The aim of this work was to study for the first time in Romania Insertion/Deletion (I/D) polymorphism of the Vascular Endothelial Growth Factor (VEGF) gene in a group of patients with established type 2 diabetes mellitus (DM) and diabetic peripheral neuropathy (DPN) compared with a control group.
This was a case-control study consisting of a group of 84 patients with type 2 DM and DPN, diagnosed by clinical neurological examination and electrophysiological nerve conduction studies and a control group of 90 healthy volunteers. For deoxyribonucleic acid (DNA) isolation, a DNA purification kit from Zymo Research was used. In vitro amplification of DNA sequences was achieved by polymerase chain reaction (PCR). Selective in vitro amplification of a DNA fragment of known sequence is based on the principle of extension of a primer (“primer and PCR amplicon”). DNA fragments were separated by gel electrophoresis. For proper viewing and interpreting of agarose gels Vilber Lourmat system was used. D allele frequency of VEGF was significantly higher in patients with diabetic peripheral neuropathy (53.57%) compared with controls (25%), p=0.0001.
There is a positive association between I/D polymorphism of VEGF gene and the presence of diabetic peripheral polyneuropathy. Our study suggests that D allele of VEGF gene is a risk factor for the occurrence of DPN.
1. Potra RA, Kacso MI, Bondor CI, Gherman-Căprioară M. The predictive value of serum intercellular adhesion molecule 1 for the progression of diabetic kidney disease in type 2 diabetic patients. Rev Romana Med Lab. 2013;21(4):399-406. DOI: 10.2478/rrlm-2013-0045
2. Michael J. Fowler Microvascular and Macrovascular Complications of Diabetes. Clinical Diabetes. 2008;26(2):77-82. DOI: 10.2337/diaclin.26.2.77
3. Pradeepa R, Anjana RM, Unnikrishnan R, Ganesan A, Mohan V, Rema M. Risk factors for microvascular complications of diabetes among South Indian subjects with type 2 diabetes-the Chennai Urban Rural Epidemiology Study (CURES) Eye Study-5. Diabetes Technol Ther. 2010;12(10):755-61. DOI: 10.1089/dia.2010.0069
4. Abbott CA, Chaturvedi N, Malik RA, Salgami E, Yates AP, Pemberton PW, et al. Explanations for the lower rates of diabetic neuropathy in Indian Asians Versus Europeans. Diabetes Care. 2010;33(6):1325-30. DOI: 10.2337/dc09-2067
5. Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992;359:843-5. DOI: 10.1038/359843a0
6. Zhang X, Bao S, Hambly BD, Gillies MC. Vascular endothelial growth factor-A: a multifunctional molecular player in diabetic retinopathy. Int J Biochem Cell Biol. 2009;41(12):2368-71. DOI: 10.1016/j.biocel.2009.07.011
7. Rosenstein JM, Krum JM, Ruhrberg C. VEGF in the nervous system. Organogenesis. 2010;6(2):107-14.DOI: 10.4161/org.6.2.11687
8. Ropper AH, Gorson KC, Gooch CL, Weinberg DH, Pieczek A, Ware JH, et al. Vascular endothelial growth factor gene transfer for diabetic polyneuropathy: a randomized, double-blinded trial. Ann Neurol. 2009;65(4):386-93. DOI: 10.1002/ana.21675
9. Isner JM. Tissue responses to ischemia: local and remote responses for preserving perfusion of ischemic muscle. J Clin Invest. 2000;106:615-9. DOI: 10.1172/ JCI10961
10. Giacca M, Zacchigna S. VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond. Gene Ther. 2012;19(6):622-9. DOI: 10.1038/gt.2012.17
11. Duh E, Aiello LP. Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox.Diabetes. 1999; 48:1899-906. DOI: 10.2337/diabetes.48.10.1899
12. Aiello LP, Wong JS. Role of vascular endothelial growth factor in diabetic vascular complications. Kidney Int Suppl. 2000;77:S113-9. DOI: 10.1046/j.1523-1755.2000.07718.x
13. Leinninger GM, Vincent AM, Feldman EL. The role of growth factors in diabetic peripheral neuropathy. J Peripher Nerv Syst. 2004;9:26-53. DOI: 10.1111/j.1085-9489.2004.09105.x
14. Tavakkoly-Bazzaz J, Amoli MM, Pravica V, Chandrasecaran R, Boulton AJ, Larijani B, et al. VEGF gene polymorphism association with diabetic neuropathy.Mol Biol Rep. 2010;37:3625-30. DOI: 10.1007/ s11033-010-0013-6
15. Quattrini C, Jeziorska M, Boulton AJ, Malik RA. Reduced vascular endothelial growth factor expression and intra-epidermal nerve fiber loss in human diabetic neuropathy. Diabetes Care. 2008;31(1):140-5. DOI: 10.2337/dc07-1556
16. Buraczynska M, Ksiazek P, Baranowicz-Gaszczyk I, Jozwiak L. Association of the VEGF gene polymorphism with diabetic retinopathy in type 2 diabetic patients.Nephrol Dial Transplant. 2007;22(3):827-32.DOI: 10.1093/ndt/gfl641
17. Stevens A, Soden J, Brenchley PE, Ralph S, Ray DW.Haplotype analysis of the polymorphic human vascular endothelial growth factor gene promoter. Cancer Res. 2003;63(4):812-6.
18. He Y, Ni J, Chen S, Jiang Y, Jia S, Gao Y. The vascular endothelial growth factor-2549 insertion/deletion polymorphism is not associated with susceptibility to hepatocellular carcinoma in Chinese. DNA Cell Biol. 2010;29(7):393-6. DOI: 10.1089/dna.2009.1015
19. Ropper AH1, Gorson KC, Gooch CL, Weinberg DH, Pieczek A, Ware JH, et al. Vascular endothelial growth factor gene transfer for diabetic polyneuropathy: a randomized, double-blinded trial. Ann Neurol. 2009;65(4):386-93. DOI: 10.1002/ana.21675
20. Deguchi T, Hashiguchi T, Horinouchi S, Uto T, Oku H, Kimura K, et al. Serum VEGF increases in diabetic polyneuropathy, particularly in the neurologically active symptomatic stage. Diabetic Medicine. 2009;26(3):247-52. DOI: 10.1111/j.1464-5491.2009.02680.x
21. Yang B, Cross DF, Ollerenshaw M, Millward BA, Demaine AG. Polymorphisms of the vascular endothelial growth factor and susceptibility to diabetic microvascular complications in patients with type 1 diabetes mellitus.J Diabetes Complications. 2003;17(1):1-6. DOI: 10.1016/S1056-8727(02)00181-2
22. Kacso MI, Trifa PA, Popp AR, Bondor IC, Farcas FM, Lenghel RA, et al. Adiponectin gene 45T>G polymorphism is not associated to plasma adiponectin in a cohort of patients with type 2 diabetes from Romania. Rev Romana Med Lab. 2012;20(1):73-9.
23. Moldovan R, Kacsò I, Gherman-Căprioară M. Relationship between soluble intercellular adhesion molecule 1 and clinically manifest cardiovascular disease in diabetic chronic hemodialysis patients. Rev Romana Med Lab. 2012;20(4):353-61.