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1
* Department of Medical Genetics,
Ophthalmology and Vision Sciences,
§ Department of Epidemiology and Public Health, Queen's University, Belfast, U.K.;
|| Eye Unit, Royal Liverpool Hospital, Liverpool, U.K.; and
The Wolfson Institute for Biomedical Research, The Rayne Institute, University College, London, London, U.K.
1Correspondence: Ophthalmology and Vision Sciences, Institute of Clinical Sciences, Grosvenor Road, Belfast BT12 6BA, U.K.
Accumulating evidence shows that the severity and rapidity of onset of diabetic retinopathy are influenced by genetic factors. Expression of the nitric oxide synthases is altered in the retinal vasculature in the early stages of diabetic retinopathy. We analyzed the allele distribution of a polymorphic pentanucleotide repeat within the 5' upstream promoter region of the NOS2A gene in samples of diabetic patients. In diabetic patients from Northern Ireland, the 14-repeat allele of the NOS2A marker was significantly associated with the absence of diabetic retinopathy. Carriers of this repeat had 0.21-fold the relative risk of developing diabetic retinopathy than noncarriers of this allele. They also had significantly fewer renal and cardiovascular complications. The ability of differing numbers of (CCTTT)n pentanucleotide repeats to induce transcription of the NOS2A gene was analyzed using a luciferase reporter gene assay in transfected colonic carcinoma cells. Interleukin 1ß (IL-1ß) induction was most effective in constructs carrying the 14-repeat allele. When cells were incubated in 25 mM glucose to mimic the diabetic state, IL-1ß induction was inhibited in all cases, but to a significantly lesser extent with the 14-repeat allele. These unique properties of the 14-repeat allele may confer selective advantages in diabetic individuals, which may delay or prevent microvascular complications of diabetes.–Warpeha, K. M., Xu, W., Liu, L., Charles, I. G., Patterson, C. C., Ah-Fat, F., Harding, S., Hart, P. M., Chakravarthy, U., Hughes, A. E. Functional analysis of the polymorphic (CCTTT)n locus of NOS2A in diabetic retinopathy.
Key Words: microvascular • transcription • NOS2A promoter • pentanucleotide repeat
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