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

• Published in: Diabetes (New York, N.Y.) Vol. 56; no. 8; pp. 2161 - 2168
• Main Authors: Al-Kateb, Hussam, Mirea, Lucia, Xie, Xinlei, Sun, Lei, Liu, Michelle, Chen, Hongtao, Bull, Shelley B., Boright, Andrew P., Paterson, Andrew D.
• Format: Journal Article
• Language: English
• Published: American Diabetes Association 01.08.2007
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db07-0376

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 Hussam Al-Kateb 1 , Lucia Mirea 2 3 , Xinlei Xie 3 , Lei Sun 1 2 , Michelle Liu 1 , Hongtao Chen 1 , Shelley B. Bull 2 3 , Andrew P. Boright 4 , Andrew D. Paterson 1 2 and for the DCCT/EDIC Research Group * 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 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 ≥ 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 × 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. 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 Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 18 May 2007. DOI: 10.2337/db07-0376. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0376 . * * A complete list of the individuals and institutions participating in the DCCT/EDIC Research Group appears in: Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group: Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353:2643–2653, 2005. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted May 1, 2007. Received March 19, 2007. DIABETES