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

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 Hamanishi 1 , Hiroto Furuta 1 , Hisako Kato 1 , Asako Doi 1 , Masanori Tamai 1 , Hiroko Shimomura 1 , Setsuya Sakagashira 1 , Masahiro Nishi 1 , Hideyuki Sasaki 1 , Tokio Sanke 2 and Kishio Nanjo 1 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 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 Abstract 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, Ala 5 /Ala 6 , and Pro198Leu). Among these polymorphisms, −602G, +2T, Ala 6 , 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 (Ala 6 /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. AGE, advanced glycation end product BAEC, bovine aortic endothelial cell GPx, glutathione peroxidase IMT, intima-media thickness PKC, protein kinase C Footnotes Accepted June 2, 2004. Received January 27, 2004. DIABETES