Glutathione related enzyme gene polymorphisms and type 1 diabetes

Type 1 diabetes mellitus (T1D) is an autoimmune disease involving pancreatic beta-cell destruction by immune effector cells and is associated with autoantibodies to islet cell autoantigens such as GAD65, IA-2 and insulin. Glutathione (GSH) protects against reactive oxygen species (ROS)-mediated cell injury in response to a variety of toxicants, maintains the thiol status of proteins, and is important for immune response and cytokine production. Peripheral blood GSH levels are depleted in many diseases such as coronary artery disease, Parkinson's disease and in diabetes. In this investigation we hypothesized that enzymes important to GSH homeostasis may be susceptibility factors for T1D. These enzymes include glutamate-cysteine ligase catalytic (GCLC) subunit (rate limiting for GSH biosynthesis), glutamate-cysteine ligase modifier (GCLM) subunit, and the glutathione-s-transferases, mu (GSTM1) and theta (GSTT1), which conjugate GSH to various endogenous and exogenous compounds. To determine if polymorphisms in these GSH related pathway genes are associated with patient age-at-onset, gender or autoantibodies, we genotyped T1D patients (ages 0--35 years) and age-matched control subjects from Sweden. The results indicate that GSH related pathway gene polymorphisms may contribute to either the risk of developing autoantibodies, T1D, or both. The GCLC trinucleotide repeat (TNR) polymorphism may be most important in T1D female patients and in patients with an earlier age-at-onset. The GCLC -129 SNP may be associated with increased GAD65 autoantibody levels in delayed age-at-onset T1D patients, the GCLM -588 SNP may be associated with gender differences in T1D but more investigation is needed and the GSTM1 has a negative association with T1D in 14--20 year olds. The GSTT1 polymorphism was not found to be associated with T1D. Taken together these results suggest that GSH synthesis and GST mediated GSH conjugation may play an important role in T1D risk.