Impact of variants in the VEGF gene on progression of proliferative diabetic retinopathy

  • Shinko Nakamura
  • Naoko Iwasaki
  • Hideharu Funatsu
  • Shigehiko Kitano
  • Yasuhiko Iwamoto
Retinal Disorders



The development of diabetic retinopathy is associated with the duration of diabetes and HbA1c levels. However, the familial aggregation of diabetic retinopathy is consistent with genetic susceptibility. Recently, a –634C/G polymorphism in the vascular endothelial growth factor (VEGF) gene was shown to be associated with diabetic retinopathy. To clarify the contribution of the VEGF gene in the development of diabetic retinopathy we analyzed variants in this gene among 469 Japanese patients with type 2 diabetes.


DNA from each patient was typed for –634C/G and –2578C/A polymorphisms using conventional polymerase chain reaction techniques. The vitreous fluid samples were obtained from 40 patients with PDR for measurement of VEGF levels.


We found a significantly higher frequency of the A allele in the group with proliferative diabetic retinopathy (PDR) than in the control group at –2578C/A polymorphism (p = 0.036). Moreover, if the subjects were grouped according to the duration of diabetes and status of diabetic retinopathy (a first group consisting of subjects with longer duration (>20 y) of diabetes without any retinopathy (n = 102), and a second group of those with shorter diabetes (<15 y) but having retinopathy (n = 35), the genotype distribution at -2578 C/A polymorphism was again significantly higher in the second group (p = 0.005) and differed significantly (p = 0.002) in a recessive model. The risk of the AA for PDR was 7.7 (95%, CI: 1.8–30.9).


The AA genotype at –2578C/A polymorphism in the VEGF gene is associated with proliferative diabetic retinopathy. No significant association with –634 C/G polymorphism was confirmed.


VEFG Polymorphism Diabetic retinopathy 



This work was supported by a Grant-in-Aid for Scientific research on Priority Areas (C) Medical Genome Science from the Ministry of Education, Science, Culture and Sports of Japan to N.I.

We are indebted to the all participants of the study. We gratefully appreciate Dr. Takahiro Nakamura at The Institute of Physical and Chemical Research SNP Research Center of RIKEN for his statistical support. We also acknowledge technical assistance by Ms. Yumiko Sagisaka, Megumi Watanabe and Hisae Tomioka.


