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Genetic Signatures Help Predict Risk of Type 1 Diabetes in Children

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The research may suggest new therapies for children at the earliest stages of type 1 diabetes. | iStock

A team of scientists has discovered certain patterns in genes and the immune system that precede the onset and progress of type 1 diabetes, according to their study of 400 children.

Their discovery was published in the March 31 issue of Science Translational Medicine. The work yields important information about how the immune system contributes to the early stages of type 1 diabetes (T1D), whose exact mechanisms have eluded researchers for years.

The scientists also developed a model that could predict the onset of the disease in another group of children. Although more work is needed, the results could pave the road for clinicians to administer more effective treatments and interventions during the early stages of type 1 diabetes.

"We use[d] early changes in [gene expression] patterns to predict when type 1 diabetes will be diagnosed," said Eoin McKinney, a researcher at the University of Cambridge, United Kingdom, and senior author of the new study. "Only by accurately predicting when disease will occur can new treatments be found and tested in children at the earliest stages of the autoimmune process."

Type 1 diabetes is one of the two major types of diabetes, and typically unfolds during childhood or infancy. Unlike type 2 diabetes, type 1 diabetes is autoimmune in nature, meaning it results from the actions of the body's own immune system.

In children with type 1 diabetes, the immune system runs amok and starts destroying cells that secrete insulin in regions of the pancreas called islets, according to the study. The ensuing damage cripples the body's ability to produce insulin, which people depend on to control levels of blood sugar in the blood.

Type 1 diabetes imposes a major health and financial burden on affected patients, who deal with severe complications such as ketoacidosis and must continue to receive treatments for the rest of their lives to manage symptoms.

Getting to the Roots of Type 1 Diabetes

Scientists hope that intervening with therapies during the disease's earliest stages could alleviate some of this burden and relieve complications. However, early intervention depends on having a method that can predict when and how the disease might appear in high-risk individuals.

Investigators have made substantial progress in understanding the early signs of type 1 diabetes. For example, labs have created genetic risk scores that can help identify newborns with a higher risk of the disease. Recent studies have also showed that patients often display signs of autoimmunity in pancreatic islets for months or even years before diagnosis.

However, the earliest stages of the disease remain murky, according to McKinney. Researchers still don't know exactly what events trigger immune cells to target cells in the pancreas in the first place. Progress has also been slowed by the difficulty of collecting and analyzing enough samples from infants and young children.

Another puzzle centers on autoantibodies, which are secreted by immune cells and inflict much of the damage on the pancreas. Children with more autoantibodies against the pancreas have a higher risk of progressing to type 1 diabetes, but this information alone hasn't allowed scientists to predict when that person might actually develop the disease, McKinney said.

To tackle this challenge, Louis-Pascal Xhonneux, a Ph.D. student at the University of Cambridge and lead author of the new study, and colleagues turned to the TEDDY consortium, a prospective study that examines how genetic and environmental factors might shape type 1 diabetes.

The TEDDY study gathers samples from at-risk individuals from birth, which gave the team enough information to model and analyze patterns in genetic and immune activity in very young children before the autoimmune process had even begun, McKinney said.

A Key Immune Player Revealed

The researchers began by analyzing gene expression data in blood samples from 400 children in the TEDDY study before they had received a diagnosis of type 1 diabetes or showed signs of islet autoimmunity. By comparing changes in these patterns to genetic activity in healthy children, the team was then able to pinpoint patterns unique to the pre-diabetic children.

One of the biggest findings was the fact that the children showed extensive changes in the activity of genes in cells such as natural killer cells — a type of immune cell — before islet autoimmunity.

"By correcting for these changes, we can see very specific patterns that are only seen in children who go on to get T1D or islet autoimmunity. We interpret these changes, working out what the patterns mean, to pinpoint … natural killer cells as being important in these early stages," McKinney said.

Xhonneux's group then incorporated these signatures along with parameters such as the status of islet autoantibodies in a model, which they tested with 356 samples from a separate group of 56 children. The scientists found their model could help predict the risk of type 1 diabetes in a given individual over the course of the next 12 months.

"This creates the potential for early monitoring of at-risk infants for T1D onset, facilitating the prevention of severe complications such as ketoacidosis, effective trialing of preventive therapies, or the identification of targets for immunomodulation," the authors say.

McKinney stressed that treating any autoimmune process is more feasible if done early, rather than late. He likened treating type 1 diabetes after it's been diagnosed to putting out a house that's already on fire, while targeting early autoimmunity would be akin to extinguishing the match that caused the fire.

Scientists still face several obstacles in their efforts to treat type 1 diabetes earlier in life. Not everyone who shows autoimmunity ends up developing the disease, McKinney noted. Clinicians must therefore have a strong reason to intervene before a diagnosis with immune treatments, which carry risks and side effects.

"So there is an inevitable trade-off: we can be more confident that disease will develop if we allow autoimmunity to progress further before treating, but we are more likely to be effective if we intervene earlier," he said.

However, methods to predict the course of autoimmunity could help smooth this trade-off. McKinney said that several collaborations are now underway, and his team calls for further studies of prospective data and samples to bring these methods within reach.