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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Prediction of Autoimmune diabetes and celiac disease in childhood by Genes and perinatal Environment (PAGE)

Awarded: NOK 9.4 mill.

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. 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 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. Preliminary analyses suggest 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 has long been hypothesised 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 has also been hypothesised 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. Measuring maternal DNA in the fetal circulation is complex and time-consuming, and was completed in PAGE just before the end of the funding period. The statistical analysis has not yet been completed, but will follow shortly. 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.

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 e xpression 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 not yet identified. Nutritional and infectious factors are suspected, and the early onset and other lines of evidence suggest that in utero and early postnatal exposure is important. Such exposures are difficult to study in retrospective studies. By following over 100 000 pregnancies in the MOBA study, we can identify children who later develop type 1 diabetes and celiac disease via linkage to nation-wide registries in sufficient numbers to perform prospective studies. Stored blood samples from the mother during pregnancy and from the umbilical cord will be tested for selected mark ers of perinatal environment to investigate whether these can predict future development of celiac disease and type 1 diabetes, together with genetic factors. We will investigate the association between quantity of maternal cells in the fetal circulation ("maternal microchimerism") and type 1 diabetes or celiac disease in children. Small but variable quantitites of maternal cells may potentially mediate in utero effects. Cytokines and other biomarkers will be investigated, in addition to innovative studie s of vitamin D metabolites at two timepoints in pregnancy. With the combined effort of experts from different fields in Norway and abroad, we believe these studies can provide novel insight that may lead to preventive measures against type 1 diabetes and celiac disease in the future. The studies will also serve as models for other complex, immune mediated diseases.

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FRIMEDBIO-Fri prosj.st. med.,helse,biol

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