A genetic variant in NRP1 is associated with worse response to ranibizumab treatment in neovascular age-related macular degeneration

Abstract

Purpose: The highly variable response to anti-vascular endothelial growth factor (VEGF) drugs in neovascular age-related macular degeneration (nvAMD) patients is, in part, due to genetic predisposition. Several studies have implicated genetic variability in genes associated with VEGF signaling, such as KDR (VEGFR2), in this process but the exact mechanisms remain elusive. The aim of this study was to investigate the role of single nucleotide polymorphisms (SNPs) located in neuropilin-1 (NRP1), a co-receptor for VEGFA, in treatment response to anti-VEGF therapy in a cohort study of nvAMD patients treated with ranibizumab (Lucentis).

Methods: The SNPs rs2229935, rs2247383, rs2070296 and rs2804495 located in the NRP1 gene were genotyped in 377 nvAMD patients who received the loading dose of three monthly ranibizumab (Lucentis) injections. Treatment response was assessed as the change in visual acuity after three monthly loading injections compared to baseline. The association of the SNPs with the outcome variable was evaluated using Mann-Whitney U and Kruskal-Wallis tests.

Results: Patients carrying the GA or AA genotypes of SNP rs2070296 performed significantly worse than individuals carrying the GG genotype (p=0.01) after three months of treatment. A cumulative effect of rs2070296 in the NRP1 gene and rs4576072 located in the KDR gene, previously associated with treatment response, was observed. Patients carrying two risk alleles performed significantly worse than patients carrying zero or one risk allele (p=0.03) and patients with more than two risk alleles responded even worse to the therapy (p=3x10^-3).

Conclusions: This study demonstrates that genetic variation in NRP1, a key molecule in VEGFA-driven neovascularization, influences treatment response to ranibizumab in nvAMD patients. The results of this study may be used to generate prediction models for treatment response, which in the future may help tailor medical care to individual needs.