence responsiveness to VEGF inhibition in neovascular AMD.
The objectives were to replicate three reported pharmacogenetic associations of response in neovascular AMD and to test for novel associations. Participants consisted of 509 subjects with neovascular AMD, enrolled in the Alternative Treatments to Inhibit VEGF in Patients with Age-Related Choroidal Neovascularisation (IVAN) trial. The reseachers classified participants as responders or nonresponders to VEGF inhibition based on the optical coherence tomography (OCT) metric of total retinal thickness (TRT). They computed the change in TRT from baseline to the latest time point for which OCT data were available (three, six, nine or 12 months). The classified eyes with changes in TRT greater than or equal to the 75th percentile or more as responders, and those with changes less than or equal to the 25th percentile or lower as nonresponders. The study researchers tested three previously reported associations of response to VEGF inhibition in neovascular AMD involving single nucleotide polymorphisms (SNPs) at the CFH, FZD4 and HTRA1/ARMS2 loci for replication and tested an additional 482 SNPs using a candidate gene approach. They estimated associations as odds ratios (ORs) with confidence intervals (CIs). The primary outcome was evidence of a genetic association with response to VEGF inhibition as measured by change in TRT.
The researchers classified 126 participants as responders and 128 as nonresponders. They reported that the SNP rs10490924 in HTRA1/ARMS2 showed a borderline association with responsiveness after Bonferroni correction (OR, 1.53; CI, 0.99 to 2.36; p=0.055, Bonferroni correction). None of the other 484 additional SNPs tested for association was significant after Bonferroni correction for multiple testing. The smallest corrected p value was 0.84 (p=0.002, uncorrected) for rs9679290 in the EPAS1 (HIF2A) gene on chromosome 2. Four of the 10 most significant results were in this gene.
The researchers estimated pharmacogenetic associations using high-quality phenotype data from a randomized controlled clinical trial of neovascular AMD. They observed no significant association or replication of previous associations. Further investigation of the EPAS1 (HIF2A) gene, however, may, be merited.