  1. 1.
    The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986. doi: 10.1056/NEJM199309303291401 CrossRefGoogle Scholar
  2. 2.
    UK Prospective Diabetes Study Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853. doi: 10.1016/S0140–6736(98)07019–6 CrossRefGoogle Scholar
  3. 3.
    Cai J, Boulton M (2002) The pathogenesis of diabetic retinopathy: old concepts and new questions. Eye 16:242–260. doi: 10.1038/sj.eye.6700133 PubMedCrossRefGoogle Scholar
  4. 4.
    Chakrabarti S, Cukiernik M, Hileeto D, Evans T, Chen S (2000) Role of vasoactive factors in the pathogenesis of early changes in diabetic retinopathy. Diabetes Metab Res Rev 16:393–407. doi: 10.1002/1520–7560(0000)9999:9999<::AID-DMRR157>3.0.CO;2-G PubMedCrossRefGoogle Scholar
  5. 5.
    Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25:581–611. doi: 10.1210/er.2003–0027 PubMedCrossRefGoogle Scholar
  6. 6.
    Lutty GA, McLeod DS, Merges C, Diggs A, Plouet J (1996) Localization of vascular endothelial growth factor in human retina and choroids. Arch Ophthalmol 114:971–979PubMedGoogle Scholar
  7. 7.
    Funatsu H, Yamashita H, Nakanishi Y, Hori S (2002) Angiotensin IIand vascular endothelial growth factor in the vitreous fluid of patients with proliferative diabetic retinopathy. Br J Ophthalmol 86:311–315. doi: 10.1136/bjo.86.3.311 PubMedCrossRefGoogle Scholar
  8. 8.
    Yang B, Cross DF, Ollerenshow M, Millward BA, Demaine AG (2003) Polymorphisms of the vascular endothelial growth factor and susceptibility to diabetic microvascular complications in patients with type 1 diabetes mellitus. J Diabet Complications 17:1–6. doi: 10.1016/S1056–8727(02)00181–2 CrossRefGoogle Scholar
  9. 9.
    Awata T, Inoue I, Kurihara S, Ohkubo T, Watanabe M, Inukai K et al (2002) A common polymorphism in the 5’-untranslated region of the VEGF gene Is associated with diabetic retinopathy in type 2 diabetes. Diabetes 51:1635–1639. doi: 10.2337/diabetes.51.5.1635 PubMedCrossRefGoogle Scholar
  10. 10.
    Szaflik JP, Kowalski TW, Majsterek I, Borucka AI, Blasiak J, Szaflik J (2007) An association between vascular endothelial growth factor gene promoter polymorphisms and diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 246(1)39–43Google Scholar
  11. 11.
    Roberto DB, Marina S, Serena G et al (2006) VEGF gene variability and type 1 diabetes: evidence for a protective role. Immunogenetics 58:107–112. doi: 10.1007/s00251–006–0089–2 CrossRefGoogle Scholar
  12. 12.
    World Health Organ Tech Rep Ser (1985) Diabetes mellitus. Rep WHO Study Group 727:1–113.Google Scholar
  13. 13.
    Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Chah ST et al (1994) Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1(331):1480–1487. doi: 10.1056/NEJM199412013312203 CrossRefGoogle Scholar
  14. 14.
    Hyodo I, Doi T, Endo H et al (1998) Clinical significance of plasma vascular endothelial growth factor in gastrointestinal cancer. Eur J Cancer 34:2041–2045. doi: 10.1016/S0959–8049(98)00282–2 PubMedCrossRefGoogle Scholar
  15. 15.
    Kitamura Y, Moriguchi M, Kaneko H, Morisaki T, Toyama K, Kamatani N (2002) Determination of probability distribution of diplotype configuration (diplotype distribution) for each subject from genotypic data using EM algorithm. Ann Hum Genet 66:183–193. doi: 10.1046/j.1469–1809.2002.00112.x PubMedCrossRefGoogle Scholar
  16. 16.
    Koukourakis MI, Papazoglou D, Giatromanolaki A, Bougioukas G, Maltezos E, Siviridis E (2004) VEGF gene sequence variation defines VEGF gene expression status and angiogenic activity in non-small cell lung cancer. Lung Cancer 6:293–298. doi: 10.1016/j.lungcan.2004.04.037 CrossRefGoogle Scholar
  17. 17.
    Howell WM, Ali SJ, Rose-Zerilli M, Ye S (2005) VEGF polymorphisms and severity of atherosclerosis. J Med Genet 42:485–490. doi: 10.1136/jmg.2004.025734 PubMedCrossRefGoogle Scholar
  18. 18.
