Glutamate Cysteine Ligase Catalytic Subunit Promoter Polymorphisms and Associations with Type 1 Diabetes Age-at-onset and GAD65 Autoantibody Levels

L. M. Bekris; C. Shephard; M. Janer; J. Graham; B. McNeney; J. Shin; M. Zarghami; W. Griffith; F. Farin; T. J. Kavanagh; A. Lernmark

doi:10.1055/s-2007-970574

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2007; 115(4): 221-228
DOI: 10.1055/s-2007-970574

Article

Glutamate Cysteine Ligase Catalytic Subunit Promoter Polymorphisms and Associations with Type 1 Diabetes Age-at-onset and GAD65 Autoantibody Levels

L. M. Bekris¹ ^, ² , C. Shephard² ^, ⁴ , M. Janer⁵ , J. Graham³ , B. McNeney³ , J. Shin³ , M. Zarghami¹ , W. Griffith² , F. Farin² ^, ⁴ , T. J. Kavanagh² ^, ⁴ , A. Lernmark¹

¹Department of Medicine, University of Washington, Seattle, WA
²Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA
³Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, B.C., Canada
⁴UW/NIEHS Center for Ecogenetics and Environmental Health, University of Washington, Seattle, WA
⁵Institute for Systems Biology, Seattle, WA

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.

Key words

type 1 diabetes - GCLC - promoter polymorphisms - glutathione

Full Text

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Correspondence

L. M. Bekris

Department of Medicine

University of Washington

Box 358280

Seattle

WA 98195

Phone: +206/277/64 55

Fax: +206/543/31 69