Association of the VEGF Gene With Proliferative Diabetic Retinopathy But Not Proteinuria in Diabetes

Ray, David; Mishra, Manoj Kumar; Ralph, Shirley; Read, Ian; Davies, Robert D. M.; Brenchley, Paul

doi:10.2337/diabetes.53.3.861

Cited by 164 publications

(107 citation statements)

References 21 publications

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“…Three studies (25,27,28) investigated rs2010963, a promoter variant, of which two studies were performed in type 2 diabetes (27,28) and one in both type 1 and type 2 diabetes (25). Two studies (25,28) found no association between this SNP and diabetic retinopathy. While rs2010963 (C on the forward strand) approached nominal significance with time to severe retinopathy in the DCCT/EDIC probands in our single-marker analysis (HR 1.21 [95% CI 0.98 -1.50], P ϭ 0.078), it was not retained in backward or forward selection models.…”

Section: Discussionmentioning

confidence: 99%

“…Several cross-sectional studies have investigated the genetic involvement of VEGFA in diabetic retinopathy (25)(26)(27)(28)(29). Three studies tested rs833061 (Ϫ460) for association with diabetic retinopathy in patients with type 2 diabetes (25-27): one observed an association with the C-allele and the C/C genotype (25), another found association with the C/T genotype (26), whereas the third one found no association (27).…”

Section: Research Design and Methods-a Total Of 1369 Caucasian Subjementioning

confidence: 99%

“…Three studies tested rs833061 (Ϫ460) for association with diabetic retinopathy in patients with type 2 diabetes (25-27): one observed an association with the C-allele and the C/C genotype (25), another found association with the C/T genotype (26), whereas the third one found no association (27). Two studies investigated the association of an 18-bp deletion in the promoter with diabetic retinopathy (28,29) in type 1 (29) and type 2 (28) diabetes but produced conflicting results.…”

Section: Research Design and Methods-a Total Of 1369 Caucasian Subjementioning

confidence: 99%

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Multiple Variants in Vascular Endothelial Growth Factor (VEGFA) Are Risk Factors for Time to Severe Retinopathy in Type 1 Diabetes

et al. 2007

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OBJECTIVE-We sought to determine if any common variants in the gene for vascular endothelial growth factor (VEGFA) are associated with long-term renal and retinal complications in type 1 diabetes.RESEARCH DESIGN AND METHODS-A total of 1,369 Caucasian subjects with type 1 diabetes from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study had an average of 17 retinal photographs and 10 renal measures over 15 years. In the DCCT/EDIC, we studied 18 single nucleotide polymorphisms (SNPs) in VEGFA that represent all linkage disequilibrium bins (pairwise r 2 Ն 0.64) and tested them for association with time to development of severe retinopathy, three or more step progression of retinopathy, clinically significant macular edema, persistent microalbuminuria, and severe nephropathy.RESULTS-In a global multi-SNP test, there was a highly significant association of VEGFA SNPs with severe retinopathy (P ϭ 6.8 ϫ 10 Ϫ5 )-the four other outcomes were all nonsignificant. In survival analyses controlling for covariate risk factors, eight SNPs showed significant association with severe retinopathy (P Ͻ 0.05). The most significant single SNP association was rs3025021 (hazard ratio 1.37 [95% CI 1.13-1.66], P ϭ 0.0017). Family-based analyses of severe retinopathy provide evidence of excess transmission of C at rs699947 (P ϭ 0.029), T at rs3025021 (P ϭ 0.013), and the C-T haplotype from both SNPs (P ϭ 0.035). Multi-SNP regression analysis including 15 SNPs, and allowing for pairwise interactions, independently selected 6 significant SNPs (P Ͻ 0.05).CONCLUSIONS-These data demonstrate that multiple VEGFA variants are associated with the development of severe retinopathy in type 1 diabetes. Diabetes

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Section: Discussionmentioning

confidence: 99%

Section: Research Design and Methods-a Total Of 1369 Caucasian Subjementioning

confidence: 99%

Section: Research Design and Methods-a Total Of 1369 Caucasian Subjementioning

confidence: 99%

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Multiple Variants in Vascular Endothelial Growth Factor (VEGFA) Are Risk Factors for Time to Severe Retinopathy in Type 1 Diabetes

et al. 2007

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“…thiolactone) increase the expression of the vascular endothelial growth factor (VEGF) in cell cultures via activation of its transcription (Maeda et al 2003a;Roybal et al 2004). The VEGF is a pro-angiogenic factor known to play a key role in the development and progression of DR (Roybal et al 2004;Ray et al 2004). For these reasons, it may be readily postulated that the C677T MTHFR gene polymorphism might be involved in the development of DR.…”

Section: Discussionmentioning

confidence: 99%

The relationship between C677T methylenetetrahydrofolate reductase gene polymorphism and retinopathy in type 2 diabetes: a meta-analysis

et al. 2005

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The association between retinopathy in type 2 diabetes [diabetic retinopathy (DR)] and the C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene has been investigated in several case-control studies. These studies rendered contradictory results, some indicating that the polymorphism is associated with the risk of developing DR whereas others concluded there is no association. To shed light on these inconclusive findings, a meta-analysis of all available studies relating the C677T polymorphism to the risk of developing DR was conducted. Four out of five identified studies included populations of East Asian descent, and only one involved samples from European descent (Caucasians). Overall, the meta-analysis suggested large heterogeneity between studies (p = 0.08, I 2 = 52%) and marginal association between C677T transition and the risk of developing DR: random effects odds ratio (OR) = 1. There is a source of bias in the selected studies: the largest studies failed to show association while the smallest study claimed an association. The above findings reinforce the need for larger and more rigourous studies in this area.

