Background and Objectives: Vascular endothelial growth factor (VEGF) has been shown to play an important role in the development and progress of diabetic retinopathy (DR). A number of case-control studies focused on the association between VEGF -2578C/A and risk for DR. But the results were not always consistent, so we performed a meta-analysis to evaluate the precise association between this variant and risk for DR. Methods: All publications on the association between VEGF -2578C/A polymorphism and DR were searched in the following electronic databases: PubMed, Embase, the Cochrane Library and Chinese Biomedical Literature Database, with the last report up to January 2013. This meta-analysis was assessed by Review Manager 5.1. Results: A total of 6 studies were involved in this meta-analysis, including 835 cases and 867 controls. Overall, we found a significant association between this polymorphism and DR (A vs. C: OR = 1.49, 95% CI = 1.26-1.77, p < 0.00001; AA vs. CA + CC: OR = 1.26, 95% CI = 0.94-1.68, p = 0.12; AA + CA vs. CC: OR = 1.56, 95% CI = 1.27-1.91, p < 0.00001; AA vs. CC: OR = 1.67, 95% CI = 1.20-2.32, p = 0.003; CA vs. CC: OR = 1.51, 95% CI = 1.21-1.87, p = 0.0002), but we did not find any significant association in Caucasians in subgroup analysis. The results were not materially altered after the studies which did not fulfill the Hardy-Weinberg equilibrium were excluded. Conclusion: Our meta-analysis supports the association between the VEGF -2578C/A polymorphism and DR, but not in the Caucasian population.

Keywords:
Diabetic retinopathy, Vascular endothelial growth factor, Polymorphism
1.
Congdom N, Friedman DS, Lietman T: Important causes of visual impairment in the world today. JAMA 2003;290:2057-2060.
2.
Crawford TN, Alfaro DV 3rd, Kerrison JB, Jablon EP: Diabetic retinopathy and angiogenesis. Curr Diabetes Rev 2009;1:8-13.
3.
Penn JS, Madan A, Caldwell RB, Bartoli M, Caldwell RW, et al: Vascular endothelial growth factor in eye disease. Prog Retin Eye Res 2008;27:331-371.
4.
Wirostko B, Wong TY, Simo R: Vascular endothelial growth factor and diabetic complications. Prog Retin Eye Res 2008;27:608-621.
5.
Aiello LP, Wong JS: Role of vascular endothelial growth factor in diabetic vascular complications. Kidney Int Suppl 2000;77:S113-S119.
6.
Duh E, Aiello LP: Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox. Diabetes 1999;48:1899-1906.
7.
Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO: Vascular endothelial growth factor and angiogenesis in eye disease. Prog Retin Eye Res 2003;22:1-29.
8.
Boulton M, Foreman D, Williams G, McLeod D: VEGF localization in diabetic retinopathy. Br J Ophthalmol 1998;82:561-568.
9.
Ishida S, Shinoda K, Kawashima S, Oguchi Y, Okada Y, et al: Coexpression of VEGF receptors VEGF-R2 and neuropilin-1 in proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 2000;41:1649-1656.
10.
Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, et al: Suppression of retinal neovascularization in-vivo by inhibition of vascular endothelial growth-factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc Natl Acad Sci USA 1995;92:10457-10461.
11.
Konopatskaya O, Churchill A, Harper S, Bates DO, Gardiner T: VEGF165b, an endogenous C-terminal splice variant of VEGF, inhibits retinal neovascularization in mice. Mol Vis 2006;12:626-632.
12.
Watson CJ, Webb NJ, Bottomley MJ, Brenchley PE: Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: correlation with variation in VEGF protein production. Cytokine 2000;12:1232-1235.
13.
Chun MY, Hwang HS, Cho HY, Chun HJ, Woo JT, et al: Association of vascular endothelial growth factor polymorphisms with nonproliferative and proliferative diabetic retinopathy. J Clin Endocrinol Metab 2010;95:3547-3551.
14.
Abhary S, Burdon KP, Gupta A, Lake S, Selva D, et al: Common sequence variation in the VEGFA gene predicts risk of diabetic retinopathy. Invest Ophthalmol Vis Sci 2009;50:5552-5558.
15.
Nakamura S, Iwasaki N, Funatsu H, Kitano S, Iwamoto Y: Impact of variants in the VEGF gene on progression of proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2009;247:21-26.
16.
Kangas-Kontio T, Vavuli S, Kakko SJ, Penna J, Savolainen ER, et al: Polymorphism of the manganese superoxide dismutase gene but not of vascular endothelial growth factor gene is a risk factor for diabetic retinopathy. Br J Ophthalmol 2009;93:1401-1406.
17.
Yang X, Deng Y, Gu H, Lim A, Altankhuyag A, et al: Polymorphisms in the vascular endothelial growth factor gene and the risk of diabetic retinopathy in Chinese patients with type 2 diabetes. Mol Vis 2011;17:3088-3096.
18.
Bleda S, De Haro J, Varela C, Esparza L, Ferruelo A, et al: Vascular endothelial growth factor polymorphisms are involved in the late vascular complications in type II diabetic patients. Diab Vasc Dis Res 2012;9:68-74.
19.
Awata T, Kurihara S, Takata N, Neda T, Iizuka H, 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;333:679-685.
20.
Al-Kateb H, Mirea L, Xie X, Sun L, Liu M, et al, DCCT/EDIC Research Group: Multiple variants in vascular endothelial growth factor (VEGFA) are risk factors for time to severe retinopathy in type 1 diabetes: the DCCT/EDIC genetics study. Diabetes 2007;56:2161-2168.
21.
