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Predictive value of VEGF A and VEGFR2 polymorphisms in the response to intravitreal ranibizumab treatment for wet AMD

  • Genetics
  • Published:
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Abstract

Background

To determine whether gene polymorphisms of the vascular endothelial growth factor A (VEGF A) and its receptor (VEGFR) influence the response to a variable-dosing treatment regimen with ranibizumab for age-related macular degeneration.

Methods

This prospective cohort study included 94 patients (94 eyes) with exudative age-related macular degeneration (AMD) treated with ranibizumab. Patients underwent a 1-year treatment as in the Study of Ranibizumab in Patients with Subfoveal Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (SUSTAIN). Injections were administered monthly during 3 months to all the patients diagnosed of neovascular AMD; reinjections were made when a patient lost 5 letters on the Early Treatment Diabetic Retinopathy Study chart or gained 100 μm in central subfield retinal thickness measured by OCT. Genotypes (VEGF A (rs 699947, rs833061) and VEGFR (rs 2071559)) were analyzed using TaqMan probes. Best-corrected visual acuity (BCVA), subjective improvement, and macular thickness measured with OCT values were compared with VEGF A and VEGFR genotypes. Multiple regression analysis was used to assess the statistical significance.

Results

We found statistically significant differences in allelic distribution of VEGF A rs833061 polymorphism in relation with the response to intravitreal ranibizumab regarding to visual acuity improvement [p = 0,.34; OR: 1.619 (1.098–2.386)]. Patients carrying “protector” genotype CC had higher probability of best corrected visual acuity improvement. When we analyzed VEGF A rs699947 polymorphism we found that patients expressing AA genotype had a higher chance of increasing their best corrected visual acuity [p:0,022; OR 1,532 (1,015–2,313)]. We did not find statistically significant differences reagarding VEGFR rs2071559 polymorphism and treatment response.

Conclusions

Polymorphisms of VEGF A seem to influence the different response to antiangiogenic treatment in patients with AMD in our population, although further investigation is needed to know the mechanisms of this relationship.

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References

  1. Friedman DS, O’Colmain BJ, Munoz B, Tomany SC, McCarty C, de Jong PT, Nemesure B, Mitchell P, Kempen J (2004) Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 122:564–572

    Article  PubMed  Google Scholar 

  2. Montezuma SR, Sobrin L, Seddon JM (2007) Review of genetics in age related macular degeneration. Semin Ophthalmol 22:229–240

    Article  PubMed  Google Scholar 

  3. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676

    Article  CAS  PubMed  Google Scholar 

  4. Hubschman JP, Reddy S, Schwartz SD (2009) Age-related macular degeneration: experimental and emerging treatments. Clin Ophthalmol 3:167–174

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K (2000) Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res 60:203–212

    CAS  PubMed  Google Scholar 

  6. Grisanti S, Tatar O (2008) The role of vascular endothelial growth factor and other endogenous interplayers in age-related macular degeneration. Prog Retin Eye Res 27:372–390

    Article  CAS  PubMed  Google Scholar 

  7. Zeng G, Gao L, Birkle S, Yu RK (2000) Suppression of ganglioside GD3 expression in a rat F-11 tumor cell line reduces tumor growth, angiogenesis, and vascular endothelial growth factor production. Cancer Res 60:6670–6676

    CAS  PubMed  Google Scholar 

  8. Churchill AJ, Carter JG, Lovell HC, Ramsden C, Turner SJ, Yeung A, Escardo J, Atan D (2006) VEGF polymorphisms are associated with neovascular age-related macular degeneration. Hum Mol Genet 15:2955–2961

    Article  CAS  PubMed  Google Scholar 

  9. Haines JL, Schnetz-Boutaud N, Schmidt S, Scott WK, Agarwal A, Postel EA, Olson L, Kenealy SJ, Hauser M, Gilbert JR, Pericak-Vance MA (2006) Functional candidate genes in age-related macular degeneration: significant association with VEGF, VLDLR, and LRP6. Invest Ophthalmol Vis Sci 47:329–335

    Article  PubMed  Google Scholar 

  10. Lin JM, Wan L, Tsai YY, Lin HJ, Tsai Y, Lee CC, Tsai CH, Tseng SH, Tsai FJ (2008) Vascular endothelial growth factor gene polymorphisms in age-related macular degeneration. Am J Ophthalmol 145:1045–1051

