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Barbara Kloeckener-Gruissem, Moreno Menghini, Daniel Barthelmes, Stephan Labs, Malaika Kurz-Levin, Stephan Michels, Johannes Fleischhauer, Florian Sutter, Wolfgang Berger; A Swiss Patient Cohort Reveals Genetic Predisposition Of Known And New Genetic Loci To AMD And To Intravitreal Ranibizumab (lucentis®) Treatment Outcome. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5249.
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Current standard treatment for neovascular age-related macular degeneration (AMD) is intravitreal anti-VEGF therapy (ranibizumab), but responses to treatment show large variability. Within a Swiss patient population we searched for genetic factors that influence AMD and that affect the outcome of ranibizumab treatment.
Changes of visual acuity (VA) were measured during 12 months after initiation of anti-VEGF treatment and percentiles of VA course were calculated. Genotypes of polymorphisms in known AMD susceptibility loci (CFH, CFB, HTRA1, AMRS2 and VEGFA) as well as not yet reported AMD associated candidate genes (KDR, LRP5 and FZD4) were determined and their frequencies compared.
We completed VA assessment for 243 eyes. On average, approximately four ranibizumab injections were administered. Based on the change of visual acuity, two responder groups were established: poor responders (25th percentile) and good responders (75th percentile) each containing 63 eyes. Individuals with genotypes CT and TT of p.Y402H in CFH were about 3.5 times more likely to improve visual acuity (p=0.006), while individuals with genotype CC did not fair well. Furthermore, individuals simultaneously heterozygous at SNPs in the two loci, CFH (p.Y402H) and FZD4 (SNP rs10898563) showed improved visual acuity (p=0.0044) compared to the not heterozygous patients. Association with AMD was confirmed at the known genetic susceptibility loci CFH, HTRA1 and AMRS2 and furthermore we identified a risk conferring polymorphism in one new locus, LRP5.
Genetic predisposition is likely to account for the variability in response to anti-VEGF treatment. LRP5 and FZD4, two proteins involved in retinal vascular development as co-receptors of the Wnt-signalling pathway, may also influence the development of AMD and response to treatment with anti VEGF, respectively.
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