Abstract
Background
Recent experimental studies suggest that vascular endothelial growth factor (VEGF) can play an important role in the development of retinopathy of prematurity (ROP). There are interesting observations of VEGF concentration in the serum, depending on its gene polymorphism which can have an impact on abnormal vessel development in the retina.
Aim
Analysis of: (1) association of VEGF gene polymorphisms and the incidence of ROP, (2) correlation between serum concentration of VEGF and soluble VEGF receptor 1 (sVEGFR-1) during the 1st month of life and the risk of ROP, and (3) correlation between VEGF gene polymorphisms and VEGF serum concentrations.
Methods
A sample of 181 newborns with mean birthweight 1054 g (range: 500–1500 g) was prospectively evaluated. Molecular analysis of VEGF −460T>C and 405G>C polymorphisms were performed in the whole studied population, and concentrations of VEGF and sVEGFR-1 were measured by Elisa assay in the 2nd, 3rd and 4th weeks of life in the group of 128 children. The infants were divided into 3 groups: A) no ROP (n = 101), B) ROP not requiring treatment (n = 20), and C) ROP requiring laser or cryotherapy (n = 60).
Results
The frequency of VEGF 405G>C polymorphism was similar in all studied groups. The carriage of polymorphic allele −460 T was significantly overrepresented in ROP newborns who required treatment as compared to the no ROP group (54.2% vs 42.6%; OR: 1.63; 95% CI: 1.03–2.55). VEGF serum concentrations in the patients ascribed to different groups depending on the 405G>C or −460 T>C polymorphisms were similar. VEGF and sVEGFR−1 concentration on the 10th day of life did not differ significantly between the studied groups. Consecutive measurements showed a gradual increase in VEGF serum concentration in children without ROP, whereas in children with ROP requiring treatment the levels remained low.
Conclusions
Based on our observations and previously published data, the association of the VEGF gene promoter polymorphisms and the risk of advanced ROP is weak. VEGF serum concentration assessment as early as on the 20th day of life appears to be a promising approach to recognize newborns at risk of the development of advanced ROP.
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References
Haines JL, Fielder A, Baker H, Wilkinson AR (2005) UK population based study of severe retinopathy of prematurity: screening, treatment, and outcome. Arch Dis Child Fetal Neonatal Ed 90:240–244
Kaiser RS, Trese MT, Williams GA, Cox MS (2001) Adult retinopathy of prematurity: outcomes of rhegmatogenous retinal detachments and retinal tears. Ophthalmology 108:1647–1653
Gilbert C, Fielder A, Gordillo L, Quinn G, Semiglia R, Visintin P, Zin A (2005) Characteristics of infants with severe retinopathy of prematurity in countries with low, moderate, and high levels of development: implications for screening programs. Pediatrics 115:e518–e525
Tompkins C (2001) A sudden rise in the prevalence of retinopathy of prematurity blindness? Pediatrics 108:526–526
Palmer EA (2003) Implications of the Natural Course of Retinopathy of Prematurity. Pediatrics 111:885–886
Holmstrom GE, Broberger U, Thomassen P (1998) Neonatal risk factors for retinopathy of prematurity-a population- based study. Acta Ophthalmol Scand 76:204–207
Karna P, Muttineni J, Angell L, Karmaus W (2005) Retinopathy of prematurity and risk factors: a prospective cohort study. BMC Pediatr 5:18
Wheatley CM, Dickinson JL, Mackey DA, Craig JE, Sale MM (2002) Retinopathy of prematurity: recent advances of our understanding. Arch Dis Child Fetal Neonatal Ed 87:F78–F82
Schaffer DB, Palmer EA, Plotsky DF, Metz HS, Flynn JT, Tung B, Hardy RJ (1993) Prognostic factors in the natural course of retinopathy of prematurity. The Cryotherapy for Retinopathy of Prematurity Cooperative Group. Ophthalmology 100:230–237
Hutchinson AK, O’Neil JW, Morgan EN, Cervenak MA, Saunders RA (2003) Retinopathy of prematurity in infants with birth weights greater than 1250 grams. J AAPOS 7:190–194
Bizzarro MJ, Hussain N, Jonsson B, Feng R, Ment LR, Gruen JR, Zhang H, Bhandari V (2006) Genetic Susceptibility to Retinopathy of Prematurity. Pediatrics 118:1858–1863
