Glutamic acid decarboxylase antibodies in relation to other autoantibodies and genetic risk markers in children with newly diagnosed insulin-dependent diabetes

To study the frequency of antibodies to glutamic acid decarboxylase (GAD65A) at the diagnosis of insulin-dependent diabetes mellitus (IDDM) and to evaluate the relation of these antibodies to other IDDM-associated autoantibodies and genetic risk markers of the disease, we analyzed 747 newly diagnosed diabetic children younger than 15 yr of age (mean, 8.4 yr) for GAD65A, islet cell antibodies, insulin autoantibodies, and human leukocyte antigen DR alleles. GAD65A were detected in 73.2% of the children, with a higher frequency in females than in males (77.1% vs. 70.1%; P = 0.04) and in index cases aged 10 yr or older than in younger children (79.0% vs. 68.7%; P = 0.004). The index cases positive for GAGD65A had higher levels of islet cell antibodies (median, 40 vs. 34 Juvenile Diabetes Foundation units; P = 0.003) and insulin autoantibodies (median, 55 vs. 43 nU/mL; P = 0.03) than those testing negative for GAD65A. Human leukocyte antigen DR3/non-DR4 children had the highest GAD65A levels, whereas DR2-positive cases had levels of GAD65A similar to those found in other subjects. One third of the index cases (33.9%) tested positive for all three autoantibodies, 43.1% for two antibodies, and 18.2% for one antibody, whereas 4.8% were triple negative. The females had multiple antibodies (at least two antibodies) more often than the males (81.3% vs. 73.5%; P = 0.01). There was a significant trend for a higher frequency of multiple antibodies in young children (83.0% in those under 5 yr and 73.2% in those 10 yr or older; P = 0.02) and a higher frequency in DR3/4 heterozygous children than in those with DR3/non-DR4 (83.3% vs. 63.2%; P = 0.02). The results show that GAD65A antibodies are more frequent in girls and adolescents with newly diagnosed IDDM and suggest that DR3/non-DR4 subjects have increased GAD65A levels. Multiple antibodies in diabetic children are associated with young age, female sex, and DR3/4 heterozygosity.