The combination of antibodies to GAD-65 and IA-2ic can replace the islet-cell antibody assay to identify subjects at risk of type 1 diabetes mellitus

First-degree relatives of type 1 diabetic patients are at increased risk of developing diabetes and, until recently, islet cell antibodies (ICA) have represented the major risk marker used for identification of individuals at increased risk for subsequent progression to diabetes. In order to determi ne the value of antibodies to GAD-65 and IA-2ic to identify individuals at high risk for type 1 diabetes mellitus, we measured both autoantibodies and ICA in 1436 first-degree relatives of patients with type 1 diabetes. In ad dition, the sera were analyzed for thyroid, adrenal and gastric-parietal ce ll autoantibodies as markers for possible polyendocrine involvement. GAD-65 Abs were found in 135 out of 1436 (9.4%) first-degree relatives and in 57 of 98 (58.2%) ICA-positive subjects. IA-2ic were detected in 52 of 1436 (3. 6%) first-degree relatives and in 44 of 98 (44.8%) ICA-positive relatives. IA-2ic and/or GAD-65 were detected in 73 of 98 (74.5%) ICA-positive relativ es. Interestingly, antibodies to GAD-65 and/or IA-2ic were present in 91.2% of individuals with more than 20 JDF-units. Anti-IA-2ic and GAD-65 were po sitively correlated with high levels of ICA. Anti-IA-2ic and GAD-65 were fo und in 19% and 48.5% of subjects with ICA levels of 5-20 JDF-u but in 68.8% and 76.5% of individuals with ICA of 40 JDF-u or more, respectively (p < 0 .001), compared to subjects with ICA levels less than 5 JDF-u. When autoant ibody frequencies among the relatives were analyzed according to relationsh ip to the proband, the offspring and siblings had a higher frequency of ICA and IA-2ic (p < 0.05) than the subgroup of parents. A significant associat ion was observed between IA-2ic and thyroid antibodies. In addition, higher levels of IA-2ic were found in relatives with positive TPO antibodies (p < 0.001); this correlation was particularly strong in offspring and siblings (p < 0.01). Determination of GAD-65 and IA-2ic antibodies may be considere d as an alternative to primary ICA-screening, enabling the screening of lar ge populations.