VEGFA and VEGFR2 gene polymorphisms and response to anti-vascular endothelial growth factor therapy: comparison of age-related macular degeneration treatments trials (CATT).

IMPORTANCE Individual variation in response and duration of anti-vascular endothelial growth factor (VEGF) therapy is seen among patients with neovascular age-related macular degeneration. Identification of genetic markers that affect clinical response may result in optimization of anti-VEGF therapy. OBJECTIVE To evaluate the pharmacogenetic relationship between genotypes of single-nucleotide polymorphisms (SNPs) in the VEGF signaling pathway and response to treatment with ranibizumab or bevacizumab for neovascular age-related macular degeneration. DESIGN, SETTING, AND PARTICIPANTS In total, 835 of 1149 patients (72.7%) participating in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) at 43 CATT clinical centers. INTERVENTION Each patient was genotyped for 7 SNPs in VEGFA (rs699946, rs699947, rs833069, rs833070, rs1413711, rs2010963, and rs2146323) and 1 SNP in VEGFR2 (rs2071559) using TaqMan SNP genotyping assays. MAIN OUTCOMES AND MEASURES Genotypic frequencies were compared with clinical measures of response to therapy at 1 year, including the mean visual acuity, mean change in visual acuity, at least a 15-letter increase, retinal thickness, mean change in total foveal thickness, presence of fluid on optical coherence tomography, presence of leakage on fluorescein angiography, mean change in lesion size, and mean number of injections administered. Differences in response by genotype were evaluated with tests of linear trend calculated from logistic regression models for categorical outcomes and linear regression models for continuous outcomes. The method of controlling the false discovery rate was used to adjust for multiple comparisons. RESULTS For each of the measures of visual acuity evaluated, no association was observed with any of the genotypes or with the number of risk alleles. Four VEGFA SNPs demonstrated an association with retinal thickness: rs699947 (P = .03), rs833070 (P = .04), rs1413711 (P = .045), and rs2146323 (P = .006). However, adjusted P values for these associations were all statistically nonsignificant (range, P = .24 to P = .45). Among the participants in 2 as-needed groups, no association was found in the number of injections among the different genotypes or for the total number of risk alleles. The effect of risk alleles on each clinical measure did not differ by treatment group, drug, or dosing regimen (P > .01 for all). CONCLUSIONS AND RELEVANCE This study provides evidence that no pharmacogenetic associations exist between the studied VEGFA and VEGFR2 SNPs and response to anti-VEGF therapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00593450.

[1]  S. Harding,et al.  Pharmacogenetic associations with vascular endothelial growth factor inhibition in participants with neovascular age-related macular degeneration in the IVAN Study. , 2013, Ophthalmology.

[2]  M. Nardi,et al.  VEGF-A polymorphisms predict short-term functional response to intravitreal ranibizumab in exudative age-related macular degeneration. , 2013, Pharmacogenomics.

[3]  Ivana K. Kim,et al.  Pharmacogenetics for genes associated with age-related macular degeneration in the Comparison of AMD Treatments Trials (CATT). , 2013, Ophthalmology.

[4]  L. Schmetterer,et al.  A randomised double-masked trial comparing the visual outcome after treatment with ranibizumab or bevacizumab in patients with neovascular age-related macular degeneration , 2013, British Journal of Ophthalmology.

[5]  E. Makalic,et al.  Variants in the VEGFA gene and treatment outcome after anti-VEGF treatment for neovascular age-related macular degeneration. , 2013, Ophthalmology.

[6]  E. Chew,et al.  Genetic studies of age-related macular degeneration: lessons, challenges, and opportunities for disease management. , 2012, Ophthalmology.

[7]  Christian Simader,et al.  Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. , 2012, Ophthalmology.

[8]  L. Canani,et al.  The C allele of -634G/C polymorphism in the VEGFA gene is associated with increased VEGFA gene expression in human retinal tissue. , 2012, Investigative ophthalmology & visual science.

[9]  J. Jonas,et al.  Role of vascular endothelial growth factor polymorphisms in the treatment success in patients with wet age-related macular degeneration. , 2012, Ophthalmology.

[10]  Ebenezer Daniel,et al.  Photographic assessment of baseline fundus morphologic features in the Comparison of Age-Related Macular Degeneration Treatments Trials. , 2012, Ophthalmology.

[11]  M. Nardi,et al.  The rs2071559 AA VEGFR-2 Genotype Frequency Is Significantly Lower in Neovascular Age-Related Macular Degeneration Patients , 2012, TheScientificWorldJournal.

[12]  M. Nardi,et al.  Pharmacogenetics of antiangiogenic and antineovascular therapies of age-related macular degeneration. , 2012, Pharmacogenomics.

[13]  G. Ying,et al.  Ranibizumab and Bevacizumab for Treatment of Neovascular Age-Related Macular Degeneration: 2-Year Results: Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group‡* , 2012 .

