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

The DCCT/EDIC Genetics Study

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

Address correspondence and reprint requests to Andrew Paterson, Program in Genetics and Genome Biology, The Hospital for Sick Children, TMDT East Tower, 101 College St., Toronto, ON, Canada M5G 1L7. E-mail: andrew.paterson{at}utoronto.ca

Abbreviations: AER, albumin excretion rate; AMD, age-related macular degeneration; CSME, clinically significant macular edema; DCCT, Diabetes Control and Complications Trial; EDIC, Epidemiology of Diabetes Interventions and Complications; ETDRS, Early Treatment Diabetic Retinopathy Study; LD, linkage disequilibrium; PDR, proliferative diabetic retinopathy; SNP, single nucleotide polymorphism

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 r² 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 = 6.8 x 10^–5)—the four other outcomes were all nonsignificant. In survival analyses controlling for covariate risk factors, eight SNPs showed significant association with severe retinopathy (P < 0.05). The most significant single SNP association was rs3025021 (hazard ratio 1.37 [95% CI 1.13–1.66], P = 0.0017). Family-based analyses of severe retinopathy provide evidence of excess transmission of C at rs699947 (P = 0.029), T at rs3025021 (P = 0.013), 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 6 significant SNPs (P < 0.05).

CONCLUSIONS—These data demonstrate that multiple VEGFA variants are associated with the development of severe retinopathy in type 1 diabetes.

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