Endothelial Nitric Oxide Synthase Gene Is Associated With Diabetic Macular Edema in Type 2 Diabetes

Abstract

OBJECTIVE -We examined the endothelial nitric oxide (eNOS) gene polymorphisms to assess its possible association with diabetic retinopathy and macular edema.RESEARCH DESIGN AND METHODS -A total of 226 patients with type 2 diabetes and 186 healthy subjects were studied. Type 2 diabetic patients consisted of 110 patients without retinopathy, 46 patients with nonproliferative diabetic retinopathy, and 71 patients with proliferative diabetic retinopathy. Diabetic macular edema was present in 48 patients. Three polymorphisms of the eNOS gene were determined: T-786C in the promoter region, 27-bp repeat in intron 4, and Glu298Asp in exon 7.RESULTS -Close linkage disequilibrium was observed between the T-786C polymorphism and the 27-bp repeat, as has been previously reported, but Glu298Asp was not in linkage disequilibrium with the other two polymorphisms. The eNOS gene polymorphisms were not significantly associated with the presence of retinopathy or with retinopathy severity or type 2 diabetes itself. However, by both association study and multiple logistic regression analysis, the T-786C and 27-bp repeat polymorphisms were significantly associated with a risk of developing macular edema with the Ϫ786C allele and the "a" allele increasing the risk.CONCLUSIONS -The present study suggests that the eNOS gene is a novel genetic risk factor for diabetic macular edema. The eNOS gene polymorphisms may contribute to the development of macular edema by impairing basal eNOS expression and resulting in the breakdown of the blood-retina barrier. Diabetes Care 27:2184 -2190, 2004D iabetic retinopathy (DR) remains the major cause of blindness among adults (1). In addition, diabetic maculopathy or macular edema (ME), which may occur at any stage of DR, is an important cause of visual impairment (1-3). Among the pathophysiological steps involved in the development of ME, the most important mechanism is breakdown of the blood-retina barrier (BRB) (2,3). Both the inner BRB formed by the retinal capillary endothelial cell tight junctions and the outer BRB formed by the retinal pigment epithelial cell tight junctions can be affected during the development of ME.Nitric oxide (NO) is a multifunctional molecule that plays a key role in physiological processes such as the regulation of vascular tone and the antiproliferative effects on vascular smooth muscle cells (4,5). NO is produced by three different isoforms of NO synthase (NOS): endothelial NOS (eNOS), neural NOS, and inducible NOS (iNOS). Although NO produced in large amounts by iNOS is regarded as a toxic, damaging agent, it is suggested that a low concentration of NO produced by constitutively expressed eNOS is necessary to maintain good endothelial function (5). Thus, eNOS appears to present an attractive candidate susceptibility gene for diabetic microvascular complications as well as cardiovascular diseases.Several polymorphisms have been identified in the eNOS gene (NOS3) (6,7). In particular, T-786C in the promoter region, 27-bp repeat in intron 4, and Glu298Asp in exon 7 have...

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