Saunders RA, Donahue ML, Christmann LM, Pakalnis AV, Tung B, Hardy RJ, Phelps DL (1997) Racial variation in retinopathy of prematurity. The Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol 115:604–608
Arnold RW, Kesler K, Avila E (1994) Susceptibility to retinopathy of prematurity in Alaskan Natives. J Pediatr Ophthalmol Strabismus 31:192–194
Smith LE (2005) IGF-1 and retinopathy of prematurity in the preterm infant. Biol Neonate 88:237–244
Sennlaub F, Chemtob S (2004) VEGFR-1: a safe target for prophylaxis of retinopathy of prematurity? Pediatr Res 55:1–2
Shastry BS, Qu X (2007) Lack of association of the VEGF gene promoter (−634 G−>C and −460 C−>T) polymorphism and the risk of advanced retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol 245:741–743
Wei MH, Popescu NC, Lerman MI, Merrill MJ, Zimonjic DB (1996) Localization of the human vascular endothelial growth factor gene, VEGF, at chromosome 6p12. Hum Genet 97:794–797
Renner W, Kotschan S, Hoffmann C, Obermayer-Pietsch B, Pilger E (2000) A common 936 C/T mutation in the gene for vascular endothelial growth factor is associated with vascular endothelial growth factor plasma levels. J Vasc Res 37:443–448
Early Treatment for Retinopathy of Prematurity Cooperative Group (2003) Revised indications for the treatment of retinopathy of prematurity - Results of the early treatment for retinopathy of prematurity randomized trial. Arch. Ophthalmol 121:1684–1696
Awata T, Inoue K, Kurihara S, Ohkubo T, Watanabe M, Inukai K, Inoue I, Katayama S (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
Awata T, Kurihara S, Takata N, Neda T, Iizuka H, Ohkubo T, Osaki M, Watanabe M, Nakashima Y, Inukai K, Inoue I, Kawasaki I, Mori K, Yoneya S, Katayama S (2005) 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 333:679–685
Suganthalakshmi B, Anand R, Kim R, Mahalakshmi R, Karthikprakash S, Namperumalsamy P, Sundaresan P (2006) Association of VEGF and eNOS gene polymorphisms in type 2 diabetic retinopathy. Mol Vis 12:336–341
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
Cooke RW, Drury JA, Mountford R, Clark D (2004) Genetic polymorphisms and retinopathy of prematurity. Invest Ophthalmol Vis Sci 45:1712–1715
Vannay A, Dunai G, Banyasz I, Szabo M, Vamos R, Treszl A, Hajdu J, Tulassay T, Vasarhelyi B (2005) Association of genetic polymorphisms of vascular endothelial growth factor and risk for proliferative retinopathy of prematurity. Pediatr Res 57:396–398
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
Kim SH, Choi YM, Choung SH, Jun JK, Kim JG, Moon SY (2005) Vascular endothelial growth factor gene +405 C/G polymorphism is associated with susceptibility to advanced stage endometriosis. Hum Reprod 20:2904–2908
Pierce EA, Folez ED, Smith LE (1996) Regulation of Vascular Endothelial Growth Factor by Oxygen in a Model of Retinopathy of Prematurity. Arch Ophthalmol 114:1219–1228
Leske DA, Wu J, Mookadam M, Chen Y, Fautsch MP, Holmes JM, Lanier WL (2006) The relationship of retinal VEGF and retinal IGF-1 mRNA with neovascularization in an acidosis-induced model of retinopathy of prematurity. Curr Eye Res 31:163–169
Leske DA, Wu J, Fautsch MP, Karger RA, Berdahl JP, Lanier WL, Holmes JM (2004) The role of VEGF and IGF-1 in a hypercarbic oxygen-induced retinopathy rat model of ROP. Mol Vis 10:43–50
Werdich XQ, McCollum GW, Rajaratnam VS, Penn JS (2004) Variable oxygen and retinal VEGF levels: correlation with incidence and severity of pathology in a rat model of oxygen-induced retinopathy. Exp Eye Res 79:623–630
Lip PL, Belgore F, Blann AD, Hope-Ross MW, Gibson JM, Lip GY (2000) Plasma VEGF and soluble VEGF receptor FLT-1 in proliferative retinopathy: relationship to endothelial dysfunction and laser treatment. Invest Ophthalmol Vis Sci 41:2115–2119
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Kwinta, P., Bik-Multanowski, M., Mitkowska, Z. et al. The clinical role of vascular endothelial growth factor (VEGF) system in the pathogenesis of retinopathy of prematurity. Graefes Arch Clin Exp Ophthalmol 246, 1467–1475 (2008). https://doi.org/10.1007/s00417-008-0865-9
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DOI: https://doi.org/10.1007/s00417-008-0865-9