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“…VEGF seems to be important for the formation of ascites and pleural effusion in advanced cancer patients (11,12). Moreover, VEGF expression is associated with the abnormal angiogenesis that occurs in diabetic retinopathy (13) as well as with several kinds of cancers, such as colorectal, gastric, pancreatic, breast, prostate, lung, and melanoma (14 -20). In the clinical setting, bevacizumab, a recombinant humanized monoclonal antibody to VEGF with efficacy against colorectal and other malignancies, has already been approved for patients (21).…”

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confidence: 99%

YM-359445, an Orally Bioavailable Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor, Has Highly Potent Antitumor Activity against Established Tumors

Amino¹,

Ideyama²,

Yamano³

et al. 2006

Clinical Cancer Research

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Purpose: The vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase has been implicated in the pathologic angiogenesis associated with tumor growth. YM-359445 was a (3Z)-3-quinolin-2(1H)-ylidene-1,3-dihydro-2H-indol-2-one derivative found while screening based on the inhibition of VEGFR2 tyrosine kinase.The aim of this study was to analyze the efficacy of this compound both in vitro and in vivo. Experimental Design:We tested the effects ofYM-359445 onVEGFR2 tyrosine kinase activity, cell proliferation, and angiogenesis. The antitumor activity of YM-359445 was also tested in nude mice bearing various established tumors and compared with other VEGFR2 tyrosine kinase inhibitors (ZD6474, CP-547632, CGP79787, SU11248, and AZD2171), a cytotoxic agent (paclitaxel), and an epidermal growth factor receptor tyrosine kinase inhibitor (gefitinib). Results: The IC 50 of YM-359445 for VEGFR2 tyrosine kinase was 0.0085 Amol/L. In human vascular endothelial cells, the compound inhibited VEGF-dependent proliferation, VEGFR2 autophosphorylation, and sprout formation at concentrations of 0.001 to 0.003 Amol/L. These concentrations had no direct cytotoxic effect on cancer cells. In mice bearing various established tumors, including paclitaxel-resistant tumors, once daily oral administration of YM-359445 at doses of 0.5 to 4 mg/kg not only inhibited tumor growth but also reduced its vasculature. YM-359445 had greater antitumor activity than other VEGFR2 tyrosine kinase inhibitors. Moreover, in human lung cancer A549 xenografts, YM-359445 markedly regressed the tumors (73%) at a dose of 4 mg/kg, whereas gefitinib caused no regression even at 100 mg/kg. Conclusion: Our results show that YM-359445 is more potent than orally bioavailable VEGFR2 tyrosine kinase inhibitors, which leads to great expectations for clinical applicability.Morbidity rate of cancer has been increasing remarkably in recent decades, and the development of diagnostic rapid capabilities has supported early detection and treatment. Although chemotherapy using anticancer drugs began >50 years ago, and the number of anticancer drugs has increased considerably, the prognosis of most patients has not yet been improved because of serious side effects or multidrug resistance (1). As a means of overcoming these problems, antiangiogenesis therapy targeting the vascular endothelial cells in tumors has attracted attention. This is because endothelial cells rarely acquire resistance due to their genetic stability, but cancer cells easily acquire resistance during chemotherapy through the use of cytotoxic agents (2, 3).Angiogenesis is the complex process of forming new blood vessels from the preexisting vessels that occurs due to many physiologic and pathologic conditions (4, 5). The protrusion of endothelial cells allows local degradation of the basement membrane of the parent vessel; then, endothelial cells migrate outward in tandem to form a capillary sprout. The cells then proliferate followed by lumen formation with subsequent branching; however, th...

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Association of the VEGF Gene With Proliferative Diabetic Retinopathy But Not Proteinuria in Diabetes

Cited by 164 publications

References 21 publications

Multiple Variants in Vascular Endothelial Growth Factor (VEGFA) Are Risk Factors for Time to Severe Retinopathy in Type 1 Diabetes

Multiple Variants in Vascular Endothelial Growth Factor (VEGFA) Are Risk Factors for Time to Severe Retinopathy in Type 1 Diabetes

The relationship between C677T methylenetetrahydrofolate reductase gene polymorphism and retinopathy in type 2 diabetes: a meta-analysis

YM-359445, an Orally Bioavailable Vascular Endothelial Growth Factor Receptor-2 Tyrosine Kinase Inhibitor, Has Highly Potent Antitumor Activity against Established Tumors

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