    Article  CAS  PubMed  Google Scholar 

  11. Boekhoorn SS, Isaacs A, Uitterlinden AG, van Duijn CM, Hofman A, de Jong PT, Vingerling JR (2008) Polymorphisms in the vascular endothelial growth factor gene and risk of age-related macular degeneration: the Rotterdam Study. Ophthalmology 115:1899–1903

    Article  PubMed  Google Scholar 

  12. Janik-Papis K, Zaras M, Krzyzanowska A, Wozniak K, Blasiak J, Szaflik J, Szaflik JP (2009) Association between vascular endothelial growth factor gene polymorphisms and age-related macular degeneration in a Polish population. Exp Mol Pathol 87:234–238

    Article  CAS  PubMed  Google Scholar 

  13. Qu Y, Dai H, Zhou F, Zhang X, Xu X, Bi H, Pan X, Wang H, Jiang H, Yin N, Dang G (2011) Vascular endothelial growth factor gene polymorphisms and risk of neovascular age-related macular degeneration in a Chinese cohort. Ophthalmic Res 45:142–148

    Article  CAS  PubMed  Google Scholar 

  14. Richardson AJ, Islam FM, Guymer RH, Cain M, Baird PN (2007) A tag-single nucleotide polymorphisms approach to the vascular endothelial growth factor-A gene in age-related macular degeneration. Mol Vis 13:2148–2152

    PubMed  Google Scholar 

  15. Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T (2009) Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: 2-year results of the ANCHOR study. Ophthalmology 116(57–65):e55

    Google Scholar 

  16. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355:1419–1431

    Article  CAS  PubMed  Google Scholar 

  17. Zachary I (2005) Neuroprotective role of vascular endothelial growth factor: signalling mechanisms, biological function, and therapeutic potential. Neurosignals 14:207–221

    Article  CAS  PubMed  Google Scholar 

  18. Mitchell P, Korobelnik JF, Lanzetta P, Holz FG, Prunte C, Schmidt-Erfurth U, Tano Y, Wolf S (2010) Ranibizumab (Lucentis) in neovascular age-related macular degeneration: evidence from clinical trials. Br J Ophthalmol 94:2–13

    Article  CAS  PubMed  Google Scholar 

  19. Galan A, Ferlin A, Caretti L, Buson G, Sato G, Frigo AC, Foresta C (2010) Association of age-related macular degeneration with polymorphisms in vascular endothelial growth factor and its receptor. Ophthalmology 117:1769–1774

    Article  PubMed  Google Scholar 

  20. Cruz-González F, Cieza-Borrella C, Cabrillo-Estévez L, Cañete-Campos C, Escudero-Domínguez F, González-Sarmiento R (2013) VEGF A (rs699947 and rs833061) and VEGFR2 (rs2071559) gene polymorphisms are not associated with AMD susceptibility in a Spanish population. R Curr Eye Res 38(12):1274–1277

    Article  Google Scholar 

  21. Lazzeri S, Orlandi P, Figus M, Fioravanti A, Cascio E, Di Desidero T, Agosta E, Canu B, Sartini MS, Danesi R, Nardi M, Bocci G (2012) The rs2071559 AA VEGFR-2 genotype frequency is significantly lower in neovascular age-related macular degeneration patients. Sci World J 2012:420190

    Article  Google Scholar 

  22. Fang AM, Lee AY, Kulkarni M, Osborn MP, Brantley MA Jr (2009) Polymorphisms in the VEGFA and VEGFR-2 genes and neovascular age-related macular degeneration. Mol Vis 15:2710–2719

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Kloeckener-Gruissem B, Barthelmes D, Labs S, Schindler C, Kurz-Levin M, Michels S, Fleischhauer J, Berger W, Sutter F, Menghini M (2011) Genetic association with response to intravitreal ranibizumab in patients with neovascular AMD. Invest Ophthalmol Vis Sci 52:4694–4702

    Article  CAS  PubMed  Google Scholar 

  24. McKibbin M, Ali M, Bansal S, Baxter PD, West K, Williams G, Cassidy F, Inglehearn CF (2011) CFH, VEGF and HTRA1 promoter genotype may influence the response to intravitreal ranibizumab therapy for neovascular age-related macular degeneration. Br J Ophthalmol 96(2):208–212

    Article  PubMed  Google Scholar 

  25. Lazzeri S, Figus M, Orlandi P, Fioravanti A, Di Desidero T, Agosta E, Sartini MS, Posarelli C, Nardi M, Danesi R, Bocci G (2013) VEGF-A polymorphisms predict short-term functional response to intravitreal ranibizumab in exudative age-related macular degeneration. Pharmacogenomics 14(6):623–630

    Article  CAS  PubMed  Google Scholar 

  26. Smailhodzic D, Muether PS, Chen J, Kwestro A, Zhang AY, Omar A, Van de Ven JP, Keunen JE, Kirchhof B, Hoyng CB, Klevering BJ, Koenekoop RK, Fauser S, den Hollander AI (2012) Cumulative effect of risk alleles in CFH, ARMS2, and VEGFA on the response to ranibizumab treatment in age-related macular degeneration. Ophthalmology 119(11):2304–2311

    Article  PubMed  Google Scholar 

  27. Chang W, Noh DH, Sagong M, Kim IT (2013) Pharmacogenetic association with early response to intravitreal ranibizumab for age-related macular degeneration in a Korean population. Mol Vis 19:702–709

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Tsuchihashi T, Mori K, Horie-Inoue K, Gehlbach PL, Kabasawa S, Takita H, Ueyama K, Okazaki Y, InoueS AT, Katayama S, Yoneya S (2011) Complement factor H and high-temperature requirement A-1 genotypes and treatment response of age-related macular degeneration. Ophthalmology 118:93–100

    Article  PubMed  Google Scholar 

  29. Stevens A, Soden J, Brenchley PE, Ralph S, Ray DW (2003) Haplotype analysis of the polymorphic human vascular endothelial growth factor gene promoter. Cancer Res 63:812–816

    CAS  PubMed  Google Scholar 

  30. Boltz A, Ruiz M, Jonas JB, Tao Y, Rensch F, Weger M, Garhöfer G, Frantal S, El-Shabrawi Y, Schmetterer L (2012) Role of vascular endothelial growth factor polymorphisms in the treatment success in patients with wet age-related macular degeneration. Ophthalmology 119(8):1615–1620

    Article  PubMed  Google Scholar 

  31. Schmidt S, Hauser MA, Scott WK, Postel EA, Agarwal A, Gallins P, Wong F, Chen YS, Spencer K, Schnetz-Boutaud N, Haines JL, Pericak-Vance MA (2006) Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration. Am J Hum Genet 78:852–864

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. de Santa C, Pau E, Arias FC, Caso Pelaez E, Munoz Molina GM, Sanchez Hernandez I, Muguruza Trueba I, Moreno Balsalobre R, Sacristan Lopez S, Gomez Pinillos A, del Val Toledo Lobo M (2009) Prognostic significance of the expression of vascular endothelial growth factors A, B, C, and D and their receptors R1, R2, and R3 in patients with nonsmall cell lung cancer. Cancer 115:1701–1712

    Article  Google Scholar 

  33. Forsti A, Jin Q, Altieri A, Johansson R, Wagner K, Enquist K, Grzybowska E, Pamula J, Pekala W, Hallmans G, Lenner P, Hemminki K (2007) Polymorphisms in the KDR and POSTN genes: association with breast cancer susceptibility and prognosis. Breast Cancer Res Treat 101:83–93

    Article  PubMed  Google Scholar 

  34. Pabst S, Karpushova A, Diaz-Lacava A, Herms S, Walier M, Zimmer S, Cichon S, Nickenig G, Nöthen MM, Wienker TF, Grohé C (2010) VEGF gene haplotypes are associated with sarcoidosis. Chest 137:156–163

    Article  CAS  PubMed  Google Scholar 

  35. Wang Y, Zheng Y, Zhang W, Yu H, Lou K, Zhang Y, Qin Q, Zhao B, Yang Y, Hui R (2007) Polymorphisms of KDR gene are associated with coronary heart disease. J Am Coll Cardiol 50:760–767

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Fernando Cruz-Gonzalez.

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Cruz-Gonzalez, F., Cabrillo-Estévez, L., López-Valverde, G. et al. Predictive value of VEGF A and VEGFR2 polymorphisms in the response to intravitreal ranibizumab treatment for wet AMD. Graefes Arch Clin Exp Ophthalmol 252, 469–475 (2014). https://doi.org/10.1007/s00417-014-2585-7

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  • DOI: https://doi.org/10.1007/s00417-014-2585-7

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