β-Cell Autoimmunity, Genetic Susceptibility, and Progression to Type 1 Diabetes in Unaffected Schoolchildren

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Abstract
The current focus of the screening for individuals at risk for type 1 diabetes has moved from first-degree relatives to the general population. However, there is a shortage of data on the predictive utility of various risk markers in the background population in various countries, and predictive strategies for the general population remains open. We studied the frequency of diabetes-associated autoantibodies in a series of 3,652 unaffected Finnish school-children, and determined the relationships between autoantibodies and HLA-DQB1 risk markers. In addition, all subjects were observed for progression to type 1 diabetes. The reported frequencies of autoantibodies in the general population have varied widely. In the present study, the frequencies of ICA (islet cell antibodies), GADA (GAD antibodies), IA-2A (antibodies to IA-2 protein), and IAA (insulin autoantibodies) were 2.8, 0.5, 0.6, and 0.9%, respectively. Multiple antibodies (i.e., two or more) were detected in 21 children (0.6%), and 9 children (0.25%) had three or four antibody specificities in their initial blood sample. The present cut-off limits for antibody-positivity (determined as the 99th percentile in >370 healthy control subjects) are close to the 99.5th percentile for IA-2A and GADA and the 99.0th percentile for IAA in the present series of 3,652 children. The use of different approaches for the definition of cut-off limits (1,2) resulted in somewhat higher frequencies of autoantibodies, although this did not improve the diagnostic sensitivity of any autoantibody. These data illustrate the difficulties in defining borderline positivity …