September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Pooled GWAS identifies a novel gene: OR52B4 influencing anti-VEGF treatment response in Age related macular degeneration
Author Affiliations & Notes
  • Moeen Riaz
    Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
    Department of Surgery, Ophthalmology, University of Melbourne, Melbourne, Victoria, Australia
  • Laura Lorés de Motta
    Department of Ophthalmology, Radboud University medical Center, Nijmegen, Netherlands
  • Andrea J. Richardson
    Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
    Department of Surgery, Ophthalmology, University of Melbourne, Melbourne, Victoria, Australia
  • Yi Lu
    Statistical Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • Grant Montgomery
    Molecular Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • Eiko de Jong
    Department of Ophthalmology, Radboud University medical Center, Nijmegen, Netherlands
  • Carel C B Hoyng
    Department of Ophthalmology, Radboud University medical Center, Nijmegen, Netherlands
  • Ttuart Macgregor
    Statistical Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • Robyn H Guymer
    Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
    Department of Surgery, Ophthalmology, University of Melbourne, Melbourne, Victoria, Australia
  • Anneke I Den Hollander
    Department of Ophthalmology, Radboud University medical Center, Nijmegen, Netherlands
    Department of Human Genetics, Radboud University medical Center, Nijmegen, Netherlands
  • Paul N Baird
    Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
    Department of Surgery, Ophthalmology, University of Melbourne, Melbourne, Victoria, Australia
  • Footnotes
    Commercial Relationships   Moeen Riaz, None; Laura Lorés de Motta, None; Andrea J. Richardson, None; Yi Lu, None; Grant Montgomery , None; Eiko de Jong, None; Carel Hoyng, None; Ttuart Macgregor, None; Robyn Guymer, Bayer (S), Novartis (S); Anneke Den Hollander, None; Paul Baird, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 2640. doi:
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      Moeen Riaz, Laura Lorés de Motta, Andrea J. Richardson, Yi Lu, Grant Montgomery, Eiko de Jong, Carel C B Hoyng, Ttuart Macgregor, Robyn H Guymer, Anneke I Den Hollander, Paul N Baird; Pooled GWAS identifies a novel gene: OR52B4 influencing anti-VEGF treatment response in Age related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2016;57(12):2640.

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      © 2017 Association for Research in Vision and Ophthalmology.

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Abstract

Purpose : Anti-Vascular endothelial growth factor (anti-VEGF) is a key treatment for neovascular AMD (nAMD) but its response is variable. This variability is likely to be, in part, due to genetic heterogeneity; although known AMD risk associated genes have been inconclusive in explaining this response. We sought to use a pooled genome wide association study (GWAS) to identify genetic variants that might explain this response.

Methods : A total of 297 nAMD patients, each received 3 monthly ranibizumab injections followed by an inject and extend protocol. Patients were divided into non-responders, (loss of ≥5 EDTRS letters visual acuity (VA)) and the rest were responders following 6 months of ranibizumab treatment. Six separate equimolar DNA pools (3 for responder, 3 for non-responders) based on baseline VA underwent genotyping with the Illumina HumanOmni5-Quad Beadchip array. A pooled GWAS was carried out comparing responders vs non-responders for the three baseline VA categories and results were combined in a meta-analysis via a custom pipeline.Significant SNPs underwent individual genotyping in the same patient cohort. Three validated SNPs were then replicated in a second ranibizumab treated nAMD cohort consists of 376 patients. Meta-analysis on both cohorts was performed using METAL.

Results : Following GWAS, 44 SNPs; of which 37 associated at genome-wide significance, 2 in pharmagenes P<5x10-5 and 5 missense changes P<5x10-4 were selected for validation. Three SNPs; rs4910623, rs323085, rs10158937, remained significant (P = 8.3x10-5, P = 6.4x10-4, P = 6.4x10-3 respectively) with response/no response to ranibizumab at 6 months. These 3 SNPs were assessed in a second replication cohort, SNP rs4910623 in the promoter region of the Olfactory Receptor, Family 52, Subfamily B, Member 4 (OR52B4) was significantly associated with treatment outcome at 6 months (P=4.6x10-2) and also at 3 months (P < 0.001). Meta-analysis of both cohorts confirmed association of rs4910623 with poor VA outcome at 3 (P = 6.9x10-6) and 6 months (P = 2.4x10-5) of ranibizumab treatment.

Conclusions : We identified a novel variant rs4910623 in the OR52B4 gene associated with poor VA outcome following ranibizumab treatment in nAMD. The OR52B4 gene encodes a G protein-coupled receptor suggesting that other non VEGF biological pathways may also be involved in response to anti-VEGF treatments.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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