Cumulative Effect of High Risk Alleles in CFH, ARMS2 and VEGF on Response to Ranibizumab Treatment in Age-Related Macular Degeneration

Abstract

Purpose: : Intravitreal ranibizumab injections are currently the standard treatment for neovascular AMD, however, a broad range in response rates have been observed, for which the reasons are poorly understood. We evaluated the impact of high-risk alleles in CFH and ARMS2, and SNPs in VEGF, VEGF receptor KDR and genes involved in angiogenesis (LRP5, FZD4) on response to ranibizumab treatment and on the age of treatment onset. In contrast to previous studies, we stratified the data according to the number of high-risk alleles to enable us to study the combined effects of these genotypes on treatment response in neovascular AMD.

Methods: : We evaluated 420 eyes of 397 unrelated Caucasian neovascular AMD patients treated only with intravitreal 0.5 mg ranibizumab injections. Each participant underwent best-corrected visual acuity testing prior and after treatment with three ranibizumab injections. Genotyping of SNPs in the CFH, ARMS2, VEGF, KDR, LPR5 and FZD4 was performed, and associations were assessed using general linear models.

Results: : After ranibizumab treatment, AMD patients without high-risk alleles in CFH and ARMS2 genes demonstrated a mean VA improvement of 10.5 ETDRS letters while no VA improvement was observed in the carriers of all four CFH and ARMS2 high-risk alleles (p=0.009). Carriers of 4 risk alleles in the CFH and ARMS2 genes were also significantly younger at the onset of treatment than the carriers of 3 high-risk alleles (p=0.008) and 5.3 years younger than the AMD carriers of 1 or 2 risk alleles, respectively (p<0.0001). Adding VEGF SNP to the model demonstrated a significant decrease of the age at treatment onset. The mean age at which the first ranibizumab treatment was carried out among the carriers of all 6 high-risk alleles in CFH, ARMS2 and VEGF was 70.2 years versus 80.2 years in the AMD carriers of none or one high-risk allele (p<0.0001). Compared to the carriers of 0-1 risk allele, carriers of all 6 risk alleles demonstrated a mean visual loss of 20.5 ETDRS letters (p<0.0001).

Conclusions: : In this study we evaluated the largest pharmacogenetic AMD cohort studied to date. A cumulative effect of high-risk alleles in CFH, ARMS2 en VEGF may lead to a younger age of onset in combination with bad response rates to ranibizumab treatment and thus to a more aggressive form of AMD.

Keywords: age-related macular degeneration • retinal neovascularization • genetics