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. 2016 Nov 28:6:37924.
doi: 10.1038/srep37924.

GWAS study using DNA pooling strategy identifies association of variant rs4910623 in OR52B4 gene with anti-VEGF treatment response in age-related macular degeneration

Moeen Riaz  1   2 , Laura Lorés-Motta  3 , Andrea J Richardson  1   2 , Yi Lu  4 , Grant Montgomery  5 , Amer Omar  6 , Robert K Koenekoop  7 , John Chen  8 , Philipp Muether  9 , Lebriz Altay  9 , Tina Schick  9 , Sascha Fauser  9 , Dzenita Smailhodzic  3 , Freekje van Asten  3 , Eiko K de Jong  3 , Carel B Hoyng  3 , Kathryn P Burdon  10 , Stuart MacGregor  4 , Robyn H Guymer  1   2 , Anneke I den Hollander  3   11 , Paul N Baird  1   2
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GWAS study using DNA pooling strategy identifies association of variant rs4910623 in OR52B4 gene with anti-VEGF treatment response in age-related macular degeneration

Moeen Riaz et al. Sci Rep. .

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 × 10-4 and 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 × 10-3 and 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.

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Figures

Figure 1
Figure 1. Manhattan plot of SNPs tested in a pooled GWAS for response to anti-VEGF treatment.
The X-axis indicates the chromosomal position of the SNPs and the Y-axis shows their corresponding p-value (−log10). The red line indicates the threshold for genome-wide significance (p < 5 × 10−8) and the blue line indicates the threshold for suggestive association (p < 1 × 10−5).
Figure 2
Figure 2. Mean change in visual acuity (VA) after three and also the six month time period (pro re nata treated only) of treatment stratified by rs4910623 genotype for the Melbourne discovery and replication cohorts.
Vertical lines represent the standard error (SE) of the mean change in VA.
See this image and copyright information in PMC

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