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.
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 AMDpatients. 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, AMDpatients 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 AMDpatients 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 AMDpatients 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.
Authors: Laura Lorés-Motta; Moeen Riaz; Michelle Grunin; Jordi Corominas; Freekje van Asten; Marc Pauper; Mathieu Leenders; Andrea J Richardson; Philipp Muether; Angela J Cree; Helen L Griffiths; Connie Pham; Marie-Claude Belanger; Magda A Meester-Smoor; Manir Ali; Iris M Heid; Lars G Fritsche; Usha Chakravarthy; Richard Gale; Martin McKibbin; Chris F Inglehearn; Reinier O Schlingemann; Amer Omar; John Chen; Robert K Koenekoop; Sascha Fauser; Robyn H Guymer; Carel B Hoyng; Eiko K de Jong; Andrew J Lotery; Paul Mitchell; Anneke I den Hollander; Paul N Baird; Itay Chowers Journal: JAMA Ophthalmol Date: 2018-08-01 Impact factor: 7.389
Authors: Gabriëlle H S Buitendijk; Elena Rochtchina; Chelsea Myers; Cornelia M van Duijn; Kristine E Lee; Barbara E K Klein; Stacy M Meuer; Paulus T V M de Jong; Elizabeth G Holliday; Ava G Tan; André G Uitterlinden; Theru S Sivakumaran; John Attia; Albert Hofman; Paul Mitchell; Johannes R Vingerling; Sudha K Iyengar; A Cecile J W Janssens; Jie Jin Wang; Ronald Klein; Caroline C W Klaver Journal: Ophthalmology Date: 2013-10-10 Impact factor: 12.079
Authors: Anjali R Shah; Steven Williams; Caroline R Baumal; Bernard Rosner; Jay S Duker; Johanna M Seddon Journal: Am J Ophthalmol Date: 2015-12-15 Impact factor: 5.258
Authors: John Paul SanGiovanni; Jing Chen; Przemyslaw Sapieha; Christopher M Aderman; Andreas Stahl; Traci E Clemons; Emily Y Chew; Lois E H Smith Journal: PLoS One Date: 2013-01-15 Impact factor: 3.240