Skip to main content

Advertisement

Log in

CFH, VEGF, and PEDF genotypes and the response to intravitreous injection of bevacizumab for the treatment of age-related macular degeneration

  • Published:
Journal of Ocular Biology, Diseases, and Informatics

Abstract

We determined whether there is an association between complement factor H (CFH), high-temperature requirement A-1 (HTRA1), vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor (PEDF) genotypes and the response to treatment with a single intravitreous injection of bevacizumab for age-related macular degeneration (AMD). Eighty-three patients with exudative AMD treated by bevacizumab injection were genotyped for three single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996) in the CFH gene, a rs11200638-SNP in the HTRA1 gene, three SNPs (rs699947, rs1570360, rs2010963) in the VEGF gene, and four SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the PEDF gene using a TaqMan assay. The CT genotype (heterozygous) of CFH-rs1061170 was more frequently represented in nonresponders in vision than TT genotypes (nonrisk allele homozygous) at the time points of 1 and 3 months, while there was no CC genotype (risk allele homozygous) in our study cohort (p = 7.66 × 10−3, 7.83 × 10−3, respectively). VEGF-rs699947 was also associated with vision changes at 1 month and PEDF-rs1136287 at 3 months (p = 5.11 × 10−3, 2.05 × 10−2, respectively). These variants may be utilized for genetic biomarkers to estimate visual outcomes in the response to intravitreal bevacizumab treatment for AMD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Age-Related Eye Disease Study Research Group. Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: age-related eye disease study report number 3. Ophthalmology. 2000;107:2224–32.

    Article  Google Scholar 

  2. Age-Related Eye Disease Study Research Group. Potential public health impact of age-related eye disease study results. AREDS report no. 11. Arch Ophthalmol. 2003;121:1621–4.

    Article  Google Scholar 

  3. Age-Related Eye Disease Study Research Group. Risk factors for the incidence of advanced age-related macular degeneration in the age-related eye disease study. AREDS report no. 19. Am J Ophthalmol. 2005;112:533–9.

    Google Scholar 

  4. Klein R, Peto T, Bird AC, Vannewkirk MR. The epidemiology of age-related macular degeneration. Am J Ophthalmol. 2004;137:486–95.

    Article  PubMed  Google Scholar 

  5. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385–9.

    Article  PubMed  CAS  Google Scholar 

  6. Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, et al. Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005;308:419–21.

    Article  PubMed  CAS  Google Scholar 

  7. Edward AO, Ritter 3rd R, Abel KJ, Manning A, Panhuysen C, Farrer LA, et al. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;314:989–92.

    Google Scholar 

  8. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hageman JL, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA. 2005;102:7227–32.

    Article  PubMed  CAS  Google Scholar 

  9. Li M, Atmaca-Sonmez P, Othman M, Branham KE, Khanna R, Wade MS, et al. CFH haplotypes without the Y402H cording variant show strong association with susceptibility to age-related macular degeneration. Nat Genet. 2006;38:1049–54.

    Article  PubMed  CAS  Google Scholar 

  10. Maller J, George S, Purcell S, Fagerness J, Altshuler D, Daly MJ, et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet. 2006;38:1055–9.

    Article  PubMed  CAS  Google Scholar 

  11. Jackobsdottir J, Conley YP, Weeks DE, Mah TS, Ferrell RE, Gorin MB, et al. Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet. 2005;77:389–407.

    Article  Google Scholar 

  12. Rivera A, Fisher SA, Fritsche LG, Keilhauer CN, Lichtner P, Meitinger T, et al. Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet. 2005;14:3227–36.

    Article  PubMed  CAS  Google Scholar 

  13. Schmidt S, Hauser MA, Scott WK, Postel EA, Agarwal A, Gallins P, et al. Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration. Am J Hum Genet. 2006;78:852–64.

    Article  PubMed  CAS  Google Scholar 

  14. Fritsche LG, Loenhardt T, Janssen A, Fisher SA, Rivera A, Keilhauer CN, et al. Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nat Genet. 2008;40:892–6.

    Article  PubMed  CAS  Google Scholar 

  15. Kanda A, Chen W, Othman M, Branham KE, Brooks M, Khanna R, et al. A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc Natl Acad Sci USA. 2007;104:16227–32.

