Early Changes in Gene Expression Observed Pre-Diagnosis in Type 1 Diabetes

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Research from an international study shows that children who go on to develop type 1 diabetes have distinct changes in gene expression before they develop the condition.

Currently, islet autoimmunity—a measure of autoantibodies in the blood against pancreatic beta cells—is used to assess how likely someone is to develop type 1 diabetes, as it tends to be a precursor to the condition.

But the researchers in this study showed that abnormal gene expression changes can occur even before islet autoimmunity is present from months to years before type 1 diabetes is diagnosed. This finding could help predict who is most likely to progress to full-blown diabetes and raises the possibility of early intervention in these individuals if effective preventative treatments can be developed.

As reported in the journal Science Translational Medicine, Eoin McKinney, M.D., Ph.D., a senior researcher at the University of Cambridge who led the study, and colleagues tested blood samples from 400 children enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) consortium.

TEDDY is an ongoing study searching for gene-environment interactions that could lead to the development of type 1 diabetes in infants that are already at high risk (eg. due to family history).

The researchers carried out transcriptomics analysis on 2013 blood samples taken between birth and 5 years from the 400 children in the study. Of the children, 62 have developed type 1 diabetes since birth.

The researchers found that gene expression in children who went on to develop type 1 diabetes or islet autoimmunity differed from those that did not. The exact nature of the expression signatures differed depending on whether the first appearing islet autoantibody was IAAs (against insulin) or GADA (against glutamic acid decarboxylase).

They found a natural killer (NK) cell-based signature linked to disease onset. This signature increased in expression as the children moved closer to islet autoimmunity and type 1 diabetes in those whose first islet autoantibody was IAAs. Similarly, in those whose first autoantibody was GADA, this signature was linked to time to islet autoimmunity, but not type 1 diabetes. The team also found a very similar signature in a separate validation cohort of older children.

“Our identification of specific changes in the blood related to natural killer cells provides evidence for the potential involvement of these immune cells in the onset or progression of type 1 diabetes in asymptomatic children,” said Hemang Parikh, Ph.D., an assistant professor at University of San Francisco’s Health Morsani College of Medicine, and study co-author. “This creates a possible new target for early therapeutic intervention using immune modulation.”

The study authors are now researching this NK signature further to confirm their results and to try and determine how causal these changes are.

“It remains to be determined whether this change reflects a causal contribution to type 1 diabetes 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,” they conclude.

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