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Originally published In Press as doi:10.1167/iovs.09-3694 on June 24, 2009
 (Investigative Ophthalmology and Visual Science. 2009;50:5552-5558.)
© 2009 by The Association for Research in Vision and Ophthalmology, Inc.
doi:10.1167/iovs.09-3694
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Common Sequence Variation in the VEGFA Gene Predicts Risk of Diabetic Retinopathy

Sotoodeh Abhary,1 Kathryn P. Burdon,1 Aanchal Gupta,2 Stewart Lake,1 Dinesh Selva,2 Nikolai Petrovsky,3 and Jamie E. Craig1

From the Departments of 1Ophthalmology and 3Endocrinology, Flinders Medical Centre and Flinders University, Adelaide, South Australia; and the 2South Australian Institute of Ophthalmology, Department of Ophthalmology and Visual Sciences, Adelaide University and Royal Adelaide Hospital, Adelaide, South Australia.

Corresponding author: Jamie E. Craig, Department of Ophthalmology, Flinders Medical Centre, Bedford Park 5042, Adelaide, South Australia, Australia; jamie.craig{at}flinders.edu.au.

Purpose. Vascular endothelial growth factor (VEGF) is a multifunctional cytokine that plays a role in angiogenesis and microvascular permeability. This study was conducted to determine whether common sequence variation in the VEGFA gene plays a role in the development of diabetic retinopathy (DR).

Method. Five hundred fifty-four subjects with diabetes mellitus (DM) including 190 type 1 DM (T1DM) and 364 type 2 DM (T2DM) were recruited. The study group consisted of 235 participants without DR, 158 with nonproliferative DR (NPDR), 132 with proliferative DR (PDR), and 93 with clinically significant macular edema (CSME). Blinding DR was defined as severe NPDR, PDR, or CSME. Fifteen VEGFA tag single-nucleotide polymorphisms (SNPs) were genotyped in all subjects and tested for association with blinding DR.

Results. Multiple tag SNPs in the VEGFA gene were associated with blinding DR. After controlling for sex, HbA1c, and duration of disease, in T1DM, the AA genotype of rs699946 (P = 0.007, odds ratio [OR], 4.1; 95% confidence interval [CI], 1.5–11.4) and the GG genotype of rs833068 (P = 0.017, OR, 3.1; 95% CI, 1.3–7.2) were most significantly associated. In T2DM, the C allele of rs3025021 (P = 0.002; OR, 3.8; 95% CI, 1.5–10.0) and the G allele of rs10434 (P = 0.002; OR, 2.6; 95% CI, 1.3–5.3) were most significantly associated with blinding DR. Haplotype analyses suggested an important role for the haplotype TCCGCG in blinding DR (P = 0.0004).

Conclusions. Sequence variation in the VEGFA gene is associated with risk of developing blinding DR in T1DM and T2DM. Identifying specific genetic markers will allow for refined screening algorithms and earlier intervention in patients at highest risk.






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