title: Genetic association with response to intravitreal ranibizumab in patients with neovascular AMD.
abstract: OBJECTIVE
  Neovascular age-related macular degeneration (AMD) resulting in decreased central vision severely impairs affected individuals. Current standard treatment is an intravitreal anti-VEGF therapy (ranibizumab), but responses to treatment show large variability. Genetic factors that influence AMD and that affect the outcome of ranibizumab treatment were sought within a sample of Swiss patients.
  
  
  METHODS
  Changes in visual acuity (VA) after initiation of anti-VEGF treatment were observed during 12 months, and percentiles of VA were calculated. Genotypes of polymorphisms in known AMD susceptibility loci (CFH, CFB, HTRA1, AMRS2, and VEGFA) as well as not yet reported AMD-associated genes (KDR, LRP5, and FZD4) were determined, and their frequencies were compared.
  
  
  RESULTS
  Of the 309 eyes included in the study, 243 completed VA assessment. On average, 3.9 ±2.6 ranibizumab injections were administered. Based on the change in visual acuity, two responder groups were established: 63 eyes were assigned to the poor responders (≤25th percentile) and 63 eyes to the good responders (≥75th percentile). Individuals with genotype CC of p.Y402H in CFH had a decreased chance of positive treatment outcome compared with those with the CT and TT genotypes (P = 0.005 and P = 0.006). In this study, the genotype combination of AG at CFH with CT at FZD4 (SNP rs10898563) promised an increased chance of positive treatment outcome (P = 0.004). Furthermore, the association with the known genetic susceptibility loci CFH, HTRA1, and AMRS2 were confirmed, and a risk-conferring polymorphism in one new locus, LRP5, was identified.
  
  
  CONCLUSIONS
  Genetic predisposition may account for the variability in response to anti-VEGF treatment.
authors.affiliation: Institute of Medical Molecular Genetics, University of Zurich, Schwerzenbach, Switzerland. kloeckener@medgen.uzh.ch
authors.forename: Barbara
authors.initials: B
authors.lastname: Kloeckener-Gruissem
authors.forename: Daniel
authors.initials: D
authors.lastname: Barthelmes
authors.forename: Stephan
authors.initials: S
authors.lastname: Labs
authors.forename: Christian
authors.initials: C
authors.lastname: Schindler
authors.forename: Malaika
authors.initials: M
authors.lastname: Kurz-Levin
authors.forename: Stephan
authors.initials: S
authors.lastname: Michels
authors.forename: Johannes
authors.initials: J
authors.lastname: Fleischhauer
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Berger
authors.forename: Florian
authors.initials: F
authors.lastname: Sutter
authors.forename: Moreno
authors.initials: M
authors.lastname: Menghini
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D011415:Complement Factor B / Q000235:genetics; D017242:Complement Factor H / Q000235:genetics; D004247:DNA / Q000032:analysis / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D020022:Genetic Predisposition to Disease; D005838:Genotype; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D058449:Intravitreal Injections; D008268:Macular Degeneration / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics; D000069579:Ranibizumab; D015861:Retinal Neovascularization / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D013997:Time Factors; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D014792:Visual Acuity
chemical_list: C514392:ARMS2 protein, human; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D011506:Proteins; D042461:Vascular Endothelial Growth Factor A; D017242:Complement Factor H; D004247:DNA; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases; D011415:Complement Factor B; D000069579:Ranibizumab