Genetic variants in glutamate cysteine ligase confer protection against type 2 diabetes.

Oxidative stress contributes to the pathogenesis of type 2 diabetes (T2D). This study investigated whether single nucleotide polymorphisms (SNPs) at genes encoding glutamate cysteine ligase catalytic (rs12524494, rs17883901, rs606548, rs636933, rs648595, rs761142 at GCLC) and modifier (rs2301022, rs3827715, rs7517826, rs41303970 at GCLM) subunits are associated with susceptibility to type 2 diabetes. 2096 unrelated Russian subjects were enrolled for the study. Genotyping was done with the use of the MassArray System. Plasma levels of reactive oxygen species (ROS) and glutathione in the study subjects were analyzed by fluorometric and colorimetric assays, respectively.The present study found, for the first time, an association of SNP rs41303970 in the GCLM gene with a decreased risk of T2D (P = 0.034, Q = 0.17). Minor alleles such as rs12524494-G GCLC gene (P = 0.026, Q = 0.17) and rs3827715-C GCLM gene (P = 0.03, Q = 0.17) were also associated with reduced risk for T2D. Protective effects of variant alleles such as rs12524494-G at GCLC (P = 0.02, Q = 0.26) and rs41303970-A GCLM (P = 0.013, Q = 0.25) against the risk of T2D were seen solely in nonsmokers. As compared with healthy controls, diabetic patients had markedly increased levels of ROS and decreased levels of total GSH in plasma. Interestingly, fasting blood glucose level positively correlated with oxidized glutathione concentration (rs = 0.208, P = 0.01). Three SNPs rs17883901, rs636933, rs648595 at GCLC and one rs2301022 at GCLM were associated with decreased levels of ROS, while SNPs rs7517826, rs41303970 at GCLM were associated with increased levels of total GSH in plasma. Single nucleotide polymorphisms in genes encoding glutamate cysteine ligase subunits confer protection against type 2 diabetes and their effects are mediated through increased levels of glutathione.

Glutathione S-transferase genes and the risk of type 2 diabetes mellitus: Role of sexual dimorphism, gene-gene and gene-smoking interactions in disease susceptibility.

BACKGROUND: Compromised defense against reactive oxygen species (ROS) is considered important in the pathogenesis of type 2 diabetes mellitus (T2DM); therefore, genes encoding antioxidant defense enzymes may contribute to disease susceptibility. This study investigated whether polymorphisms in genes encoding glutathione S-transferase M1 (GSTM1), T1 (GSTT1), and P1 (GSTP1) jointly contribute to the risk of T2DM. METHODS: In all, 1120 unrelated Russian subjects (600 T2DM patients, 520 age- and sex-matched healthy subjects), were recruited to the study. Genotyping was performed by multiplex polymerase chain reaction (PCR; del/del polymorphisms of GSTM1 and GSTT1) and TaqMan-based PCR (polymorphisms I105V and A114V of GSTP1). Plasma ROS and glutathione levels in study subjects were analyzed by fluorometric and colorimetric assays, respectively. RESULTS: Genotype del/del GSTT1 was significantly associated with the risk of T2DM (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.17-2.21, P = 0.003). Gender-stratified analysis showed that the deletion genotypes of GSTM1 (OR 1.99, 95% CI 1.30-3.05; P = 0.0002, Q = 0.016) and GSTT1 (OR 2.23, 95% CI 1.22-4.09; P = 0.008, Q = 0.0216), as well as genotype 114A/V of GSTP1 (OR 2.85, 95% CI 1.44-5.62; P = 0.005, Q = 0.02) were associated with an increased risk of T2DM exclusively in males. Three genotype combinations (i.e. GSTM1+ × GSTT1+, GSTM1+ × GSTP1 114A/A and GSTT1+ × GSTP1 114A/A) showed significant associations with a decreased risk of T2DM in males. CONCLUSIONS: This study demonstrates, for the first time, that genes encoding glutathione S-transferases jointly contribute to the risk of T2DM, and that their effects on disease susceptibility are gender specific.