title: Glutathione-s-transferase M1 and T1 polymorphisms and associations with type 1 diabetes age-at-onset.
abstract: Type 1 diabetes (T1D) is an autoimmune disease characterized by pancreatic beta cell destruction involving auto-reactive T-cells, pro-inflammatory cytokines, reactive oxygen species (ROS) and loss of insulin. Monozygotic twin studies show a 20-60% concordance with T1D indicating there may be an environmental component to the disease. Glutathione (GSH) is the major endogenous antioxidant produced by the cell. GSH participates directly in the neutralization of free radicals and plays a role in the immune response. Glutathione-s-transferases (GSTs) conjugate GSH to free-radicals or xenobiotics. GST activity depletes GSH levels and may either detoxify or enhance the toxicity of a compound. Glutathione-s-transferase mu 1 (GSTM1) and glutathione-s-transferase theta 1 (GSTT1) have polymorphic homozygous deletion (null) genotypes resulting in complete absence of enzyme activity. GSTM1 and GSTT1 null genotypes in Caucasian populations have frequencies of approximately 40-60% and 15-20%, respectively. GST null genotypes have been associated with susceptibility to cancer and protection against chronic pancreatitis. The aim of this study was to investigate associations with GSTM1 and GSTT1 polymorphisms in a group T1D patients and control subjects 0-35 years old who participated in the Combined Swedish Childhood Diabetes Registry and Diabetes Incidence Study (1986-1988). Results show that the presence of the GSTM1 and not the null genotype (OR, 2.13 95% CI, 1.23-3.70, p-value, 0.007, Bonferroni corrected p-value, 0.035) may be a susceptibility factor in T1D 14-20 years old. These results suggest that the GSTM1 null genotype is associated with T1D protection and T1D age-at-onset and that susceptibility to T1D may involve GST conjugation.
authors.affiliation: Department of Environmental and Occupational Health Sciences, University of Washington, Box 357710, Seattle, WA 98195, USA. lbekris@u.washington.edu
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Bekris
authors.forename: Cindy
authors.initials: C
authors.lastname: Shephard
authors.forename: Morgan
authors.initials: M
authors.lastname: Peterson
authors.forename: Jana
authors.initials: J
authors.lastname: Hoehna
authors.forename: Brian
authors.initials: B
authors.lastname: Van Yserloo
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Rutledge
authors.forename: Federico
authors.initials: F
authors.lastname: Farin
authors.forename: Terrance J
authors.initials: TJ
authors.lastname: Kavanagh
authors.forename: Ake
authors.initials: A
authors.lastname: Lernmark
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D001323:Autoantibodies / Q000097:blood; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology; D005982:Glutathione Transferase / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007527:Isoenzymes / Q000276:immunology; D008297:Male; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012737:Sex Factors
chemical_list: D001323:Autoantibodies; D000949:Histocompatibility Antigens Class II; D007527:Isoenzymes; D005982:Glutathione Transferase; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2