Type 1 Diabetes: Risk Differs Depending on Affected Family Member
Type 1 diabetes is an autoimmune disease in which the immune system destroys the body's own insulin-producing beta-cells in the pancreas, leaving patients with a lifelong dependency on external insulin. Children whose parents or siblings have type 1 diabetes have an 8- to 15-fold increased risk of developing the autoimmune disease themselves. However, this risk is not evenly distributed: the child of a mother with type 1 diabetes has a lower risk of developing type 1 diabetes than a child with a father or sibling with type 1 diabetes. Of interest, genetic susceptibility to type 1 diabetes has been shown to be comparable between the offspring of mothers and the offspring of fathers with type 1 diabetes. Therefore, researchers suspected that early-life epigenetic programming may be a key mechanism through which maternal type 1 diabetes confers a protective effect.
Epigenetic mechanisms such as DNA methylation determine which genes are ultimately read and expressed. By changing DNA methylation patterns, environmental influences in the womb such as smoking by the mother, medical conditions, stress, or diet can have far-reaching effects on a child's health by switching genes on or off in the early life period and later in life. Hence, specific environmental conditions in the womb of a mother with type 1 diabetes, the so-called intrauterine environment, may influence the child's risk for islet autoimmunity through epigenetic modifications.
Blood Methylation Changes at T1D Risk Genes Appear to Protect Against Islet Autoimmunity
"We observed DNA methylation changes at multiple type 1 diabetes susceptibility genes in children born to mothers with type 1 diabetes," says Prof. Sandra Hummel, researcher at the Helmholtz Munich Institute for Diabetes Research and last author of the study.
Her team investigated how maternal type 1 diabetes influences the child's epigenome. In a new epigenome-wide association study, they identified that maternal type 1 diabetes is associated with specific epigenetic marks in the form of DNA methylation in the child. These changes appear to affect the expression of several genes involved in immune function.
The researchers examined blood samples from 1,752 children at around two years of age from the BABYDIAB, BABYDIET, and POInT cohorts. All children included had an increased genetic risk for type 1 diabetes. They compared DNA methylation patterns of 790 children with and 962 children without a mother affected by type 1 diabetes to identify differences linked to maternal diabetes.
"Our study identified numerous differentially methylated genetic locations, predominantly in the HOXA gene cluster and the MHC region in offspring of mothers with type 1 diabetes. The MHC region is known to confer the major genetic susceptibility and resistance to type 1 diabetes. We observed that the epigenomic changes in these children were associated with the expression of 15 type 1 diabetes susceptibility genes," explains Dr. Raffael Ott, lead scientist at the Institute of Diabetes Research and first author of the study.
Using 34 differentially methylated positions at type 1 diabetes susceptibility loci that best reflected exposure to maternal type 1 diabetes, the researchers created a methylation propensity score. Testing this score in children without a mother with type 1 diabetes, they found that those who developed islet autoimmunity had significantly lower scores, indicating less protective epigenetic modification. These findings suggest that environmental factors may modulate the risk of islet autoimmunity through epigenetic changes to key susceptibility genes.
550,000 US Dollars to Advance Research on Maternal Type 1 Diabetes Protection
In a following project led by Sandra Hummel, the researchers will take a closer look at the relative protection of children born to mothers with type 1 diabetes. Together with Prof. Ezio Bonifacio and colleagues from the Center for Regenerative Therapies Dresden at the TU Dresden University of Technology, the team aims to identify which type 1 diabetes susceptibility genes are epigenetically modulated by maternal type 1 diabetes and whether similar epigenetic effects occur in children born to mothers with gestational diabetes.
In collaboration with further Helmholtz Munich researchers, the project will also explore potential protein and metabolomic biomarkers linked to DNA methylation patterns and how these molecular changes contribute to protection against islet autoimmunity. To this end, they will analyze bio-samples collected within GPPAD trials, the BABYDIAB and the BABYDIET cohorts, and the Fr1da study. The project is supported by a grant of over 550,000 USD from The Leona M. and Harry B. Helmsley Charitable Trust.
About the Researchers
Dr. Raffael Ott, Institute of Diabetes Research, Helmholtz Munich
Prof. Sandra Hummel, Institute of Diabetes Research, Helmholtz Munich
About Helmholtz Munich
Helmholtz Munich is a leading biomedical research center. Its mission is to develop breakthrough solutions for better health in a rapidly changing world. Interdisciplinary research teams focus on environmentally triggered diseases, especially the therapy and prevention of diabetes, obesity, allergies, and chronic lung diseases. With the power of artificial intelligence and bioengineering, researchers accelerate the translation to patients. Helmholtz Munich has around 2,500 employees and is headquartered in Munich/Neuherberg. It is a member of the Helmholtz Association, with more than 43,000 employees and 18 research centers the largest scientific organization in Germany. More about Helmholtz Munich (Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt GmbH): www.helmholtz-munich.de/en
