Association of a Variant in VWA3A with Response to Anti-Vascular Endothelial Growth Factor Treatment in Neovascular AMD

PURPOSE: Anti–vascular endothelial growth factor (VEGF) therapy for neovascular AMD (nvAMD) obtains a variable outcome. We performed a genome-wide association study for anti-VEGF treatment response in nvAMD to identify variants potentially underlying such a variable outcome. METHODS: Israeli patients with nvAMD who underwent anti-VEGF treatment (n = 187) were genotyped on a whole exome chip containing approximately 500,000 variants. Genotyping was correlated with delta visual acuity (deltaVA) between baseline and after three injections of anti-VEGF. Top principal components, age, and baseline VA were included in the analysis. Two lead associated variants were genotyped in an independent validation set of patients with nvAMD (n = 108). RESULTS: Linear regression analysis on 5,353,842 variants revealed five exonic variants with an association P value of less than 6 × 10(−5). The top variant in the gene VWA3A (P = 1.77 × 10(−6)) was tested in the validation cohort. The minor allele of the VWA3A variant was associated with worse response to treatment (P = 0.02). The average deltaVA of discovery plus validation was –0.214 logMAR (≈ a gain of 10.7 Early Treatment Diabetic Retinopathy Study letters) for homozygote for the major allele, 0.172 logMAR for heterozygotes (≈ a loss of 8.6 Early Treatment Diabetic Retinopathy Study letters), and 0.21 logMAR for homozygote for the minor allele (≈ a loss of 10.5 Early Treatment Diabetic Retinopathy Study letters). Minor allele carriers had a higher frequency of macular hemorrhage at baseline. CONCLUSIONS: An VWA3A gene variant was associated with worse response to anti-VEGF treatment in Israeli patients with nvAMD. The VWA3A protein is a precursor of the multimeric von Willebrand factor which is involved in blood coagulation, a system previously associated with nvAMD.