Functional Vascular Endothelial Growth Factor −634G>C SNP Is Associated With Proliferative Diabetic Retinopathy

Abstract

OBJECTIVE -The purpose of this study was to evaluate the effect of the single nucleotide polymorphism (SNP) Ϫ634GϾC at the 5Ј regulatory region of the vascular endothelial growth factor (VEGF) in the risk of proliferative diabetic retinopathy (PDR) in the Brazilian population of European ancestry with type 2 diabetes. RESEARCH DESIGN AND METHODS-A case-control study was conducted in 501 type 2 diabetic patients of European ancestry. Patients underwent a standardized clinical, ophthalmological, and laboratory evaluation. Of these, 167 patients had PDR (case patients), and 334 were considered as control subjects (patients without PDR) for PDR. A reference population (110 individuals of European ancestry) was also evaluated.RESULTS -No evidence of association between Ϫ634GϾC/VEGF and the presence of diabetic retinopathy or type 2 diabetes was observed (P Ͼ 0.05). However, CC homozygous for the SNP Ϫ634GϾC was significantly more frequent in patients with PDR (37 of 167; 22.2%) than in the corresponding control group (40 of 334; 12%) in accordance with a recessive model (P ϭ 0.003). This effect was further observed when creatinine, BMI, sex, duration of type 2 diabetes, HDL cholesterol, and systolic blood pressure were taken into account (odds ratio 1.9 [95% CI 1.01-3.79], P ϭ 0.04).CONCLUSIONS -The presence of the allele Ϫ634C/VEGF in homozygosity is an independent risk factor for the development of PDR in type 2 diabetic patients of European ancestry. Diabetes Care 30:275-279, 2007D iabetic retinopathy is a common microvascular complication in patients with diabetes, constituting a major cause of blindness in this group. Although the risk of development of this complication increases with poor glycemic control, there are several indications suggesting that the occurrence or progression of diabetic retinopathy also depends on genetic factors (1-3).Proliferative diabetic retinopathy (PDR), characterized by increased vascular permeability, tissue ischemia, and neovascularization, affects 10 -20% of diabetic patients (4). This process depends on the local production of angiogenic factors and components of the extracellular matrix, which will be substrates for endothelial migration. Vascular endothelial growth factor (VEGF), a potent activator of angiogenesis, enhances collateral vessel formation and increases the permeability of the microvasculature (5,6). VEGF expression is induced by high glucose levels and hypoxia and plays an important role in normal and abnormal angiogenesis (7-9). Its levels have been found to be markedly increased in the vitreous and aqueous fluids in the eyes of patients with PDR (10 -12).Several polymorphisms at the VEGF 5Ј regulatory region have been characterized and evaluated as risk alleles for the susceptibility or progression of both diabetic retinopathy and diabetic nephropathy through case-control studies (13-16). The single nucleotide polymorphism (SNP) Ϫ634GϾC was found to be associated with nonproliferative diabetic retinopathy (NPDR) and diabetic macular edema in type 2 diabetic pa...

Adherence to diabetic eye examination guidelines in Australia: the National Eye Health Survey

“…Other gene polymorphisms in the RAGE gene 325 , the TGF-beta1 gene 326 , the VEGF gene [327][328][329][330] , the eNOS (endothelial nitric oxide synthase) gene 330 and vitamin D receptor 331 have also been associated with the presence or severity of DR from case-control studies. A meta-analysis that examined the association between DR in T2DM and polymorphisms in the gene for hyper-homocystinaemia (methylenetetrahydrofolate reductase, MTHFR) found only a marginal association with large heterogeneity between different studies 332 .…”

Association of polymorphisms at the ADIPOR1 regulatory region with type 2 diabetes and body mass index in a Brazilian population with European or African ancestry

“…Different origins of African-derived populations in the US and in Brazil or different proportions of admixture of the AfA population in Brazil could explain this. These data indicate the importance of analyzing EA and AfA separately in case-control studies, as we have already suggested (12). Moreover, the data suggest that these SNPs could represent valuable ancestry markers, which can be used to distinguish between chromosomal segments of subjects of AfA and EA.…”

“…The reference group (control) consisted of 190 healthy DM2-free blood donor volunteers at HC-USP (96 EA and 94 AfA, age: 48.28 ± 16.39 years), who were previously described by Errera et al (11,12). The main clinical and laboratory data are reported in Table 1 and were obtained as recommended previously (11,12). A group of 439 non-diabetic quilombo remnant individuals was also included.…”

“…Among them, 443 were EA (Portuguese, Spanish, Italian, and German) descendants and 124 AfA (West Africa, Angola, Mozambique) descendents (11,12). Patients were evaluated using a questionnaire, physical examination and laboratory tests.…”

Anti-VEGF agents in the treatment of diabetic macular edema

“…1 206 ) являются продуктами одного гена, образующимися в результате альтернативного сплайсинга мРНК. В гене VEGF выявлены полиморфные позиции -634, +936, -2578; обнаружены взаимосвязи ва-риантов нуклеотидов в этих позициях с риском развития диабетической ретинопатии (ДР) в разных этнических группах [12][13][14][15]. По нашим данным [16,17], для больных СД 2 типа (СД2) свойственны комбинации гомозиготных вариантов VEGF 2578CC, 936CC, генов интерлейкинов и матриксных металлопротеиназ: IL4 590СС, IL6 174GG, IL10 592СC и 1082АА, TNFА 238GG, 308GG и 863СC, MMP-2 1306CC и ММР-9 1562СС.…”