Autoantibody order, timing predict genetically at-risk child
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Children with multiple islet autoantibodies—biological markers of autoimmunity—are more likely to progress to symptomatic type 1 diabetes (T1D) than those who remain positive for a single autoantibody.

Now, new findings from The Environmental Determinants of Diabetes in the Young (TEDDY) study in the U.S. and Europe show that detailed information about the order, timing and type of autoantibodies appearing after the first autoantibody can significantly improve prediction of which children are most likely to progress to type 1 diabetes more rapidly.

For this TEDDY analysis, eligible children with increased genetic risk for T1D, were followed every three months, from the age of 3 months up to 15 years, for the development of a first-appearing autoantibody directed against pancreatic insulin-producing cells: glutamic acid decarboxylase antibody (GADA), insulin autoantibody (IAA), or insulinoma-associated-protein-2 autoantibody (IA2-2A).

The researchers also looked for the subsequent appearance of a second autoantibody and further progression to T1D. Zinc transporter 8 autoantibody(ZnT8A) was only measured in children who developed an IAA, GADA, or IA-2A. These four different autoantibodies are so far the most reliable biological indicators of early T1D, before symptoms become apparent.

Of the 608 study participants—all testing positive for either a first-appearing IAA or GADA—more than half (336) developed a second autoantibody. Furthermore, 53% of these 336 children with a second antibody progressed to T1D within about 3.5 years. Only about 10% of the 272 children testing positive for a single autoantibody at the end of the follow-up for this study had transitioned to T1D.

Among the key study findings:

-- All study participants had high-risk genotypes for T1D. However, those increased-risk children who also had a parent or sibling with T1D were more likely to develop a second-appearing autoantibody than those without a family history.
-- The younger the child at the time they tested positive for a first autoantibody, the greater their risk for developing a second autoantibody. Conversely, the risk for T1D decreased if the first autoantibody appeared when the child was older.
-- Children testing positive for a second autoantibody, regardless of the type, had at least a five-fold increased risk of progressing to T1D, compared to children who stayed single autoantibody positive. IA-2A, as a second autoantibody, conferred the highest risk, compared with GADA, IAA, or ZnT8A.
-- Risk of progression to T1D was influenced by how quickly the second autoantibody appeared. Emergence of a second autoantibody within a year of the first doubled the risk of progression to T1D. Children's likelihood of developing T1D declined as the months between the first and second-appearing autoantibodies increased.

Better stratifying the risk of progression from the start of autoimmunity to symptomatic disease could help diagnose T1D earlier and offers the opportunity to prevent diabetic ketoacidosis (DKA) and its serious complications by educating parents to watch for early signs, researchers said.