A novel polymorphism in the aldose reductase gene promoter region is strongly associated with diabetic retinopathy in adolescents with type 1 diabetes.

Kao, Yan-Lin; Donaghue, Kim C.; Chan, Albert; Knight, John; Silink, Martin

doi:10.2337/diabetes.48.6.1338

Cited by 92 publications

(70 citation statements)

References 9 publications

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“…Taken together, VEGF appears to present an attractive candidate susceptibility gene for diabetic retinopathy. Although previous studies reported an association between diabetic retinopathy and several candidate genes, including aldose reductase (8,9), HLA-DQB1 (10), ␤ 3 -adrenoreceptor (11), paraoxonase (12), and ␣2␤1 integrin (13), most of the data appear to be inconclusive and require further confirmation. Therefore, in the present study, we examined the VEGF gene to assess its possible role in diabetic retinopathy.…”

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confidence: 56%

A Common Polymorphism in the 5′-Untranslated Region of the VEGF Gene Is Associated With Diabetic Retinopathy in Type 2 Diabetes

et al. 2002

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Vascular endothelial growth factor (VEGF), a major mediator of vascular permeability and angiogenesis, may play a pivotal role in mediating the development and progression of diabetic retinopathy. In the present study, we examined the genetic variations of the VEGF gene to assess its possible relation to diabetic retinopathy in type 2 diabetic patients. Among seven common polymorphisms in the promoter region, 5-untranslated region (UTR) and 3UTR of the VEGF gene, genotype distribution of the C(؊634)G polymorphism differed significantly (P ‫؍‬ 0.011) between patients with (n ‫؍‬ 150) and without (n ‫؍‬ 118) retinopathy, and the C allele was significantly increased in patients with retinopathy compared with those without retinopathy (P ‫؍‬ 0.0037). The odds ratio (OR) for the CC genotype of C(؊634)G to the GG genotype was 3.20 (95% CI 1.45-7.05, P ‫؍‬ 0.0046). The ؊634C allele was significantly increased in patients with nonproliferative diabetic retinopathy (non-PDR) (P ‫؍‬ 0.0026) and was insignificantly increased in patients with proliferative diabetic retinopathy (PDR) (P ‫؍‬ 0.081) compared with patients without retinopathy, although frequencies of the allele did not differ significantly between the non-PDR and PDR groups. Logistic regression analysis revealed that the C(؊634)G polymorphism was strongly associated with an increased risk of retinopathy (P ‫؍‬ 0.0018). Furthermore, VEGF serum levels were significantly higher in healthy subjects with the CC genotype of the C(؊634)G polymorphism than in those with the other genotypes. These data suggest that the C(؊634)G polymorphism in the 5UTR of the VEGF gene is a novel genetic risk factor for diabetic retinopathy.

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confidence: 56%

A Common Polymorphism in the 5′-Untranslated Region of the VEGF Gene Is Associated With Diabetic Retinopathy in Type 2 Diabetes

et al. 2002

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“…62 Increasing allele size resulted in better transcription, with peak transcription occurring in constructs containing the 14-repeat allele. Further increases in allele size (15,16, and 17 repeats) did not improve transcription. 62 When similar experiments were conducted in the presence of high concentrations of glucose mimicking a diabetic state, there was inhibition of NOS2A transcription, but this inhibition effect was Eye Molecular genetics of diabetic retinopathy KM Warpeha and U Chakravarthy minimal in constructs containing the 14-repeat allele.…”

Section: Mhc and Immunity Markersmentioning

confidence: 84%

Molecular genetics of microvascular disease in diabetic retinopathy

Warpeha

Chakravarthy

2003

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“…Previously, several candidate genes were reported to be associated with DR. In particular, the gene for aldose reductase has been extensively examined, and dinucleotide polymorphism at the 5Ј-region and C-106T polymorphism were found to be associated with DR (21,22). Recently, we found that a common polymorphism, C-634G, in the 5Ј-untranslated region of the vascular endothelial growth factor (VEGF) gene was significantly associated with the presence of DR (23).…”

