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.
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.


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) > or = 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.
Al-Kateb
Hussam
H
Program in Genetics and Genome Biology, Hospital of Sick Children Research Institute, Toronto, ON, Canada.
Mirea
Lucia
L
Xie
Xinlei
X
Sun
Lei
L
Liu
Michelle
M
Chen
Hongtao
H
Bull
Shelley B
SB
Boright
Andrew P
AP
Paterson
Andrew D
AD
D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D003930:Diabetic Retinopathy / Q000453:epidemiology / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D005838:Genotype; D006801:Humans; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A