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

Abstract

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

Association of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptor-2 Genetic Polymorphisms With Outcome in a Trial of Paclitaxel Compared With Paclitaxel Plus Bevacizumab in Advanced Breast Cancer: ECOG 2100

“…The heterogeneity in outcome seen with a therapy that targets a process (ie, angiogenesis) that is host mediated might best be explained by host-imprinted variability. There are multiple prior studies that suggest that SNPs within VEGF can impact outcome in conditions regulated by angiogenesis including cancer risk and prognosis, 10,11,[26][27][28][29][30][31][32][33][34] retinopathy, [35][36][37][38][39][40][41] nephropathy, 42-45 pre-eclampsia, 46,47 recurrent pregnancy loss, 48 and vasculopathy. [49][50][51] Although the DNA evaluated here was derived from the primary tumor, we were attempting to evaluate germline variability.…”

The Role of Vascular Endothelial Growth Factor Genetic Variability in Cancer

“…These studies include those that evaluate cancer risk and prognosis (25,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36), retinopathy (20,(37)(38)(39)(40)(41)(42), nephropathy (43)(44)(45)(46), pre-eclampsia (47,48), and vasculopathy (49-51), among many others. Many of these studies show an increased association of disease and/or inferior outcomes in the subgroup with genotype that would predict a higher VEGF expression.…”

Deciphering the therapeutic mechanisms of Xiao-Ke-An in treatment of type 2 diabetes in mice by a Fangjiomics approach

“…VEGF is believed to play a significant role in the development of diabetic complications. VEGFA variants were associated with the development of diabetic retinopathy [46,47] . Ginsenoside Rb1 obviously enhanced the expression of VEGF and enhanced myocardial angiogenesis [48] .…”