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Originally published In Press as doi:10.1167/iovs.07-1383 on April 25, 2008
 (Investigative Ophthalmology and Visual Science. 2008;49:3611-3616.)
© 2008 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.07-1383
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VEGF Polymorphisms Are Associated with Severity of Diabetic Retinopathy

Amanda J. Churchill,1 James G. Carter,1 Conor Ramsden,1 Steven J. Turner,1 Anna Yeung,1 Paul E. C. Brenchley,2 and David W. Ray2

1From the Unit of Ophthalmology, Bristol Eye Hospital, University of Bristol, Bristol, United Kingdom; and the 2School of Clinical and Laboratory Medicine, University of Manchester, Manchester, United Kingdom.

PURPOSE. To determine whether single nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor (VEGF) gene are associated with severity of diabetic retinopathy.

METHODS. A case–control study was conducted in which 45 individuals with type 1 or 2 diabetes with proliferative diabetic retinopathy (PDR) and 61 individuals with type 1 or 2 diabetes without retinopathy (DWR) were genotyped for 14 SNPs in the VEGF promoter and gene.

RESULTS. Three of the promoter SNP genotypes, –160C, –152A (rs13207351), and –116A (rs1570360), showed significant independent associations with PDR, as well as the minihaplotype 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 [95% CI] = 29.92 [3.91, 228.78], P = 1.62 x 10–5) 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, two haplotype-tagged (ht) SNPs, +4618 (rs735286) and +5092 (rs2146323), and five htSNP haplotypes were associated with severity of retinopathy. When the nine promoter/5' untranslated region [UTR] and five 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. A clear association was demonstrated between VEGF SNPs and severity of diabetic retinopathy. Furthermore, two of the htSNP haplotypes appear to be more generalized markers for angiogenesis, in that these have been found in prior work to be associated with neovascular age-related macular degeneration.






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