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Diabetes 53:2455-2460, 2004
© 2004 by the American Diabetes Association, Inc.

Functional Variants in the Glutathione Peroxidase-1 (GPx-1) Gene Are Associated With Increased Intima-Media Thickness of Carotid Arteries and Risk of Macrovascular Diseases in Japanese Type 2 Diabetic Patients

Tohru Hamanishi1, Hiroto Furuta1, Hisako Kato1, Asako Doi1, Masanori Tamai1, Hiroko Shimomura1, Setsuya Sakagashira1, Masahiro Nishi1, Hideyuki Sasaki1, Tokio Sanke2, and Kishio Nanjo1

1 The First Department of Medicine, Wakayama University of Medical Science, Wakayama, Japan
2 Department of Clinical Laboratory Medicine, Wakayama University of Medical Science, Wakayama, Japan

Atherosclerosis in type 2 diabetic patients has been linked to increased oxidative stress. Glutathione peroxidase-1 (GPx-1) plays an important role in the antioxidant defense of the vascular wall. To assess the association between variants in the GPx-1 gene and atherosclerosis, we screened the gene in 184 Japanese type 2 diabetic patients and identified four polymorphisms (–602A/G, +2C/T, Ala5/Ala6, and Pro198Leu). Among these polymorphisms, –602G, +2T, Ala6, and 198Leu were in strong linkage disequilibrium with each other. The patients were divided into two groups on the basis of the codon 198 polymorphism, Pro/Pro (n = 151) and Pro/Leu (n = 33), to analyze clinical characteristics. The mean intima-media thickness (IMT) of common carotid arteries (P = 0.0028) and the prevalence of cardiovascular disease (P = 0.035) and peripheral vascular disease (P = 0.027) were significantly higher in the Pro/Leu group than in the Pro/Pro group. In vitro functional analyses indicated that the combination of polymorphisms (Ala6/198Leu) of the GPx-1 gene had a 40% decrease in enzyme activity, and the combination of polymorphisms (–602G/+2T) had a 25% decrease in transcriptional activity. These results suggest that functional variants in the GPx-1 gene are associated with increased IMT of carotid arteries and risk of cardiovascular and peripheral vascular diseases in type 2 diabetic patients.

Address correspondence and reprint requests to Kishio Nanjo, MD, PhD, The First Department of Medicine, Wakayama University of Medical Science, 811-1 Kimiidera, Wakayama 641-8509, Japan. E-mail: k-nanjo{at}wakayama-med.ac.jp


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Copyright © 2004 by the American Diabetes Association.