eNOS gene polymorphism association with retinopathy in type 1 diabetes.

PURPOSE: Nitric oxide (NO) is a major mediator in vascular biology, regulating blood pressure and regional blood flow. NO and the enzymes required for its production may contribute to the aetiology of vascular pathologies. In diabetes, over-production of NO might play a role in the development of diabetic nephropathy, while reduced NO production may be related to the development of diabetic retinopathy and neuropathy, where VEGF (vascular endothelial growth factor) levels are increased in a counter regulatory manner. Among the three nitric oxide synthase (NOS) enzymes most attention has focussed on endothelial NOS (eNOS) because of its relevance to angiopathies. METHODS: In this study the influence of a single nucleotide polymorphism at position -786 in the eNOS gene, where there is a C/T base substitution, on development of type 1 diabetes mellitus (T1DM) and its microvascular complications was studied in 249 British Caucasian type 1 diabetics using a case-control association design. Genotyping was carried out using PCR-RFLP technique. RESULTS: There was a significant association between the polymorphism -786*C/T and both T1DM and diabetic retinopathy. The distribution of eNOS gene polymorphism genotype frequencies showed a significant difference observed between diabetic patients and healthy controls [CC+CT vs. TT p = 0.05, OR = 1.5 95%CI(0.9-2.5)]. The genotype frequencies for eNOS gene polymorphism was also significantly different between diabetic retinopaths and healthy controls [CC+CT vs. TT p = 0.0000 OR = 3.4 95%CI(1.9-6.1) No significant differences for eNOS allele and genotype frequencies were found in other groups compared to the controls. CONCLUSION: Therefore, eNOS gene variation may be a factor in the genetic propensity to T1DM and diabetic retinopathy that may have a prognostic value or may suggest interventional approaches to regulate eNOS in patients with diabetes.

VEGF gene polymorphism association with diabetic neuropathy.

Vascular factors beside metabolic problems are involved in both etiopathogenesis of diabetic neuropathy, and more remarkably, later in "repair" phase, that governs the net balance between neuro-regenerative/degenerative reactions. Regarding ischemic nature of diabetic neuropathy that highlights necessity of blood vessels re-establishment during tissue healing, VEGF (vascular endothelial growth factor) has been recently the subject of extensive investigations in diabetic neuropathy (DNU). This growth factor possesses angiogenic potentials in addition to the hemodynamic functions. The distribution of VEGF gene polymorphisms at positions -7*C/T, -1001*G/C, -1154*G/A and -2578*C/A were analysed by ARMS-PCR in 248 type 1 diabetic British-Caucasian subjects (81 DNU+, 167 DNU-). We have found that distribution of a VEGF gene polymorphism at promoter region (-7*C/T) was significantly different between diabetic subjects with vs. without neuropathy and the allele (C) conferred susceptibility to DNU (P = 0.02; OR = 1.78, 95% CI 1.0-3.1). The present study indicates that polymorphism of the VEGF gene at position -7*C/T might be implicated in the pathogenesis of diabetic neuropathy as it may harbour some functional/regulatory potential in VEGF gene expression. However, this requires further studies in order to better understand its phenotypic impact and to investigate the prognostic value of this polymorphism in diabetic neuropathy as a chronic complication of diabetes.