    Del Bo R, Scarlato M, Ghezzi S, Martinelli B, Fenoglio C, Galbaiati S et al (2005) Vascular endothelial growth factor gene variability is associated with increased risk for AD. Ann Neurol 57:373–380. doi: 10.1002/ana.20390 PubMedCrossRefGoogle Scholar
  19. 19.
    Szeto CC, Chow KM, Poon P, Szeto CY, Wong TY, Li PK (2004) Genetic polymorphism of VEGF: Impact on longitudinal change of peritoneal transport and survival of peritoneal dialysis patients. Kidney Int 63:1947–1955. doi: 10.1111/j.1523–1755.2004.00605.x CrossRefGoogle Scholar
  20. 20.
    Shahbazi M, Fryer AA, Pravica V, Brogan IJ, Ramsay HM, Hutchinson IV et al (2002) Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection. J Am Soc Nephrol 13:260–264PubMedGoogle Scholar
  21. 21.
    Jin Q, Hemminki K, Forsti A et al (2005) Vascular endothelial growth factor polymorphisms in relation to breast cancer development and prognosis. Clin Cancer Res 1:3647–3653. doi: 10.1158/1078–0432.CCR-04–1803 CrossRefGoogle Scholar
  22. 22.
    Banyasz I, Bokodi G, Vannay A, Szebeni B, Treszl A, Vasarhelyi B, Tulassay T, Szabo A (2006) Genetic polymorphisms of vascular endothelial growth factor and angiopoietin 2 in retinopathy of prematurity. Curr Eye Res 31:685–690. doi: 10.1080/02713680600801123 PubMedCrossRefGoogle Scholar
  23. 23.
    Awata T, Kurihara S, Takata N, Neda T, Iizuka H, Ohkubo T et al (2005) Functional VEGF C-634G polymorphism is associated with development of diabetic macular edema and correlated with macula retinal thickness in type 2 diabetes. Biochem Biophys Res Commun 333:679–685. doi: 10.1016/j.bbrc.2005.05.167 PubMedCrossRefGoogle Scholar
  24. 24.
    Suganthalakshmi B, Anand R, Kim R, Mahalakshmi R, Karthikprakash S, Namperumalsamy P et al (2006) Association of VEGF and eNOS gene polymorphism in type 2 diabetic retinopathy. Mol Vis 12:336–341PubMedGoogle Scholar
  25. 25.
    Steto C-C, Chow K-M, Poon P, Steto CY-K, Wong TY-H, Li PK-T (2004) Genetic polymorphism of VEGF: impact on longitudinal change of peritoneal transport and survival of peritoneal dialysis patients. Kidney Int 65:1947–1955. doi: 10.1111/j.1523–1755.2004.00605.x CrossRefGoogle Scholar
  26. 26.
    Burgos R, Simo R, Audi L, Mateo C, Mesa J, Garcia-Ramirez M et al (1997) Vitreous levels of vascular endothelial growth factor are not influenced by its serum concentrations in diabetic retinopathy. Diabetologia 40:1107–1109. doi: 10.1007/s001250050794 PubMedCrossRefGoogle Scholar
  27. 27.
    Aiello LP, Iwamoto MA et al (1995) Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol 113:1538–1544PubMedGoogle Scholar
  28. 28.
    Reich SJ, Fosnot J, Kuroki A, Tang W, Yang X, Maguire AM et al (2003) Small interfering RNA (siRNA) targeting VEGF effectively inhibits ocular neovascularization in a mouse model. Mol Vis 9:210–216PubMedGoogle Scholar
  29. 29.
    Tolentino M, Brucker AJ, Fosnot J, Ying GS, Wu IH, Malik G et al (2004) Intravitreal injection of vascular endothelial growth factor small interfering RNA inhibits growth and leakage in a nonhuman primate, laser-induced model of choroidal neovascularization. Retina 24:132–138. doi: 10.1097/00006982–200402000–00018 PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Shinko Nakamura
    • 1
  • Naoko Iwasaki
    • 2
    • 3
    • 4
  • Hideharu Funatsu
    • 5
  • Shigehiko Kitano
    • 1
  • Yasuhiko Iwamoto
    • 2
  1. 1.Department of Ophthalmology, Diabetes CenterTokyo Women’s Medical UniversityShinjuku-kuJapan
  2. 2.Department of Medicine, Diabetes CenterTokyo Women’s Medical UniversityTokyoJapan
  3. 3.Institute of Advanced Biomedical Engineering and ScienceTokyo Women’s Medical UniversityTokyoJapan
  4. 4.Institute of Medical GeneticsTokyo Women’s Medical UniversityTokyoJapan
  5. 5.Department of OphthalmologyTokyo Women’s Medical University Yachiyo Medical CenterChibaJapan

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