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P<P, published online ahead of print April 25, 2008
(Investigative Ophthalmology and Visual Science. )
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-1383
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Article

VEGF Polymorphisms are Associated with Severity of Diabetic Retinopathy

Amanda Churchill 1, James George Carter 2*, Conor Miles Ramsden 1, Steve Turner 1, Anna Yeung 1, Paul Brenchley 3, and David Ray 3

1 Unit of Ophthalmology, University of Bristol, Bristol, Avon, United Kingdom
2 Unit of Ophthalmology, University of Bristol, Bristol Eye Hospital, Bristol, BS1 2LX, United Kingdom
3 School of Clinical and Laboratory Medicine, University of Manchester, Manchester, United Kingdom

* To whom correspondence should be addressed. E-mail: Jim.Carter{at}bristol.ac.uk.


  Abstract

Purpose To determine whether single nucleotide polymorphisms (SNPs) in the Vascular Endothelial Growth Factor (VEGF) gene are associated with severity of diabetic retinopathy. Methods We conducted a case-control study: 45 type 1 and 2 diabetics with proliferative retinopathy (PDR) and 61 type 1 and 2 diabetics without retinopathy (DWR) were genotyped for 14 SNPs in the VEGF promoter and gene. Results Three of the promoter SNP genotypes, -160C, -152A (rs13207351), -116A (rs1570360), showed significant independent associations with PDR as well as the mini-haplotype CAA (p=0.00017). Two promoter haplotypes were associated with severity of retinopathy: -460C, -417T, -172C, -165C, -160C, -152A, -141A, -116A, +405C was associated with PDR (OR=29.92 [3.91,228.78], p=1.62x10-5) and -460C,-2417T, -172C, -165C,-160C, -152A, -141A, -116G, +405G was associated with DWR (OR= 0.05 [0.01,0.35], p=0.000373). Furthermore 2 haplotype-tagged (ht) SNPs, +4618 (rs735286) and +5092 (rs2146323), and 5 htSNP haplotypes were associated with severity of retinopathy. When the 9 promoter/5-UTR and 5 htSNP genotypes were combined into a 14-SNP haplotype, a single haplotype, -460C, -417T, -172C, -165C, -160C, -152A, -141A, -116A, +405C, +674T, +4618C, +5092A, +9162C, +9512C was found to be significantly associated with the PDR group (OR=18.45 [2.35, 144.67], p=0.00622). Conclusions We have demonstrated a clear association between VEGF SNPs and severity of diabetic retinopathy. Furthermore 2 of the htSNP haplotypes appear to be more generalised markers for angiogenesis in that we have previously found these to be associated with neovascular age-related macular degeneration.

Key Words: diabetic retinopathy, angiogenesis, genetic diseases, age-related macular degeneration






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