Association of a variant in VWA3A with response to anti-vascular endothelial growth factor treatment in neovascular AMD

Michelle Grunin, Gala Beykin, Elior Rahmani, Regev Schweiger, Gal Barel, Shira Hagbi-Levi, Sarah Elbaz-Hayoun, Batya Rinsky, Michal Ganiel, Shai Carmi, Eran Halperin, Itay Chowers*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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 languageAmerican English
Article number2762336
JournalInvestigative Ophthalmology and Visual Science
Issue number2
StatePublished - 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


  • Age-related macular degeneration
  • Anti-vascular endothelial growth factor
  • Genetics
  • Neovascularization
  • Pharmacogenetics


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