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Type 1 Diabetes Onset Preceded by Gene Expression Changes

NEW YORK – Gene expression changes in the blood appear to precede the onset of symptoms in children with type 1 diabetes, new research suggests, pointing to the possibility of predicting T1D development with blood tests in the future.

"Together, our results indicate that T1D is characterized by early and longitudinal changes in gene expression, informing the immunopathology of disease progression and facilitating prediction of its course," senior and corresponding author Eoin McKinney, a researcher affiliated with the Jeffrey Cheah Biomedical Centre and the University of Cambridge, and his colleagues wrote.

For their study, published Wednesday in Science Translational Medicine, members of the Environmental Determinants of Diabetes in the Young (TEDDY) consortium used arrays to profile the transcriptome of more than 2,000 peripheral blood samples collected over time from 401 children from birth to age 15 who went on to develop either islet autoimmunity or T1D.

Using transcriptional network analyses, gene expression-based immune cell type frequency predictions, and other approaches, they went on to compare the samples with one another and with those from unaffected, age-matched controls, leading to a presymptomatic autoimmune signature in affected children that appeared to reflect enhanced natural killer (NK) cell activity.

In developing the age-independent model for predicting T1D and islet autoimmunity, the investigators also teased apart the gene expression profiles present in children who went on to develop each condition. They also characterized the gene expression shifts corresponding to specific endotypes of T1D, including a fast-progressing form of the disease involving autoantibodies that target insulin and a form with autoantibodies that target the glutamic acid decarboxylase enzyme in the pancreas.

"We know that autoimmune destruction of the pancreas that causes T1D can last years before diagnosis," McKinney explained in an email. "However, we are currently unable to treat the disease process, primarily because we can't measure it."

In contrast, the team's findings suggested that detecting gene expression changes in the first 18 months of a child's life could eventually help in finding and perhaps treating children who are on track to develop T1D or pancreatic islet beta-cell autoimmunity — marked by gradual islet cell autoantibody (IAbs) seroconversion — before symptoms develop.

Such early identification "is fundamentally necessary to allow earlier treatment of the pre-symptomatic T1D, the period in which stopping the autoimmune process is most likely to be successful," McKinney said.

"We have demonstrated and validated an association of NK cell gene expression signature with T1D progression," he and his co-authors reported. "It remains to be determined whether this change reflects a causal contribution to T1D-related immunopathology, a host response to an infectious trigger, or both. An answer to this fundamental question will require further analyses and more detailed investigation of prospective data and samples."

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