title: Genetic influences on the outcome of anti-vascular endothelial growth factor treatment in neovascular age-related macular degeneration.
abstract: OBJECTIVE
  To determine the association of genetic variants in known age-related macular degeneration (AMD) risk-associated genes with outcome of anti-vascular endothelial growth factor (VEGF) treatment in neovascular AMD.
  
  
  METHODS
  Prospective cohort study.
  
  
  METHODS
  We enrolled 224 consecutive patients with neovascular AMD at the Royal Victorian Eye and Ear Hospital, Australia.
  
  
  METHODS
  Patients were treated with 3 initial monthly ranibizumab or bevacizumab injections followed by 9 months of "as required" injections based on clinician's decision at each follow-up visit according to retreatment criteria. Seventeen single nucleotide polymorphisms (SNPs) in known AMD risk-associated genes including CFH (rs800292, rs3766404, rs1061170, rs2274700 and rs393955), HTRA1 (rs11200638), CFHR1-5 (rs10922153, rs16840639, rs6667243, and rs1853883), LOC387715/ARMS2 (rs3793917 and rs10490924), C3 (rs2230199 and rs1047286), C2 (rs547154), CFB (rs641153) and F13B (rs6003) were examined. Multivariate analysis was used to determine the role of each SNP in treatment outcome.
  
  
  METHODS
  The influence of selected SNPs on mean change in visual acuity (VA) at 12 months.
  
  
  RESULTS
  Mean baseline VA was 51 ± 16.8 Early Treatment Diabetic Retinopathy Study letters. Overall, the mean change in VA from baseline was +3.2 ± 14.9 letters at 12 months. The AA (homozygote risk) genotype at rs11200638 - HTRA1 promoter SNP (P = 0.001) and GG (homozygote risk) genotype at rs10490924 (A69S) in LOC387715/ARMS2 (P = 0.002) were each significantly associated with poorer VA outcome at 12 months after multiple correction. Mean ± standard deviation change in VA from baseline in patients with AA genotype at rs11200638 was -2.9 ± 15.2 letters after 12 months compared with +5.1 ± 14.1 letters in patients with AG or GG genotypes at this SNP. Patients with either of these genotypes were also significantly more likely to lose >15 letters after 12 months. SNPs rs11200638 and rs10490924 were in high linkage disequilibrium (r(2) = 0.92). None of the other examined SNPs was associated with outcome.
  
  
  CONCLUSIONS
  The HTRA1 promoter SNP (rs11200638) and A69S at LOC387715/ARMS2 were associated with a poorer visual outcome for ranibizumab or bevacizumab treatment in neovascular AMD, suggesting strong pharmacogenetic associations with anti-VEGF treatment. This finding could aid in applying more individualized treatment regimens based on patients' genotype to achieve optimal treatment response in AMD.
  
  
  BACKGROUND
  The authors have no proprietary or commercial interest in any materials discussed in this article.
authors.affiliation: Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Victoria, Australia. abedifarshad@yahoo.com
authors.forename: Farshad
authors.initials: F
authors.lastname: Abedi
authors.forename: Sanjeewa
authors.initials: S
authors.lastname: Wickremasinghe
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Richardson
authors.forename: Amirul F M
authors.initials: AF
authors.lastname: Islam
authors.forename: Robyn H
authors.initials: RH
authors.lastname: Guymer
authors.forename: Paul N
authors.initials: PN
authors.lastname: Baird
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000068258:Bevacizumab; D015331:Cohort Studies; D003180:Complement C3b Inactivator Proteins / Q000235:genetics; D017242:Complement Factor H / Q000235:genetics; D003165:Complement System Proteins / Q000235:genetics; D005260:Female; D005838:Genotype; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011506:Proteins / Q000235:genetics; D000069579:Ranibizumab; D019233:Retreatment; D012697:Serine Endopeptidases / Q000235:genetics; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; 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; D003180:Complement C3b Inactivator Proteins; D011506:Proteins; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D017242:Complement Factor H; D003165:Complement System Proteins; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases; D000069579:Ranibizumab