TY - JOUR
T1 - Cumulative effect of risk alleles in CFH, ARMS2, and VEGFA on the response to ranibizumab treatment in age-related macular degeneration
AU - Smailhodzic, Dzenita
AU - Muether, Philipp S.
AU - Chen, John
AU - Kwestro, Angela
AU - Zhang, Alice Yang
AU - Omar, Amer
AU - Van De Ven, Johannes P.H.
AU - Keunen, Jan E.E.
AU - Kirchhof, Bernd
AU - Hoyng, Carel B.
AU - Klevering, B. Jeroen
AU - Koenekoop, Robert K.
AU - Fauser, Sascha
AU - Den Hollander, Anneke I.
N1 - Funding Information:
Supported by the Netherlands Organization for Scientific Research , The Hague, the Netherlands (grant no. 016.096.309 ); the MD Fonds, Utrecht, the Netherlands; Oogfonds, Utrecht, the Netherlands; Landelijke Stichting voor Blinden en Slechtzienden, Utrecht, the Netherlands; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, Doorn, the Netherlands; Stichting A.F. Deutman Oogheelkunde Researchfonds, Nijmegen, the Netherlands; Stichting Nederlands Oogheelkundig Onderzoek, Rotterdam, the Netherlands; Stichting Blindenhulp, Den Haag, the Netherlands; the Gelderse Blindenstichting, Velp, the Netherlands; Nijmeegse Oogonderzoek Stichting, Nijmegen, the Netherlands; the Foundation Fighting Blindness Canada, Toronto, Canada; and by the Koeln Fortune Program/Faculty of Medicine, University of Cologne, Cologne, Germany.
PY - 2012/11
Y1 - 2012/11
N2 - Purpose: Intravitreal ranibizumab injections currently are the standard treatment for neovascular age-related macular degeneration (AMD). However, a broad range of response rates have been observed, the reasons for which are poorly understood. This pharmacogenetic study evaluated the impact of high-risk alleles in CFH, ARMS2, VEGFA, vascular endothelial growth factor (VEGF) receptor KDR, and genes involved in angiogenesis (LRP5, FZD4) on the response to ranibizumab treatment and on the age of treatment onset. In contrast to previous studies, the data were stratified according to the number of high-risk alleles to enable the study of the combined effects of these genotypes on the treatment response. Design: Case series study. Participants: A cohort of 420 eyes of 397 neovascular AMD patients. Methods: The change in visual acuity (VA) between baseline and after 3 ranibizumab injections was calculated. Genotyping of single nucleotide polymorphisms in the CFH, ARMS2, VEGFA, KDR, LPR5, and FZD4 genes was performed. Associations were assessed using linear mixed models. Main Outcome Measures: The VA change after 3 ranibizumab injections and the age of neovascular disease onset. Results: After ranibizumab treatment, AMD patients without risk alleles in the CFH and ARMS2 genes (4.8%) demonstrated a mean VA improvement of 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, whereas no VA improvement was observed in AMD patients with 4 CFH and ARMS2 risk alleles (6.9%; P = 0.014). Patients with 4 high-risk alleles in CFH and ARMS2 were 5.2 years younger than patients with 1 or 2 risk alleles, respectively (63.5%; P<0.0001). The mean age at which the first ranibizumab treatment was carried out among AMD patients with all 6 risk alleles in CFH, ARMS2, and VEGFA was 65.9 years (2%) versus 75.3 years in patients with 0 or 1 high-risk allele (8.8%; P = 0.001). After ranibizumab treatment, patients with 6 high-risk alleles demonstrated a mean VA loss of 10 ETDRS letters (P<0.0001). Conclusions: This study evaluated the largest pharmacogenetic AMD cohort reported to date. A cumulative effect of high-risk alleles in CFH, ARMS2, and VEGFA seems to be associated with a younger age of onset in combination with poor response rates to ranibizumab treatment. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
AB - Purpose: Intravitreal ranibizumab injections currently are the standard treatment for neovascular age-related macular degeneration (AMD). However, a broad range of response rates have been observed, the reasons for which are poorly understood. This pharmacogenetic study evaluated the impact of high-risk alleles in CFH, ARMS2, VEGFA, vascular endothelial growth factor (VEGF) receptor KDR, and genes involved in angiogenesis (LRP5, FZD4) on the response to ranibizumab treatment and on the age of treatment onset. In contrast to previous studies, the data were stratified according to the number of high-risk alleles to enable the study of the combined effects of these genotypes on the treatment response. Design: Case series study. Participants: A cohort of 420 eyes of 397 neovascular AMD patients. Methods: The change in visual acuity (VA) between baseline and after 3 ranibizumab injections was calculated. Genotyping of single nucleotide polymorphisms in the CFH, ARMS2, VEGFA, KDR, LPR5, and FZD4 genes was performed. Associations were assessed using linear mixed models. Main Outcome Measures: The VA change after 3 ranibizumab injections and the age of neovascular disease onset. Results: After ranibizumab treatment, AMD patients without risk alleles in the CFH and ARMS2 genes (4.8%) demonstrated a mean VA improvement of 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, whereas no VA improvement was observed in AMD patients with 4 CFH and ARMS2 risk alleles (6.9%; P = 0.014). Patients with 4 high-risk alleles in CFH and ARMS2 were 5.2 years younger than patients with 1 or 2 risk alleles, respectively (63.5%; P<0.0001). The mean age at which the first ranibizumab treatment was carried out among AMD patients with all 6 risk alleles in CFH, ARMS2, and VEGFA was 65.9 years (2%) versus 75.3 years in patients with 0 or 1 high-risk allele (8.8%; P = 0.001). After ranibizumab treatment, patients with 6 high-risk alleles demonstrated a mean VA loss of 10 ETDRS letters (P<0.0001). Conclusions: This study evaluated the largest pharmacogenetic AMD cohort reported to date. A cumulative effect of high-risk alleles in CFH, ARMS2, and VEGFA seems to be associated with a younger age of onset in combination with poor response rates to ranibizumab treatment. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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U2 - 10.1016/j.ophtha.2012.05.040
DO - 10.1016/j.ophtha.2012.05.040
M3 - Article
C2 - 22840423
AN - SCOPUS:84868194934
SN - 0161-6420
VL - 119
SP - 2304
EP - 2311
JO - Ophthalmology
JF - Ophthalmology
IS - 11
ER -