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.
Highlights
Age-related macular degeneration (AMD) is a common complex progressive neurodegenerative disease in the elderly, which can lead to irreversible severe vision loss[1]
10% of patients showed no improvement in visual acuity (VA), and exhibited a continuous decline in VA over two years of treatment similar to that previously reported for both ANCHOR and MARINA trials[5,6]
We investigated whether genetic factors influencing ranibizumab treatment outcomes in nAMD patients could be identified through the initial use of a genome-wide association study (GWAS) pooling strategy followed by a technical validation and subsequent replication in an independent cohort
Summary
Age-related macular degeneration (AMD) is a common complex progressive neurodegenerative disease in the elderly, which can lead to irreversible severe vision loss[1]. The most effective treatment for nAMD is inhibition of VEGF through the use of recombinant, humanised anti-VEGF monoclonal antibodies such as ranibizumab (Lucentis), aflibercept (Eylea) or off-label bevacizumab (Avastin) These drugs have been shown in multiple studies[4,5,6,7,8] to be efficacious in improving vision, but a varying response to anti-VEGF treatment has been observed. 10% of patients showed no improvement in visual acuity (VA) (loss of >1 5 ETDRS letters), and exhibited a continuous decline in VA over two years of treatment similar to that previously reported for both ANCHOR and MARINA trials[5,6] This range of variable VA response may in part be explained by genetic predisposition. We investigated whether genetic factors influencing ranibizumab treatment outcomes in nAMD patients could be identified through the initial use of a GWAS pooling strategy followed by a technical validation and subsequent replication in an independent cohort
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