    Article  PubMed  CAS  Google Scholar 

  16. DeWan A, Liu M, Hartman S, Zhang SS, Liu DT, Zhao C, et al. HTRA1 promoter polymorphism in wet age-related macular degeneration. Science. 2006;314:989–92.

    Article  PubMed  CAS  Google Scholar 

  17. Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ, et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science. 2006;314:992–3.

    Article  PubMed  CAS  Google Scholar 

  18. Aiello LP. Vascular endothelial growth factor and the eye: biochemical mechanisms of action and implications for novel therapies. Ophthalmic Res. 1997;29:354–62.

    Article  PubMed  CAS  Google Scholar 

  19. Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989;246:1306–9.

    Article  PubMed  CAS  Google Scholar 

  20. Dawson DW, Volpert OV, Gillis P, Crawford SE, Xu HJ, Benedict W, et al. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science. 1999;285:245–8.

    Article  PubMed  CAS  Google Scholar 

  21. Folkman J. Angiogenesis in cancer, vascular, rheumatoid, and other diseases. Nat Med. 1995;1:27–31.

    Article  PubMed  CAS  Google Scholar 

  22. Ohno-Matsui K, Morita I, Tombran-Tink J, Mrazek D, Onodera M, Uetama T, et al. Novel mechanism for age-related macular degeneration: an equilibrium shift between the angiogenesis factors VEGF and PEDF. J Cell Physiol. 2001;89:323–33.

    Article  Google Scholar 

  23. Holkamp NM, Bouk N, Volpert O. Pigment epithelium-derived factor is deficient in the vitreous of patients with choroidal neovascularization due to age-related macular degeneration. Am J Ophthalmol. 2002;134:220–7.

    Article  Google Scholar 

  24. Ogata N, Nishikawa M, Nishimura T, Mitsuma Y, Matsumura M. Unbalanced vitreous levels of pigment epithelium-derived factor and vascular endothelial growth factor in diabetic retinopathy. Am J Ophthalmol. 2002;134:348–53.

    Article  PubMed  CAS  Google Scholar 

  25. Gragoudas ES, Adamis AP, Cunningham Jr ET, Feinsod M, Guyer DR. VEGF inhibition study in ocular neovascularization clinical trial group. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351:2805–16.

    Article  PubMed  CAS  Google Scholar 

  26. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419–31.

    Article  PubMed  CAS  Google Scholar 

  27. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging. 2005;36:331–5.

    PubMed  Google Scholar 

  28. Brantley Jr MA, Fang AM, King JM, Tewari A, Kymes SM, Shiels A. Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab. Ophthalmology. 2007;114:2168–73.

    Article  PubMed  Google Scholar 

  29. Lee AY, Raya AK, Kymes SM, Shiels A, Brantley MA Jr. Pharmacogenetics of complement factor H (Y402H) and treatment of exudative age-related macular degeneration with ranibizumab. Br J Ophthalmol. 2009;93:610–3.

    Article  PubMed  CAS  Google Scholar 

  30. Awata T, Inoue K, Kurihara S, Ohkubo T, Watanabe M, Inukai K, et al. A common polymorphism in the 5′-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes. 2002;51:1635–9.

    Article  PubMed  CAS  Google Scholar 

  31. Awata T, Kurihara S, Takata N, Neda T, Iizuka H, Ohkubo T, et al. Functional VEGF C-634G polymorphism is associated with development of diabetic macular edema and correlated with macular retinal thickness in type 2 diabetes. Biochem Biophys Res Commun. 2005;333:679–85.

    Article  PubMed  CAS  Google Scholar 

  32. Lambrechts D, Storkebaum E, Morimoto M, Del-Favero J, Desmet F, Marklund SL, et al. VEGF is a modifier of amyotrophic lateral sclerosis in mice and humans and protects motoneurons against ischemic death. Nat Genet. 2003;34:383–94.

    Article  PubMed  CAS  Google Scholar 

  33. Haines JL, Schnetz-Boutaud N, Schmidt S, Scott WK, Agarwal A, Postel EA, et al. Functional candidate genes in age-related macular degeneration: significant association with VEGF, VLDLR and LRP6. Invest Ophthalmol Vis Sci. 2006;47:329–35.

