Abstract
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.
Original language | American English |
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Article number | 2762336 |
Journal | Investigative Ophthalmology and Visual Science |
Volume | 61 |
Issue number | 2 |
DOIs | |
State | Published - Feb 2020 |
Bibliographical note
Funding Information:Supported by a grant from the Israel Science Foundation (#1006/13). The contribution of the International AMD Genomics Consortium (IAMDGC) was supported by a grant from NIH (R01 EY022310). Genotyping was supported by a contract (HHSN268201200008I) to the Center for Inherited Disease Research.
Publisher Copyright:
© Copyright 2020 The Authors
Keywords
- Age-related macular degeneration
- Anti-vascular endothelial growth factor
- Genetics
- Neovascularization
- Pharmacogenetics