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.
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.
The First Department of Medicine, Wakayama University of Medical Science, 811-1 Kimiidera, Wakayama 641-8509, Japan.
Tohru
T
Hamanishi
Hiroto
H
Furuta
Hisako
H
Kato
Asako
A
Doi
Masanori
M
Tamai
Hiroko
H
Shimomura
Setsuya
S
Sakagashira
Masahiro
M
Nishi
Hideyuki
H
Sasaki
Tokio
T
Sanke
Kishio
K
Nanjo
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002340:Carotid Artery Diseases / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D005260:Female; D014644:Genetic Variation; D005979:Glutathione Peroxidase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors; D015533:Transcriptional Activation; D017539:Tunica Intima / Q000473:pathology; D017540:Tunica Media / Q000473:pathology; D000094765:Glutathione Peroxidase GPX1
D005979:Glutathione Peroxidase; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human