A Pilot Study of Pharmacogenetics as a Predictor of Outcome in Patients Receiving Intravitreal Anti-VEGF Therapy in Age Related Macular Degeneration (AMD)

Abstract

Purpose: : Inhibition of VEGF by intraocular injections of bevacizumab or ranibizumab is the standard therapy for wet AMD. The arbitrary duration of therapy and heterogeneous effectiveness necessitates the need for predictive biomarkers. Prior studies have demonstrated that SNPs in CFH and LOC387715 were correlated with progression to wet AMD. More recently, our group has identified SNPs in the VEGF gene that predicted efficacy of bevacizumab in a phase III clinical trial for breast cancer. We now plan to compare candidate genotypes with outcome for patients receiving intraocular anti-VEGF therapy.

Methods: : : Patients were identified by chart review and were characterized by one of 4 possible clinical outcomes with anti-VEGF treatments: 1).indefinite responders, 2).delayed relapser, 3).immediate relapser, and 4).never responder. Saliva was collected from the identified patients and DNA was extracted using Oragene® DNA sample collection kit by DNA Genotek. Samples were then genotyped for candidate SNPs in the VEGF, CFH, and LOC387715 genes by Taqman-based Real Time-PCR. Genotypes and phenotypes were compared using a chi-square test.

Results: : 99 of 100 patients that were recruited were successfully genotyped for all SNPs. The distribution of the 4 clinical outcomes was: indefinite responder (35%), delayed relapser (16%), immediate relapser (27%) and never responder (20%). Patients who carried the LOC387715 TT genotype were significantly more likely to be classified as a never responder (9/16) compared to those with alternate genotypes (12/84); p-value=0.0007. VEGF and CFH genotypes did not correlate with therapeutic outcome.

Conclusions: : Our results suggest that those patients with AMD that carry the LOC387715 TT genotype not only have a higher risk for progressive AMD, but also have a markedly higher likelihood of not responding to standard anti-VEGF therapy. Alternative therapies for this genetic subgroup should be investigated.

Keywords: age-related macular degeneration • genetics • vascular endothelial growth factor