Polymorphic Variants in gamma-glutamyltransferase 6 as New Genetic Markers of Type 2 Diabetes Mellitus

Abstract

Background: Deficiency in glutathione and overproduction of reactive oxygen species are the key features of type 2 diabetes (T2D) pathogenesis. Objective: The aim of this work was to study the associations of polymorphic variants rs11657054 (A>G) and rs2100986 (T>C) in the gamma-glutamyltransferase 6 (GGT6) gene with parameters of glucose and redox homeostasis of blood plasma and the risk of developing T2D in residents of Central Russia. Methods: The study included 1562 patients with T2D and 1575 healthy volunteers. Genotyping of the GGT6 gene polymorphisms was performed with the use of MassArray Analyzer 4 mass spectrometer (Agena Bioscience). Results: Analysis of the parameters of redox homeostasis revealed an increase in the concentration of hydrogen peroxide and a decrease in the level of total glutathione in the plasma of patients with T2D compared with the control group (P<0.05). The level of hydrogen peroxide in patients was directly proportional to the concentration of their fasting blood glucose (rs =0.54, P<0.05) and inversely proportional to the level of glutathione (rs=-0.41, P<0.05). We have also established the associations of genotypes A/G-G/G rs11657054 (OR1.19, 95CI 1.01-1.40, P=0.035) and genotypes T/C-C/C rs2100986 (OR1.22, 95CI 1.03-1.44, P=0.019) with an increased risk of T2D in patients with overweight and obesity. According to GTEx Portal data, minor alleles of rs11657054-G and rs2100986-C are associated with decreased GGT6 expression in the pancreas. Conclusion: Our findings strongly suggest that SNPs rs11657054 (A>G) and rs2100986 (T>C) in the GGT6 gene are new genetic markers of increased risk of T2D.