Nakanishi K, Watanabe C: Single nucleotide polymorphisms of vascular endothelial growth factor gene intron 2 are markers for early progression of diabetic retinopathy in Japanese with type 1 diabetes. Clin Chim Acta 2009;402:171-175.
22.
Munafo MR, Flint J: Meta-analysis of genetic association studies. Trends Genet 2004;20:439-444.
23.
Higgins JPT, Green S: Cochrane Handbook for Systematic Reviews of Interventions, version 5.0.2. Cochrane Collaboration, 2008. http://www.mrc-bsu.cam.ac.uk/cochrane/handbook/ (accessed June 25, 2012).
24.
Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group: Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535.
25.
DerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin Trial 1986;7:177-188.
26.
Thakkinstian A, McElduff P, D'Este C, Duffy D, Attia J: A method for meta-analysis of molecular association studies. Stat Med 2005;9:1291-1306.
27.
Egger M, Davey SG, Schneider M, Minder C: Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-634.
28.
Caldwell RB, Bartoli M, Behzadian MA, et al: Vascular endothelial growth factor and diabetic retinopathy: pathophysiological mechanisms and treatment perspectives. Diabetes Metab Res Rev 2003;19:442-455.
29.
The Diabetes Control and Complications Trial Research Group: Clustering of long-term complications in families with diabetes in the Diabetes Control and Complications Trial. Diabetes 1997;46:1829-1839.
30.
Hallman DM, Huber JC Jr, Gonzalez VH, Klein BE, Klein R, et al: Familial aggregation of severity of diabetic retinopathy in Mexican Americans from Starr County, Texas. Diabetes Care 2005;28:1163-1168.
31.
Arar NH, Freedman BI, Adler SG, Iyengar SK, Chew EY, et al: Heritability of the severity of diabetic retinopathy: the FIND-Eye study. Invest Ophthalmol Vis Sci 2008;49:3839-3845.
32.
Monti MC, Lonsdale JT, Montomoli C, Montross R, Schlag E, et al: Familial risk factors for microvascular complications and differential male-female risk in a large cohort of American families with type 1 diabetes. J Clin Endocrinol Metab 2007;92:4650-4655.
33.
Hietala K, Forsblom C, Summanen P, Groop PH: Heritability of proliferative diabetic retinopathy. Diabetes 2008;57:2176-2180.
34.
Awata T, Inoue K, Kurihara S, Ohkubo T, Watanabe M, 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;5:1635-1639.
35.
Frank RN: Vascular endothelial growth factor - its role in retinal vascular proliferation. N Engl J Med 1994;331:1519-1520.
36.
Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, et al: Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1480-1487.
37.
Takagi H, Watanabe D, Suzuma K, Kurimoto M, Suzuma I, et al: Novel role of erythropoietin in proliferative diabetic retinopathy. Diabetes Res Clin Pract 2007;77(suppl 1):S62-S64.
38.
Katsura Y, Okano T, Matsuno K, Osako M, Kure M, et al: Erythropoietin is highly elevated in vitreous fluid of patients with proliferative diabetic retinopathy. Diabetes Care 2005;28:2252-2254.
39.
Tolentino MJ, Brucker AJ, Fosnot J, Ying GS, Wu IH, et al: Intravitreal injection of vascular endothelial growth factor small interfering RNA inhibits growth and leakage in a non-human primate, laser-induced model of choroidal neovascularization. Retina 2004;24:132-138.
40.
Reich SJ, Fosnot J, Kuroki A, Tang W, Yang X, et al: Small interfering RNA (siRNA) targeting VEGF effectively inhibits ocular neovascularization in a mouse model. Mol Vis 2003;9:210-216.
41.
Koukourakis MI, Papazoglou D, Giatromanolaki A, Bougioukas G, Maltezos E, Siviridis E: VEGF gene sequence variation defines VEGF gene expression status and angiogenic activity in non-small cell lung cancer. Lung Cancer 2004;6:293-298.
42.
Howell WM, Ali SJ, Rose-Zerilli M, Ye S: VEGF polymorphisms and severity of atherosclerosis. J Med Genet 2005;42:485-490.
43.
Del Bo R, Scarlato M, Ghezzi S, Martinelli B, Fenoglio C, Galbaiati S, et al: Vascular endothelial growth factor gene variability is associated with increased risk for AD. Ann Neurol 2005;57:373-380.
44.
Szeto CC, Chow KM, Poon P, Szeto CY, Wong TY, Li PK: Genetic polymorphism of VEGF: impact on longitudinal change of peritoneal transport and survival of peritoneal dialysis patients. Kidney Int 2004;63:1947-1955.
45.
Shahbazi M, Fryer AA, Pravica V, Brogan IJ, Ramsay HM, Hutchinson IV, et al: Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection. J Am Soc Nephrol 2002;13:260-264.
46.
Jin Q, Hemminki K, Forsti A, et al: Vascular endothelial growth factor polymorphisms in relation to breast cancer development and prognosis. Clin Cancer Res 2005;1:3647-3653.
47.
Roberto DB, Marina S, Serena G, et al: VEGF gene variability and type 1 diabetes: evidence for a protective role. Immunogenetics 2006;58:107-112.
48.
Zhao TF, Zhao JP: Association between the -634 C/G polymorphisms of the vascular endothelial growth factor and retinopathy in type 2 diabetes: a meta-analysis. Diabetes Res Clin Pract 2010;90:45-53.
49.
Raman R, Biswas S, Gupta A, Kulothungan V, Sharma T: Association of macular pigment optical density with risk factors for wet age-related macular degeneration in the Indian population. Eye (Lond) 2012;26:950-957.
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