title: Glutamate cysteine ligase catalytic subunit promoter polymorphisms and associations with type 1 diabetes age-at-onset and GAD65 autoantibody levels.
abstract: The purpose of this study was to test the hypothesis that glutamate cysteine ligase catalytic subunit (GCLC) promoter polymorphisms are susceptibility factors for type 1 diabetes (T1D), T1D age-at-onset and T1D autoantibodies. T1D patients and control subjects from the Swedish Childhood Diabetes Registry and the Swedish Diabetes Incidence Study registry were genotyped for two GCLC promoter polymorphisms; the GCLC -129 C to T single nucleotide polymorphism (GCLC -129 SNP) and the GCLC GAG trinucleotide repeat polymorphism (GCLC TNR). Glutamate decarboxylase antibody (GAD65Ab) positive T1D patients with the GCLC -129 SNP C/T genotype have increased GAD65Ab levels (p-value, <0.05) compared to the GCLC -129 SNP C/C genotype. T1D patients with an age-at-onset of 14-35 years who possess the GCLC -129 SNP T/T genotype have a higher GAD65Ab index than T1D patients with the GCLC -129 SNP C/C genotype (p-value <0.05). In addition, T1D patients with an age-at-onset of 14-35 years possess the GCLC TNR 7/8 genotype at a lower frequency than the control subjects (OR, 0.33, 95% CI, 0.13-0.82). The GCLC -129 SNP and GCLC TNR appear to be in linkage disequilibrium (p-value<0.0001). These results suggest that GCLC promoter polymorphisms may influence GAD65Ab levels and may influence the age at which T1D is diagnosed.
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Bekris
authors.forename: C
authors.initials: C
authors.lastname: Shephard
authors.forename: M
authors.initials: M
authors.lastname: Janer
authors.forename: J
authors.initials: J
authors.lastname: Graham
authors.forename: B
authors.initials: B
authors.lastname: McNeney
authors.forename: J
authors.initials: J
authors.lastname: Shin
authors.forename: M
authors.initials: M
authors.lastname: Zarghami
authors.forename: W
authors.initials: W
authors.lastname: Griffith
authors.forename: F
authors.initials: F
authors.lastname: Farin
authors.forename: T J
authors.initials: TJ
authors.lastname: Kavanagh
authors.forename: A
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; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000276:immunology*; D005721:Glutamate-Cysteine Ligase / Q000235:genetics*; D006801:Humans; D007223:Infant; D007527:Isoenzymes / Q000276:immunology*; D008297:Male; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic
chemical_list: D001323:Autoantibodies; D007527:Isoenzymes; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2; D005721:Glutamate-Cysteine Ligase