Glutamic Acid Decarboxylase Antibodies in Screening for Autoimmune Diabetes: Influence of Comorbidity, Age, and Sex on Specificity and Threshold Values

Abstract

Antibodies against the 65-kDa isoform of glutamic acid decarboxylase (GAD65) can be applied as a predictive tool for childhood type-1 diabetes (1)(2)(3)(4)(5)(6) and to facilitate the differential diagnosis of diabetes in adults (7)(8)(9). However, the sensitivity and specificity of GAD antibody screening have not been fully characterized, and the positive predictive value of screening varies from 20% to 70%, depending on the strategy applied and the population studied (2)(3)(5)(6)(7)(9)(10)(11)(12). The current study aims to identify factors that may lead to false-positive results in GAD antibody screening. Previously, it has been demonstrated that the GAD antibody frequency in mixed connective tissue disease and stiff-man syndrome is increased, although not all patients who suffer from these diseases and are positive for GAD antibodies develop type-1 diabetes (13)(14). GAD is expressed in the islets of Langerhans, neuronal tissue, the ovaries, and the testes (15)(16). Similar to the above-mentioned examples, comorbidity involving these tissues may lead to GAD antibody formation but not to diabetes. Therefore, we compared the prevalence of GAD antibodies in patients with cystic fibrosis, epilepsy, Guillain-Barre syndrome, and premature ovarian failure to the prevalence in an unselected population of 1403 schoolchildren. In addition, thresholds for positivity for GAD antibodies have generally been defined in children. These thresholds might not be applicable when testing for type-1 diabetes in adults. Therefore, we studied whether GAD antibody concentrations are correlated to age and sex, and whether adjustment of assay thresholds to include these variables may improve screening specificity. The frequencies of positive results for GAD antibodies and the concentrations of GAD antibodies were established in a population of 1403 …