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N Engl J Med —, Bull , Andrew P. Boright , Andrew D. Diabetes 1 August ; 56 8 : — The most significant single SNP association was rs hazard ratio 1. The Diabetes Control and Complications Trial DCCT demonstrated familial clustering of severe retinopathy, but not for any retinopathy 6 , which is consistent with others 7 , 8. The essential features of diabetic retinopathy include capillary microaneurysms and increased vascular permeability leading to macular edema, vascular occlusion and ischemia, neovascularization, and contraction of fibrovascular proliferation in the vitreous.

Vascular endothelial growth factor VEGFA is a mitogen that specifically acts on endothelial cells 9 and has various effects, including mediating increased vascular permeability 10 and inducing angiogenesis 11 — 13 , cell growth, migration, and inhibition of apoptosis Many retinal cells produce VEGFA, including pigment epithelial 15 , capillary pericytes 15 , endothelial 16 , Mueller 17 , ganglion 18 , and glial 19 cells.

VEGFA expression in retinal cells is increased 3- to fold by hypoxia VEGFA is significantly upregulated in diabetic retinopathy, particularly in retinal pigmented epithelial cells, glial cells, and vitreal fibroblasts Moreover, higher plasma 21 and vitreous VEGFA 21 — 23 levels were found in individuals with proliferative diabetic retinopathy PDR when compared with nondiabetic control subjects 21 or with individuals with nonocular diseases Phase II clinical trials have shown safety and efficacy of intraocular injections of pegaptanib, an anti-VEGFA aptamer in the treatment of diabetic macular edema For these reasons, VEGFA is a functional candidate gene for the predisposition to diabetic retinopathy.

Several cross-sectional studies have investigated the genetic involvement of VEGFA in diabetic retinopathy 25 — Two studies investigated the association of an bp deletion in the promoter with diabetic retinopathy 28 , 29 in type 1 29 and type 2 28 diabetes but produced conflicting results. However, all of these studies 25 — 29 used a case-control design with various phenotype definitions and investigated only markers in the promoter region in relatively small sample sizes of Japanese type 2 diabetic patients 27 or Caucasians with a mix of type 1 and type 2 diabetes Covariates, if available, were measured at a single time point when the phenotype was also determined.