    Article  PubMed  Google Scholar 

  34. Churchill AJ, Carter JG, Lovell HC, Ramsden C, Turner SJ, Yeung A, et al. VEGF polymorphisms are associated with neovascular age-related macular degeneration. Hum Mol Genet. 2006;15:2955–61.

    Article  PubMed  CAS  Google Scholar 

  35. Mori K, Horie-Inoue K, Gehlbach PL, Takita H, Kabasawa S, Kawasaki I, et al. Phenotype and genotype characteristics of age-related macular degeneration in a Japanese population. Ophthalmology. 2010;117:928–38.

    Article  PubMed  Google Scholar 

  36. Tsuchihashi T, Mori K, Horie-Inoue K, Gehlbach PL, Kabasawa S, Takita H, et al. Complement factor H and high-temperature requirement A-1 genotypes and treatment response of age-related macular degeneration. Ophthalmology. 2010;117: in press.

  37. Boekhorn SS, Isaacs A, Uitterlinden AG, van Duijn CM, Hofman A, de Jong PT, et al. Polymorphisms in the vascular endothelial growth factor gene and risk of age-related macular degeneration. Ophthalmology. 2008;115:1899–903.

    Article  Google Scholar 

  38. Schneider BP, Wang M, Radovich M, Sledge GW, Badve S, Thor A, et al. Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol. 2008;26:4672–8.

    Article  PubMed  CAS  Google Scholar 

  39. Schneider BP, Radovich M, Miller KD. The role of vascular endothelial growth factor genetic variability in cancer. Clin Cancer Res. 2009;15:5297–302.

    Article  PubMed  CAS  Google Scholar 

  40. Bhutto IA, McLeod DS, Hasegawa T, Kim SY, Merges C, Tong P, et al. Pigment epithelium-derived factor (PEDF) and vascular endothelial growth factor (VEGF) in aged human choroid and eyes with age-related macular degeneration. Exp Eye Res. 2006;82:99–110.

    Article  PubMed  CAS  Google Scholar 

  41. Holekamp NM, Bouck N, Volpert O. Pigment epithelium-derived factor is deficient in the vitreous of patients with choroidal neovascularization due to age-related macular degeneration. Am J Ophthalmol. 2002;134:220–7.

    Article  PubMed  CAS  Google Scholar 

  42. Mori K, Duh E, Gehlbach P, Ando A, Takahashi K, Pearlman J, et al. Pigment epithelium-derived factor inhibits retinal and choroidal neovascularization. J Cell Physiol. 2001;188:253–63.

    Article  PubMed  CAS  Google Scholar 

  43. Mori K, Gehlbach P, Ando A, McVey D, Wei L, Campochiaro PA. Regression of ocular neovascularization in response to increased expression of pigment epithelium-derived factor. Invest Ophthalmol Vis Sci. 2002;43:2428–34.

    PubMed  Google Scholar 

  44. Maruko I, Iida T, Saito M, Nagayama D, Saito K. Clinical characteristics of exudative age-related macular degeneration in Japanese patients. Am J Ophthalmol. 2007;144:15–22.

    Article  PubMed  Google Scholar 

  45. Chan WM, Lai TY, Tano Y, Liu DTL, Li KKW, Lam DS. Photodynamic therapy in macular diseases of Asian populations: when East meets West. Jpn J Ophthalmol. 2006;50:161–9.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This research was supported in part by a grant from an Institutional Grant from the Medical Research Center, Saitama Medical University (KM) and a grant-in-aid for scientific research (21592242) from the Ministry of Education, Culture and Science in Japan (KM).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Keisuke Mori.

Additional information

Commercial relationship policy

None

Rights and permissions

Reprints and permissions

About this article

Cite this article

Imai, D., Mori, K., Horie-Inoue, K. et al. CFH, VEGF, and PEDF genotypes and the response to intravitreous injection of bevacizumab for the treatment of age-related macular degeneration. j ocul biol dis inform 3, 53–59 (2010). https://doi.org/10.1007/s12177-010-9055-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12177-010-9055-1

Keywords

Navigation