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

  • Daisuke Imai
  • Keisuke Mori
  • Kuniko Horie-Inoue
  • Peter L. Gehlbach
  • Takuya Awata
  • Satoshi Inoue
  • Shin Yoneya
Article

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.

Keywords

Age-related macular degeneration Bevacizumab Complement factor H Genetic biomarker High-temperature requirement A-1 Pigment epithelium-derived factor Vascular endothelial growth factor 

References

  1. 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.CrossRefGoogle Scholar
  2. 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.CrossRefGoogle Scholar
  3. 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. 4.
    Klein R, Peto T, Bird AC, Vannewkirk MR. The epidemiology of age-related macular degeneration. Am J Ophthalmol. 2004;137:486–95.PubMedCrossRefGoogle Scholar
  5. 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.PubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 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. 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.PubMedCrossRefGoogle Scholar
  9. 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.PubMedCrossRefGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.CrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 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.PubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.PubMedCrossRefGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 21.
    Folkman J. Angiogenesis in cancer, vascular, rheumatoid, and other diseases. Nat Med. 1995;1:27–31.PubMedCrossRefGoogle Scholar
  22. 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.CrossRefGoogle Scholar
  23. 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.CrossRefGoogle Scholar
  24. 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.PubMedCrossRefGoogle Scholar
  25. 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.PubMedCrossRefGoogle Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 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.PubMedGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedCrossRefGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 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.PubMedCrossRefGoogle Scholar
  33. 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.PubMedCrossRefGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. 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.Google Scholar
  37. 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.CrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 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.PubMedCrossRefGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar
  43. 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.PubMedGoogle Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press 2010

Authors and Affiliations

  • Daisuke Imai
    • 1
  • Keisuke Mori
    • 1
  • Kuniko Horie-Inoue
    • 1
    • 2
  • Peter L. Gehlbach
    • 5
  • Takuya Awata
    • 3
    • 4
  • Satoshi Inoue
    • 2
  • Shin Yoneya
    • 1
  1. 1.Department of Ophthalmology, Faculty of MedicineSaitama Medical UniversityIrumaJapan
  2. 2.Division of Gene Regulation and Signal Transduction, Research Center for Genomic MedicineSaitama Medical UniversityIrumaJapan
  3. 3.Division of Endocrinology and Diabetes, Department of MedicineSaitama Medical UniversityIrumaJapan
  4. 4.Division of RI Laboratory, Biomedical Research CenterSaitama Medical UniversityIrumaJapan
  5. 5.Department of OphthalmologyJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations