TEDDY data highlight complexities of pediatric diabetes triggers
medwireNews: Researchers speaking at the ADA’s 78th Scientific Sessions in Orlando, Florida, USA, have presented data from The Environmental Determinants of Diabetes in the Young (TEDDY) study that begin to shed light on genetic and environmental triggers of pediatric type 1 diabetes.
TEDDY investigator Jeffrey Krischer, from the University of South Florida in Tampa, USA, said the findings presented in the 2-hour symposium “will change the conversation about diabetes in youth.”
The TEDDY study is following 8676 children in four countries from birth to 15 years of age who are at increased risk for diabetes. The children currently have a median age of 10.3 years and data collection is ongoing.
Krischer showed data suggesting that there are two different diabetes-related endotypes defined by whether insulin autoantibodies (IAA) or glutamic acid decarboxylase antibodies (GADA) appear first.
Developing IAA autoimmunity first was more likely to occur at a significantly younger age (<2 years) and was associated with a significantly increased likelihood of having an HLA-DR4/8 cell type and a significantly decreased likelihood of having an HLA-DR3/3 cell type.
By contrast, children who developed GADA autoimmunity first were significantly more likely to be older than 6 years, and significantly more likely to have an HLA-DR3/3 cell type.
Children with IAA first develop type 1 diabetes significantly earlier than those with GADA first, but Krischer suggested that this is simply because IAA appear at a younger age.
He concluded that “genetic background, environmental risk factors, and type 1 diabetes risk differ when comparing these endotypes,” but added that the ability to predict who will develop IAA versus GADA autoimmunity is currently limited.
Kristian Lynch, also from The University of South Florida, used the TEDDY data to show that although gestational infections were not associated with first appearing autoantibodies overall, there was a significant interaction among children with HLA-DR4/8 and HLA DR3/3 cell types.
Specifically, not reporting a respiratory tract infection during pregnancy was associated with a significantly increased risk for developing IAA first in children with the HLA-DR4/8 cell type (hazard ratio [HR]=2.07) and a significantly increased risk for developing GADA first in those with the HLA-DR3/3 cell type (HR=1.61).
He also found that children with the CTLA-4 AG/GG polymorphism were less likely to develop IAA first and more likely to develop GADA first when a maternal respiratory infection was reported, irrespective of HLA type.
Lynch said the findings “suggest that gestational events such as respiratory infections interact with CTLA-4, a well-known T-cell regulatory protein, to influence how DR4-DQ8 or DR4-DQ2 react to a hypothetical trigger during the first years of life.”
Maria Lönnrot, from The University of Tampere in Finland, showed that gastrointestinal infections during the first year of life also modulate the risk for autoimmunity. In this case, such infections were associated with a decreased likelihood of IAA appearing first (odds ratio [OR]=0.6) and an increased likelihood of GADA appearing first (OR=1.5).
By contrast, Jill Norris, from Colorado School of Public Health in Aurora, USA, and team found that neither maternal vitamin D nor omega-3 fatty acid supplement use during pregnancy was associated with the risk for islet autoimmunity overall or according to whether IAA or GADA appeared first.
The final study looked at how a family history of any type of diabetes affects the development of autoimmunity and progression to type 1 diabetes.
Riitta Veijola, from the University of Oulu in Finland, showed that a family history of type 1 diabetes, specifically in the father or a sibling but not the mother, was associated with an increased risk for the development of islet autoimmunity.
By contrast, type 2 diabetes in a second degree relative was associated with a significantly reduced risk for progression from autoimmunity to type 1 diabetes (HR=0.61).
She said this novel finding could be because “type 2 diabetes susceptibility genes may affect the progression phase of type 1 diabetes or because families with second degree relatives with type 2 diabetes may modify their lifestyle to prevent type 1 diabetes.”
By Laura Cowen
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