title: Suggestive association between PLA2G12A single nucleotide polymorphism rs2285714 and response to anti-vascular endothelial growth factor therapy in patients with exudative age-related macular degeneration.
abstract: OBJECTIVE
  The use of anti-vascular endothelial growth factor (anti-VEGF) therapy, with drugs such as ranibizumab and bevacizumab, to treat neovascular age-related macular degeneration (nAMD) produces an effective but widely variable response. Identifying markers that predict differentiated response could serve as a valuable assay in developing more personalized medicine. This study aimed to identify single nucleotide polymorphisms (SNPs) that influence the outcome of treatment with anti-VEGF therapy for AMD.
  
  
  METHODS
  One hundred six patients with nAMD were treated with either ranibizumab or bevacizumab as needed over a period of 12 months. Visual acuity and the presence of macular fluid were measured with optical coherence tomography at baseline, six months, and 12 months. Patients were then classified as good or poor responders based on change in visual acuity and macular fluid on follow-up visits. DNA extracted from blood was genotyped with a TaqMan-based allelic discrimination SNP assay for 21 SNPs in six candidate genes (PLAG12A, IL23R, STAT3, VEGFA, KDR, and HIF1A). The SNPs were primarily selected based on previously reported associations with AMD and functional involvement in angiogenesis pathways. SNPs shown to be promising for association with anti-VEGF therapy were then assessed in an independent AMD case-control cohort.
  
  
  RESULTS
  Of the 106 patients with nAMD, 77 were classified as good responders and 29 as poor responders. For rs2285714 (PLA2G12A), the frequency of minor allele T was 40.1% for good responders compared to 51.7% for poor responders (odds ratio: 1.60, 95% confidence interval of odds ratio: 0.87-2.94, p=0.13). Genetic model analysis of rs2285714 (PLA2G12A) demonstrated an association between rs2285714 (PLA2G12A) and therapy response in a dominant genotypic model. Patients carrying at least one T allele of rs2285714 were 2.79 times (95% confidence interval=1.02-7.69, p<0.05) more likely to be poor responders (79.3% of poor responders) than good responders (57.3% of good responders). However, after adjusting for multiple testing by the false discovery rate or Bonferroni correction, the initially observed association was no longer statistically significant. No association was identified between the remaining SNPs and response status. The SNP rs2285714 of PLA2G12A was not significantly associated with AMD in an independent AMD case-control cohort.
  
  
  CONCLUSIONS
  Data suggest a possible weak association between rs2285714 (PLA2G12A) and response to anti-VEGF therapy, but the association must be confirmed in additional cohorts with larger patient samples. Identifying factors that predict the differentiated response could provide a valuable assay for developing approaches in personalized medicine.
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Vinson M
authors.initials: VM
authors.lastname: Wang
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rosen
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Meyerle
authors.forename: Shree K
authors.initials: SK
authors.lastname: Kurup
authors.forename: Daniel
authors.initials: D
authors.lastname: Ardeljan
authors.forename: Elvira
authors.initials: E
authors.lastname: Agron
authors.forename: Katy
authors.initials: K
authors.lastname: Tai
authors.forename: Matthew
authors.initials: M
authors.lastname: Pomykala
authors.forename: Emily Y
authors.initials: EY
authors.lastname: Chew
authors.forename: Chi-Chao
authors.initials: CC
authors.lastname: Chan
authors.forename: Jingsheng
authors.initials: J
authors.lastname: Tuo
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D000068258:Bevacizumab; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D054467:Phospholipases A2 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D000069579:Ranibizumab; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D014792:Visual Acuity; D057135:Wet Macular Degeneration / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D054316:Biomarkers, Pharmacological; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D054467:Phospholipases A2; D000069579:Ranibizumab