Children whose mothers have type 1 diabetes develop the disease at about half the rate of children whose fathers have it. Inherited genetic risk alone does not explain this long-observed maternal effect, according to a study led by researchers at the University of Colorado Anschutz and published in Diabetes Care. The findings point to other possible biological mechanisms that warrant further investigation.
Researchers analyzed 6,942 children in The Environmental Determinants of Diabetes in the Young (TEDDY) study, which followed children at increased genetic risk for type 1 diabetes from infancy into adolescence.
Researchers also examined a long-standing question: Could pregnancy loss help explain why children whose mothers have type 1 diabetes develop the disease less often?
“For decades, this relative maternal protection effect has been consistently observed across studies of living offspring of people with type 1 diabetes. One long-standing but unproven explanation is that this relative protection is an artefact resulting from the selective loss of pregnancies involving the highest-risk offspring,” said Randi K. Johnson, PhD, MPH, associate professor of biomedical informatics at the CU Anschutz School of Medicine and senior author of the study. “Advancements in genetics allowed us to comprehensively examine this phenomenon in the largest prospective cohort study of type 1 diabetes in the world.”
Genetic Risk Does Not Explain the Difference
Researchers compared children's inherited genetic risk for type 1 diabetes using an extended genetic risk score. They found no significant difference in the genetic risk score between children whose mothers had type 1 diabetes and those whose fathers had the disease.
Despite similar genetic risk scores, children of affected mothers developed type 1 diabetes at about half the rate during the study. They also had a lower risk of developing islet autoimmunity, an early sign of immune system activity against the insulin-producing cells of the pancreas that precedes a type 1 diabetes diagnosis.
The Effect Changes With Age
Researchers found that the reduction in islet autoimmunity among children of affected mothers disappeared after age 6. The study also found no evidence that these children progressed more slowly to a type 1 diabetes diagnosis after developing islet autoimmunity.
“Our age-specific analysis shows that the maternal protective effect operates in early life, during the initiation of preclinical type 1 diabetes. The fact that the effect wanes rather than staying constant points future research toward more dynamic mechanisms,” said Sarah D. Slack, senior information science professional in the Department of Biomedical Informatics at CU Anschutz and lead author of the study.
Opening New Avenues for Prevention
Although the study does not identify the cause of maternal protection or establish pregnancy as its direct source, the findings challenge the hypothesis that pregnancy loss explains the phenomenon and point toward other possible explanations.
“Our goal is to find ways to prevent type 1 diabetes from occurring. Establishing that the relative maternal protection in type 1 diabetes is not an artefact of pregnancy survival tells us that there may be some mechanism at work in a type 1 diabetes pregnancy that confers a benefit to the offspring. Our next task is to find and understand that mechanism so we can develop solutions that might mimic that benefit for all children,” said Johnson.
Epigenetic changes are one possible biological mechanism under investigation by Johnson and team. Epigenetic changes affect how genes are switched on or off without changing the underlying DNA sequence. These changes can be influenced by factors during pregnancy and early life.
The study was supported by a grant from The Leona M. and Harry B. Charitable Trust.
“Helmsley supports this important work because we are committed to developing strategies to prevent or delay the development of type 1 diabetes, including through identifying factors underlying maternal protection,” said Maryaline Coffre, Program Officer at Helmsley.
Identifying the mechanisms behind maternal protection could help researchers determine whether early-life biological processes offer opportunities to prevent or delay type 1 diabetes.
Key Points
- Children whose mothers have type 1 diabetes developed the disease at about half the rate of children whose fathers have the condition.
- Researchers analyzed 6,942 children enrolled in the TEDDY study, which follows children at increased genetic risk for type 1 diabetes.
- Inherited genetic risk did not differ significantly between children of affected mothers and children of affected fathers.
- The maternal protective effect was most evident during early childhood and diminished after age 6.
- Findings challenge the theory that pregnancy loss explains the difference and point toward other possible biological mechanisms.
- Understanding maternal protection could help researchers identify new ways to prevent or delay type 1 diabetes in children.
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