[14]  Usha Chakravarthy,et al.  Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. , 2012, Ophthalmology.

[15]  G. Ying,et al.  Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. , 2012, Ophthalmology.

[16]  Zhenping Huang,et al.  Pooled-analysis of the associations between three polymorphisms in the VEGF gene and age-related macular degeneration , 2012, Molecular Biology Reports.

[17]  P. A. Pereira,et al.  Homozygosity for the +674C>T polymorphism on VEGF gene is associated with age-related macular degeneration in a Brazilian cohort , 2012, Graefe's Archive for Clinical and Experimental Ophthalmology.

[18]  A. Tsujikawa,et al.  VEGF gene polymorphism and response to intravitreal bevacizumab and triple therapy in age-related macular degeneration , 2011, Japanese Journal of Ophthalmology.

[19]  W. Berger,et al.  Genetic association with response to intravitreal ranibizumab in patients with neovascular AMD. , 2011, Investigative ophthalmology & visual science.

[20]  Glenn J Jaffe,et al.  Ranibizumab and bevacizumab for neovascular age-related macular degeneration. , 2011, The New England journal of medicine.

[21]  M. McKibbin,et al.  CFH, VEGF and HTRA1 promoter genotype may influence the response to intravitreal ranibizumab therapy for neovascular age-related macular degeneration , 2011, British Journal of Ophthalmology.

[22]  Giovanni Sato,et al.  Association of age-related macular degeneration with polymorphisms in vascular endothelial growth factor and its receptor. , 2010, Ophthalmology.

[23]  K. Horie-Inoue,et al.  CFH, VEGF, and PEDF genotypes and the response to intravitreous injection of bevacizumab for the treatment of age-related macular degeneration , 2010, Journal of ocular biology, diseases, and informatics.

[24]  P. Tommila,et al.  Vascular endothelial growth factor gene variation and the response to photodynamic therapy in age-related macular degeneration. , 2010, Ophthalmology.

[25]  Aaron Y. Lee,et al.  Polymorphisms in the VEGFA and VEGFR-2 genes and neovascular age-related macular degeneration , 2009, Molecular vision.

[26]  J. Błasiak,et al.  Association between vascular endothelial growth factor gene polymorphisms and age-related macular degeneration in a Polish population. , 2009, Experimental and molecular pathology.

[27]  A. Hofman,et al.  Polymorphisms in the vascular endothelial growth factor gene and risk of age-related macular degeneration: the Rotterdam Study. , 2008, Ophthalmology.

[28]  Steven J. Harper,et al.  VEGF-A splicing: the key to anti-angiogenic therapeutics? , 2008, Nature Reviews Cancer.

[29]  F. Tsai,et al.  Vascular endothelial growth factor gene polymorphisms in age-related macular degeneration. , 2008, American journal of ophthalmology.

[30]  R. Guymer,et al.  A tag-single nucleotide polymorphisms approach to the vascular endothelial growth factor-A gene in age-related macular degeneration. , 2007, Molecular vision.

[31]  R. Danesi,et al.  Vascular endothelial growth factor pharmacogenetics: a new perspective for anti-angiogenic therapy. , 2007, Pharmacogenomics.

[32]  A. Augustin,et al.  Emerging drugs for age-related macular degeneration , 2006, Expert opinion on emerging drugs.

[33]  Philip J Rosenfeld,et al.  Ranibizumab for neovascular age-related macular degeneration. , 2006, The New England journal of medicine.

[34]  Susan Schneider,et al.  Ranibizumab versus verteporfin for neovascular age-related macular degeneration. , 2006, The New England journal of medicine.

[35]  J. Escardo,et al.  VEGF polymorphisms are associated with neovascular age-related macular degeneration. , 2006, Human molecular genetics.

[36]  Chia-Hung Liu,et al.  FASTSNP: an always up-to-date and extendable service for SNP function analysis and prioritization , 2006, Nucleic Acids Res..

[37]  J. Duker,et al.  Normal macular thickness measurements in healthy eyes using Stratus optical coherence tomography. , 2006, Archives of ophthalmology.

[38]  Peter K. Kaiser,et al.  ANCHOR STUDY GROUP. RANIBIZUMAB VERSUS VERTEPORFIN FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION , 2006 .

[39]  J. Gilbert,et al.  Functional candidate genes in age-related macular degeneration: significant association with VEGF, VLDLR, and LRP6. , 2006, Investigative ophthalmology & visual science.

[40]  N. Ferrara,et al.  The biology of VEGF and its receptors , 2003, Nature Medicine.

[41]  Chris A Johnson,et al.  A computerized method of visual acuity testing: adaptation of the early treatment of diabetic retinopathy study testing protocol. , 2003, American journal of ophthalmology.

[42]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .