Genetic association of glutathione peroxidase-1 with coronary artery calcification in type 2 diabetes: a case control study with multi-slice computed tomography.
BACKGROUND
Although oxidative stress by accumulation of reactive oxygen species (ROS) in diabetes has become evident, it remains unclear what genes, involved in redox balance, would determine susceptibility for development of atherosclerosis in diabetes. This study evaluated the effect of genetic polymorphism of enzymes producing or responsible for reducing ROS on coronary artery calcification in type 2 diabetes (T2D).


METHODS
An index for coronary-arteriosclerosis, coronary artery calcium score (CACS) was evaluated in 91 T2D patients using a multi-slice computed tomography. Patients were genotyped for ROS-scavenging enzymes, Glutathione peroxidase-1 (GPx-1), Catalase, Mn-SOD, Cu/Zn-SOD, as well as SNPs of NADPH oxidase as ROS-promoting elements, genes related to onset of T2D (CAPN10, ADRB3, PPAR gamma, FATP4). Age, blood pressure, BMI, HbA1c, lipid and duration of diabetes were evaluated for a multivariate regression analysis.


RESULTS
CACS with Pro/Leu genotype of the GPx-1 gene was significantly higher than in those with Pro/Pro (744 +/- 1,291 vs. 245 +/- 399, respectively, p = 0.006). In addition, genotype frequency of Pro/Leu in those with CACS >or= 1000 was significantly higher than in those with CACS < 1000 (45.5% vs. 18.8%; OR = 3.61, CI = 0.97-13.42; p = 0.045) when tested for deviation from Hardy-Weinberg's equilibrium. Multivariate regression analyses revealed that CACS significantly correlated with GPx-1 genotypes and age.


CONCLUSIONS
The presence of Pro197Leu substitution of the GPx-1 gene may play a crucial role in determining genetic susceptibility to coronary-arteriosclerosis in T2D. The mechanism may be associated with a decreased ability to scavenge ROS with the variant GPx-1.
Nemoto
Masami
M
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan. mnemoto@kje.biglobe.ne.jp
Nishimura
Rimei
R
Sasaki
Takashi
T
Hiki
Yoshito
Y
Miyashita
Yumi
Y
Nishioka
Makiko
M
Fujimoto
Kei
K
Sakuma
Toru
T
Ohashi
Toya
T
Fukuda
Kunihiko
K
Eto
Yoshikatsu
Y
Tajima
Naoko
N
D019943:Amino Acid Substitution; D002114:Calcinosis / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics*; D016022:Case-Control Studies; D003327:Coronary Disease / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics*; D003925:Diabetic Angiopathies / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics*; D005260:Female; D005838:Genotype; D005979:Glutathione Peroxidase / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D014057:Tomography, X-Ray Computed; D000094765:Glutathione Peroxidase GPX1