title: Pharmacogenetic associations with long-term response to anti-vascular endothelial growth factor treatment in neovascular AMD patients.
abstract: OBJECTIVE
  To investigate the pharmacogenetic associations between the genetic risk variants of age-related macular degeneration (AMD) and long-term outcome after intravitreal anti-vascular endothelial growth factor (VEGF) treatment in Korean neovascular AMD patients.
  
  
  METHODS
  This prospective study included 394 treatment-naïve patients (394 eyes) that underwent intravitreal anti-VEGF treatment for neovascular AMD for at least 12 months. Patients were genotyped for 17 single nucleotide polymorphisms within 13 AMD-relevant genes. Initially, patients underwent three monthly injections of intravitreal ranibizumab and were retreated as needed with ranibizumab or bevacizumab. For each candidate polymorphism, genotypic associations with treatment outcome measures at months 12 and 24, including mean change in best-corrected visual acuity (BCVA) from baseline, visual gain of ≥15 letters, mean change in central subfield macular thickness (CSMT) from baseline on spectral domain optical coherence tomography (OCT), presence of fluid on OCT, and mean number of injections, were investigated using logistic or linear regression models with adjustment for non-genetic covariates.
  
  
  RESULTS
  At month 24, BCVA improved by 4.5 ± 22.5 letters and CSMT decreased by 69.4 ± 112.6 µm from baseline. Regression analysis with Bonferroni correction showed that the TT genotype for VEGFA rs3025039 was associated with a significantly higher chance of a visual gain of ≥15 letters at month 24 than other genotypes (odds ratio, 4.57; 95% confidence interval, 1.89 - 11.1; corrected p = 0.0434). As for tomographic outcome, the minor allele homozygotes for ARMS2 rs10490924 and HTRA1 rs1100638 (GG genotype for both) were associated with a larger CSMT reduction at month 12 than other genotypes, with borderline significance after Bonferroni correction (118.6 ± 132.7 µm versus 62.7 ± 89.7 µm, corrected p = 0.0656 for rs10490924; 115.7 ± 131.7 µm versus 63.6 ± 89.8 µm, corrected p = 0.0528 for rs11200638). No polymorphism showed a significant association with the number of injections.
  
  
  CONCLUSIONS
  In this Korean neovascular AMD cohort, treatment outcome after anti-VEGF was found to differ by the genotypes of VEGFA rs3025039, ARMS2 rs10490924, and HTRA1 rs11200638. Given more evidence of pharmacogenetic associations with the anti-VEGF agent, individualized therapeutic approaches based on genetic background could lead to optimal treatment in neovascular AMD.
authors.affiliation: Department of Ophthalmology, College of Medicine, Seoul National University, Seoul, Korea ; Department of Ophthalmology, National Medical Center, Seoul, Korea.
authors.forename: Un Chul
authors.initials: UC
authors.lastname: Park
authors.affiliation: Department of Ophthalmology, College of Medicine, Seoul National University, Seoul, Korea.
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Shin
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom.
authors.forename: Linda C
authors.initials: LC
authors.lastname: McCarthy
authors.affiliation: Department of Ophthalmology, College of Medicine, Seoul National University, Seoul, Korea ; Department of Ophthalmology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Sang Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Ophthalmology, College of Medicine, Seoul National University, Seoul, Korea ; Department of Ophthalmology, Seoul Paik Hospital, Inje University, Seoul, Korea.
authors.forename: Jung Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Ophthalmology, College of Medicine, Seoul National University, Seoul, Korea.
authors.forename: Hum
authors.initials: H
authors.lastname: Chung
authors.affiliation: Department of Ophthalmology, College of Medicine, Seoul National University, Seoul, Korea ; Sensory Organs Institute, Medical Research Center, Seoul National University, Seoul, Korea.
authors.forename: Hyeong Gon
authors.initials: HG
authors.lastname: Yu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D044466:Asian People / Q000235:genetics; D000068258:Bevacizumab / Q000627:therapeutic use*; D015331:Cohort Studies; D005260:Female; D000074289:High-Temperature Requirement A Serine Peptidase 1; D006801:Humans; D008268:Macular Degeneration / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D011506:Proteins / Q000235:genetics; D000069579:Ranibizumab / Q000627:therapeutic use*; D056910:Republic of Korea; D012697:Serine Endopeptidases / Q000235:genetics; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics*; D014792:Visual Acuity / Q000187:drug effects
chemical_list: C514392:ARMS2 protein, human; D020533:Angiogenesis Inhibitors; D011506:Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000074289:High-Temperature Requirement A Serine Peptidase 1; C474012:HTRA1 protein, human; D012697:Serine Endopeptidases; D000069579:Ranibizumab