The PAGE Study: Prediction of Autoimmune diabetes and celiac disease in childhood by Genes and perinatal Environment
PAGE is an acronym for «Prediction of Autoimmune diabetes and celiac disease in childhood by Genes and perinatal Environment». The overall goal is to gain new knowledge about environmental risk factors for type 1 diabetes and celiac disease, which in the future may be translated into preventive interventions. It is a substudy in the Norwegian Mother, Father and Child Cohort study (MoBa), which recruited pregnant women throughout the country from 1999-2008 and continues to follow the offspring.
Type 1 diabetes and celiac disease are common chronic diseases in children, associated with serious complications and reduced quality of life. Genes (HLA-DQ2 and -DQ8) strongly predispose for both diseases. Consumption of wheat products is necessary for expression of celiac disease, but most of the susceptible children do not develop disease. Increasing incidence over the past decades suggests involvement of non-genetic factors which are yet to be identified.
The early onset of both diseases, and other lines of evidence, suggest that in utero and early postnatal exposure is important. By following 100 000 pregnancies in the Norwegian Mother, Father and Child Cohort Study (MoBa), we have identified children who later develop type 1 diabetes and celiac disease, yielding the world’s largest pregnancy cohort of this kind. Stored blood samples from the mother during pregnancy and from the umbilical cord has been tested for selected markers of perinatal environment to investigate whether these can predict future development of celiac disease and type 1 diabetes, together with genetic factors. These include vitamin D metabolites, circulating immune mediators, and quantity of maternal cells in the fetal circulation (maternal microchimerism). We also test the potential influence of several exposures of the mother during pregnancy and of the child in early life, based on information collected in questionnaires. These include frequencies of infections, smoking habits, use of medication and dietary intake. Some sub-studies are done in collaboration with a similar large cohort: The Danish National Birth Cohort.
The project is run by the Norwegian Institute of Public Health, in close collaboration with collaborators at several institutions, including Oslo University Hospital, Haukeland University hospital and University of Bergen, University of Southern Denmark, Statens Serum institut in Denmark, University of Bristol, and University of Colorado.
A number of specific research questions have been answered:
* PERINATAL VITAMIN D. The hypotheses that maternal and perinatal vitamin D predicts lower risk of type 1 diabetes or celiac disease, were not supported by our data. We also found a possible complex interaction of vitamin D and its binding protein with genes in the aetiology of type 1 diabetes.
* PERINATAL SYSTEMIC INFLAMMATION. The hypothesis that maternal or perinatal circulating immunological mediators predict future risk of celiac disease in childhood was not supported, but there was a potential relation between selected markers and risk of type 1 diabetes in children, which requires further study to provide conclusive evidence.
* INFECTION FREQUENCY. While gastrointestinal infections have long been hypothesized to influence the risk of celiac disease, there are few studies of this. PAGE found that frequency of infections (as reported by the mother) was associated with a slightly higher risk of celiac disease. A novel and interesting finding was that this was also the case for respiratory infections. This indicates supports that infections may contribute towards disease risk, together with the established influence by genetic factors and gluten intake, and that this is not confined to gastrointestinal infections. While infections have also been hypothesized to influence the risk of type 1 diabetes, data from PAGE did not support this.
* INFANT GROWTH. Increased infant and early childhood weight gain is related to a statistically significant, but yet quite modest increase in risk of type 1 diabetes. For celiac disease, it is well established that affected children on average has lower weight and height for age at diagnosis, because of intestinal malabsorption. The PAGE study found, however, that linear growth deficits can be traced back to the second year of life, which is earlier than expected from current knowledge of when the disease process starts.
* MATERNAL MICROCHIMERISM. MMc is the transfer of small quantities of maternal cells to the fetus in utero, but the physiological functions of this process is still unclear. It has been proposed that this is associated with a state of tolerance. Measuring maternal DNA in the fetal circulation, a complex and time-consuming, process, was done for cases of T1D and controls. The main conclusion was that the quantity of maternal cells (DNA) in the fetal circulation at birth, was not associated with risk of type 1 diabetes in children. Our hypothesis that a larger quantity of maternal cells would protect the child from T1D was therefore not supported.
* DIETARY FIBRE: maternal dietary fibre during pregnancy intake was not associated with type 1 diabetes in children, despite very similar design and harmonized analysis with a previous study in the BMJ from the Danish National Birth Cohort study. In addition, we contributed with data on the child’s intake of fibre (estimated quantity of gluten intake per day) during early childhood, and higher intake was associated with higher risk of type 1 diabetes. The results were published in PloS Medicine: https://pubmed.ncbi.nlm.nih.gov/32119659/
SUMMARY. The study has contributed important new knowledge regarding early environmental exposures in the aetiology of type 1 diabetes and celiac disease. The funding from The Research Council of Norway has created a set of data and network of investigators that will continued harvesting of new knowledge from these unique resources.
News from 2022:
Two MSc student from Tromsø have successfully completed their master theses based on the PAGE study (main supervisor Nicolai Lund Blix)
Publications 2022:
Abstract/conference presentation:
Øien MZ, Stene LC, Tapia G, Skrivarhaug T, Joner G, Njølstad PR, Størdal K, Lund-Blix NA. Vitamin A consumption in pregnancy and risk of offspring type 1 diabetes (Abstract). European Diabetes Epidemiology Group (EDEG) 56th Annual Meeting, Crete, Greece, April 2-5, 2022.
Primary investigator: Lars Christian Stene
Co-investigators/participants:
Geir Joner
Torild Skrivarhaug
Benedicte A. Lie
German Tapia
Nicolai A. Lund-Blix
Marte K. Viken
Ketil Størdal
and others, see list on project website:
https://www.fhi.no/en/studies/page/forskere-og-samarbeidspartnere-i-page/
External collaborators:
Pål R. Njølstad, Bergen
C. Legido-Quigley, T. Suvitaival and L. Ahonen, Steno Diabetes Center Copenhagen
and others, see list on project website:
https://www.fhi.no/en/studies/page/forskere-og-samarbeidspartnere-i-page/