title: GWAS study using DNA pooling strategy identifies association of variant rs4910623 in OR52B4 gene with anti-VEGF treatment response in age-related macular degeneration.
abstract: Pooled DNA based GWAS to determine genetic association of SNPs with visual acuity (VA) outcome in anti-vascular endothelial growth factor (anti-VEGF) treated neovascular age-related macular degeneration (nAMD) patients. We performed pooled DNA based GWAS on 285 anti-VEGF treated nAMD patients using high density Illumina 4.3 M array. Primary outcome was change in VA in Early Treatment Diabetic Retinopathy Study (ETDRS) letters after 6 months of anti-VEGF treatment (patients who lost ≥5 ETDRS letters classified as non-responders and all remaining classified as responders). GWAS analysis identified 44 SNPs of interest: 37 with strong evidence of association (p < 9 × 10-8), 2 in drug resistance genes (p < 5 × 10-6) and 5 nonsynonymous changes (p < 1 × 10-4). In the validation phase, individual genotyping of 44 variants showed three SNPs (rs4910623 p = 5.6 × 10-5, rs323085 p = 6.5 × 10-4and rs10198937 p = 1.30 × 10-3) remained associated with VA response at 6 months. SNP rs4910623 also associated with treatment response at 3 months (p = 1.5 × 10-3). Replication of these three SNPs in 376 patients revealed association of rs4910623 with poor VA response after 3 and 6 months of treatment (p = 2.4 × 10-3and p = 3.5 × 10-2, respectively). Meta-analysis of both cohorts (673 samples) confirmed association of rs4910623 with poor VA response after 3 months (p = 1.2 × 10-5) and 6 months (p = 9.3 × 10-6) of treatment in nAMD patients.
authors.affiliation: Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Australia.|Ophthalmology, Department of Surgery, University of Melbourne, Australia.
authors.forename: Moeen
authors.initials: M
authors.lastname: Riaz
authors.affiliation: Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, the Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Lorés-Motta
authors.affiliation: Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Australia.|Ophthalmology, Department of Surgery, University of Melbourne, Australia.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Richardson
authors.affiliation: Statistical Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Molecular Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Grant
authors.initials: G
authors.lastname: Montgomery
authors.affiliation: Montreal Retina Institute, Westmount, Canada.
authors.forename: Amer
authors.initials: A
authors.lastname: Omar
authors.affiliation: Paediatric Surgery, Human Genetics, and Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
authors.affiliation: Department of Ophthalmology, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Muether
authors.affiliation: Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Lebriz
authors.initials: L
authors.lastname: Altay
authors.affiliation: Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Schick
authors.affiliation: Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Fauser
authors.affiliation: Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, the Netherlands.
authors.forename: Dzenita
authors.initials: D
authors.lastname: Smailhodzic
authors.affiliation: Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, the Netherlands.
authors.forename: Freekje
authors.initials: F
authors.lastname: van Asten
authors.affiliation: Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, the Netherlands.
authors.forename: Eiko K
authors.initials: EK
authors.lastname: de Jong
authors.affiliation: Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, the Netherlands.
authors.forename: Carel B
authors.initials: CB
authors.lastname: Hoyng
authors.affiliation: Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS and Dept: Ophthalmology, Flinders University, Adelaide, SA, Australia.
authors.forename: Kathryn P
authors.initials: KP
authors.lastname: Burdon
authors.affiliation: Statistical Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Stuart
authors.initials: S
authors.lastname: MacGregor
authors.affiliation: Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Australia.|Ophthalmology, Department of Surgery, University of Melbourne, Australia.
authors.forename: Robyn H
authors.initials: RH
authors.lastname: Guymer
authors.affiliation: Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, the Netherlands.|Department of Human Genetics, Radboud university medical center, Nijmegen, the Netherlands.
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
authors.affiliation: Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Australia.|Ophthalmology, Department of Surgery, University of Melbourne, Australia.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Baird
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006801:Humans; D008268:Macular Degeneration / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000069579:Ranibizumab / Q000494:pharmacology / Q000627:therapeutic use; D018035:Receptors, Odorant / Q000235:genetics*; D015861:Retinal Neovascularization / Q000188:drug therapy / Q000235:genetics; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; C000627682:OR52B4 protein, human; D018035:Receptors, Odorant; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000069579:Ranibizumab