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Multiple variants in Vascular Endothelial Growth Factor (VEGF) are risk factors for time to severe retinopathy in type 1 diabetes: The DCCT/EDIC genetics study

¹Program in Genetics and Genome Biology, Hospital of Sick Children Research Institute, Toronto, Canada
²Department of Public Health Sciences, University of Toronto, Toronto, Canada
³Samuel Lunenfeld Research Institute of Mount Sinai Hospital, Prosserman Centre for Health Research, University of Toronto, Toronto, Canada
⁴Department of Medicine, University Health Network, University of Toronto, Toronto, Canada

Correspondence: andrew.paterson{at}utoronto.ca

Objective:To determine if any common variants in the gene for Vascular Endothelial Growth Factor (VEGF) are associated with long-term renal and retinal complications in type 1 diabetes (T1D).

Research Design and Methods:1369 white subjects with T1D 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 VEGF that represent all linkage disequilibrium bins (pairwise r² 0.64), and tested them for association with time to development of: severe retinopathy (SR); 3-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 VEGF SNPs with SR (P = 6.8 x 10^-5) -- the four other outcomes were all non-significant. In survival analyses controlling for covariate risk factors, eight SNPs showed significant association with SR (P<0.05). The most significant single-SNP association was rs3025021 (Hazard Ratio = 1.37, 95% confidence interval [1.13-1.66], P= 0.0017). Family-based analyses of SR provide evidence of excess transmission of C at rs699947 (P = 0.029), T at rs3025021 (P = 0.024) and the C-T haplotype from both SNPs (P = 0.035). Multi-SNP regression analysis including 15 SNPs, and allowing for pairwise interactions, independently selected six significant SNPs (P < 0.05).

Conclusions:These data demonstrate that multiple VEGF variants are associated with the development of SR in T1D.

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