Potential risk modifications of GSTT1, GSTM1 and GSTP1 (glutathione-S-transferases) variants and their association to CAD in patients with type-2 diabetes

Abstract

Background: Type-2 diabetes mellitus (T2DM) is a major risk factor for coronary artery disease (CAD) resulting in high morbidity and mortality. Glutathione S-transferases (GSTM1, GSTT1 and GSTP1) are known for their broad range of detoxification and in the metabolism of xenobiotics. Recent studies revealed the relationship of GSTs variants with T2DM and CAD. In this case-control study we ascertained the association of GSTs variants in association with the development of CAD in patients with T2DM.

Methods: From the Southern part of India, we enrolled 222 T2DM patients, 290 T2DM patients with CAD and 270 healthy controls matched for age, sex and origin. Serum lipid profiles were measured and DNA was extracted from the blood samples. Multiplex PCR for GSTM1/T1 (null polymorphism) and PCR-RFLP for GSTP1 (105 A>G), were performed for genotyping of study participants. Gene frequency and lipid profiles were statistically analyzed for disease association.

Results: Regression analysis showed that, GSTM1-null genotype is associated with a 2-fold increase (OR=2.925; 95% CI=2.078-4.119; P<0.0001) and GSTT1-null genotype is associated with a 3-fold increase (OR=3.114; 95% CI=2.176-4.456; P<0.0001) to T2DM development. Ile/Val and Val/Val genotypes of GSTP1 also showed a significant risk for T2DM (OR=1.423, CI=1.041-1.946; P=0.027 and OR=1.829, CI=1.064-3.142; P=0.029). Increased odds ratio showed that GSTT1-null genotype had a moderately higher occurrence in T2DM-CAD patients (OR=1.918, 95% CI=1.144-3.214; P=0.014) than T2DM patients without CAD. The level of HDL has significantly decreased in GSTT1-present than in GSTT1-null genotype (43.50±4.10 vs. 45.20±3.90; P=0.004) when compared with control and T2DM patients. However, LDL level showed a significant increase in GSTT1-null than GSTT1-present genotype (108.70±16.90 vs. 102.20±12.60; P=0.005). Although the GSTM1-null polymorphism showed no correlation with lipid profiles among T2DM and T2DM with CAD patients, GSTT1-null polymorphism attained a statistical significance for the level of LDL (127±28.20 vs. 134±29.10; P=0.039) and triglycerides in T2DM with CAD patients (182.10±21.10 vs. 191.20±24.10; P=0.018).

Conclusion: Our work concludes that GSTM1, GSTT1 and GSTP1 variants might contribute to the development of T2DM and GSTT1 variant alone is involved in the development of T2DM associated CAD complications in the South Indian population.