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Diabetes Care 27:2184-2190, 2004
© 2004 by the American Diabetes Association, Inc.

Pathophysiology/Complications
Original Article

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

Takuya Awata, MD1,2, Tamotsu Neda, MD1, Hiroyuki Iizuka, MD2, Susumu Kurihara, MD1, Tomoko Ohkubo, MD1, Nobuki Takata, MD1, Masataka Osaki, MD1, Masaki Watanabe, MD1, Youhei Nakashima, MD1, Takahiro Sawa, MD1, Kouichi Inukai, MD1, Ikuo Inoue, MD1, Masayuki Shibuya, MD3, Keisuke Mori, MD3, Shin Yoneya, MD3 and Shigehiro Katayama, MD1

1 The Fourth Department of Medicine, Saitama Medical School, Saitama, Japan
2 Division of RI Laboratory, Biomedical Research Center, Saitama Medical School, Saitama, Japan
3 Department of Ophthalmology, Saitama Medical School, Saitama, Japan

Address correspondence and reprint requests to Dr. Takuya Awata, the Fourth Department of Medicine, Saitama Medical School, 38 Morohongo, Moroyama, Iruma-gun, Saitama, 350-0495, Japan. E-mail: awata{at}saitama-med.ac.jp

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 –786C 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.

Abbreviations: BRB, blood-retina barrier • DN, diabetic nephropathy • DR, diabetic retinopathy • eNOS, endothelial nitric oxide synthase • iNOS, inducible nitric oxide synthase • ME, macular edema • NOS, nitric oxide synthase • NPDR, nonproliferative diabetic retinopathy • PDR, proliferative diabetic retinopathy • SBP, systolic blood pressure • SNP, single nucleotide polymorphism • VEGF, vascular endothelial growth factor


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