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J. S. Ehrlich, K. Zhang, T. Ianchulev, H. Shapiro, R. Graham; Further Analyses of AMD Genetic Risk Variants Associated With CNV Phenotypes and Treatment Response in Ranibizumab Pivotal Trials. Invest. Ophthalmol. Vis. Sci. 2009;50(13):248.
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© ARVO (1962-2015); The Authors (2016-present)
Genetic polymorphisms enriched in AMD patients appear to increase risk of progression to neovascular disease, and potentially impact response to treatment. We have reported associations of variants in CFH, C3, C5, and HTRA1 with baseline CNV phenotypes and treatment response in ranibizumab clinical studies. Here, we extend our prior analyses to include additional known and candidate AMD risk variants.
DNA of 296 patients from the DAWN study was genotyped for alleles enriched in AMD and candidate SNPs. The association of each SNP with mean VA change at month 12 and baseline clinical phenotypes (age, VA, total lesion area, total CNV area, classic CNV area, total area of leakage + RPE staining, percent of fellow eyes with CNV, and percent of study eyes with predominantly classic [PC] CNV) were analyzed. Statistical methods for exploratory assessment of associations included linear regression and pair-wise t-tests for continuous outcomes, and exact Cochran-Armitage test of linear trend and pair-wise Wald (Chi-square) tests for categorical outcomes.
For SNPs in IL8 rs2227306, VEGFA rs1413711, and VEGFA rs3024997, no significant associations were found for baseline VA, classic CNV area, percent study eyes with PC CNV, percent fellow eyes with CNV, or VA change from baseline (p>0.05). Significant linear regressions for association with increased number of risk alleles were found in rs2227306 for smaller lesion size (p=0.01) and CNV areas (p=0.009); and rs1413711 for older age (p=0.02) and larger lesion size (p=0.02), CNV (p=0.04) and leakage areas (p=0.01). Presence of a single risk allele in rs3024997 was associated with larger lesion size (p=0.02) and CNV areas (p=0.02) compared to no risk alleles.
In neovascular AMD, patient age and CNV baseline characteristics were correlated with variants in IL8 and VEGFA. Further studies are needed to validate these findings. Variants in IL8 and VEGFA will be examined for interactions with confirmed AMD risk alleles, and additional variants in CFD, TLR3, and SERPING1 will be examined.
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