title: Cumulative effect of risk alleles in CFH, ARMS2, and VEGFA on the response to ranibizumab treatment in age-related macular degeneration.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Case series study.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
authors: Department of Ophthalmology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors: Dzenita
authors: D
authors: Smailhodzic
authors: Philipp S
authors: PS
authors: Muether
authors: John
authors: J
authors: Chen
authors: Angela
authors: A
authors: Kwestro
authors: Alice Yang
authors: AY
authors: Zhang
authors: Amer
authors: A
authors: Omar
authors: Johannes P H
authors: JP
authors: Van de Ven
authors: Jan E E
authors: JE
authors: Keunen
authors: Bernd
authors: B
authors: Kirchhof
authors: Carel B
authors: CB
authors: Hoyng
authors: B Jeroen
authors: BJ
authors: Klevering
authors: Robert K
authors: RK
authors: Koenekoop
authors: Sascha
authors: S
authors: Fauser
authors: Anneke I
authors: AI
authors: den Hollander
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D015331:Cohort Studies; D017242:Complement Factor H / Q000235:genetics; D005260:Female; D005451:Fluorescein Angiography; D051157:Frizzled Receptors / Q000235:genetics; D005838:Genotype; D006801:Humans; D058449:Intravitreal Injections; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D000069579:Ranibizumab; D012307:Risk Factors; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics; D014792:Visual Acuity / Q000502:physiology; D057135:Wet Macular Degeneration / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology
chemical_list: C514392:ARMS2 protein, human; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C493495:CFH protein, human; C402930:FZD4 protein, human; D051157:Frizzled Receptors; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D011506:Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D017242:Complement Factor H; D040301:Vascular Endothelial Growth Factor Receptor-2; D000069579:Ranibizumab