Section: Enos Gene and Diabetic Macular Edemamentioning

confidence: 97%

Endothelial Nitric Oxide Synthase Gene Is Associated With Diabetic Macular Edema in Type 2 Diabetes

et al. 2004

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OBJECTIVE -We examined the endothelial nitric oxide (eNOS) gene polymorphisms to assess its possible association with diabetic retinopathy and macular edema.RESEARCH DESIGN AND METHODS -A total of 226 patients with type 2 diabetes and 186 healthy subjects were studied. Type 2 diabetic patients consisted of 110 patients without retinopathy, 46 patients with nonproliferative diabetic retinopathy, and 71 patients with proliferative diabetic retinopathy. Diabetic macular edema was present in 48 patients. Three polymorphisms of the eNOS gene were determined: T-786C in the promoter region, 27-bp repeat in intron 4, and Glu298Asp in exon 7.RESULTS -Close linkage disequilibrium was observed between the T-786C polymorphism and the 27-bp repeat, as has been previously reported, but Glu298Asp was not in linkage disequilibrium with the other two polymorphisms. The eNOS gene polymorphisms were not significantly associated with the presence of retinopathy or with retinopathy severity or type 2 diabetes itself. However, by both association study and multiple logistic regression analysis, the T-786C and 27-bp repeat polymorphisms were significantly associated with a risk of developing macular edema with the Ϫ786C allele and the "a" allele increasing the risk.CONCLUSIONS -The present study suggests that the eNOS gene is a novel genetic risk factor for diabetic macular edema. The eNOS gene polymorphisms may contribute to the development of macular edema by impairing basal eNOS expression and resulting in the breakdown of the blood-retina barrier. Diabetes Care 27:2184 -2190, 2004D iabetic retinopathy (DR) remains the major cause of blindness among adults (1). In addition, diabetic maculopathy or macular edema (ME), which may occur at any stage of DR, is an important cause of visual impairment (1-3). Among the pathophysiological steps involved in the development of ME, the most important mechanism is breakdown of the blood-retina barrier (BRB) (2,3). Both the inner BRB formed by the retinal capillary endothelial cell tight junctions and the outer BRB formed by the retinal pigment epithelial cell tight junctions can be affected during the development of ME.Nitric oxide (NO) is a multifunctional molecule that plays a key role in physiological processes such as the regulation of vascular tone and the antiproliferative effects on vascular smooth muscle cells (4,5). NO is produced by three different isoforms of NO synthase (NOS): endothelial NOS (eNOS), neural NOS, and inducible NOS (iNOS). Although NO produced in large amounts by iNOS is regarded as a toxic, damaging agent, it is suggested that a low concentration of NO produced by constitutively expressed eNOS is necessary to maintain good endothelial function (5). Thus, eNOS appears to present an attractive candidate susceptibility gene for diabetic microvascular complications as well as cardiovascular diseases.Several polymorphisms have been identified in the eNOS gene (NOS3) (6,7). In particular, T-786C in the promoter region, 27-bp repeat in intron 4, and Glu298Asp in exon 7 have...

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A novel polymorphism in the aldose reductase gene promoter region is strongly associated with diabetic retinopathy in adolescents with type 1 diabetes.

Cited by 92 publications

References 9 publications

A Common Polymorphism in the 5′-Untranslated Region of the VEGF Gene Is Associated With Diabetic Retinopathy in Type 2 Diabetes

A Common Polymorphism in the 5′-Untranslated Region of the VEGF Gene Is Associated With Diabetic Retinopathy in Type 2 Diabetes

Molecular genetics of microvascular disease in diabetic retinopathy

Endothelial Nitric Oxide Synthase Gene Is Associated With Diabetic Macular Edema in Type 2 Diabetes

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