Prediction of autoimmune diabetes and celiac disease in childhood by genes and perinatal environment: Design and initial aims of the PAGE study

Type 1 diabetes and celiac disease result from misdirected immune mediated destruction of host cells, and are among the most common chronic diseases in children. Despite changes in incidence over the past 3 decades, little is known about non-genetic risk factors (except for dietary gluten for celiac disease). Norway is among the countries in the world with the highest incidence of these two diseases. We describe here plans and study design for the PAGE study (Prediction of Autoimmune diabetes and celiac disease in childhood by Genes and perinatal Environment). PAGE is a sub-study within the Norwegian Mother and Child Cohort study, including follow-up of more than 100,000 pregnancies. Children who develop type 1 diabetes or celiac disease are identified via linkage to the Norwegian Patient Register and the Norwegian Childhood Diabetes Registry, with complementing information from questionnaires. The overall aim is to test hypotheses about potential non-genetic risk factors for type 1 diabetes and for celiac disease, with focus on factors operating early in life. In addition to a full cohort analysis of factors registered in questionnaires, we will analyse biomarkers in maternal blood plasma and cord blood plasma. Mothers and children will be genotyped for well-established susceptibility polymorphisms. Biomarkers will be analysed in cases and controls within the cohort. Factors to be tested in the full cohort include infant feeding, diet and dietary supplements in the mother during pregnancy and in the child, and use of antibiotics and non-prescription drugs. Biomarkers to be tested include 25-hydroxyvitamin D, markers of immune activation, and small metabolites (metabolomics). We will also explore the potential role of maternal cells in the fetal circulation (maternal microchimerism) in later risk of celiac disease and type 1 diabetes.

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Shared Genetic Risk Factors for Type 1 Diabetes and Celiac Disease

New England Journal of Medicine ◽

10.1056/nejme0809719 ◽

2008 ◽

Vol 359 (26) ◽

pp. 2837-2838 ◽

Cited By ~ 16

Author(s):

Robert M. Plenge

Keyword(s):

Risk Factors ◽

Type 1 Diabetes ◽

Celiac Disease ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Shared Genetic

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Genetic Risk Factors for CVD in Type 1 Diabetes: The DCCT/EDIC Study

Diabetes Care ◽

10.2337/dc20-2388 ◽

2021 ◽

pp. dc202388

Author(s):

Ionut Bebu ◽

Sareh Keshavarzi ◽

Xiaoyu Gao ◽

Barbara H. Braffett ◽

Angelo J. Canty ◽

...

Keyword(s):

Risk Factors ◽

Type 1 Diabetes ◽

Genetic Risk ◽

Genetic Risk Factors

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Novel genetic risk factors influence progression of islet autoimmunity to type 1 diabetes

Scientific Reports ◽

10.1038/s41598-020-75690-6 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Suna Onengut-Gumuscu ◽

Umadevi Paila ◽

Wei-Min Chen ◽

Aakrosh Ratan ◽

Zhennan Zhu ◽

...

Keyword(s):

Risk Factors ◽

Type 1 Diabetes ◽

Genetic Risk ◽

Viral Infections ◽

Genetic Risk Factors ◽

Islet Autoimmunity ◽

Islet Autoantibody ◽

Critical Pathways ◽

Genome Wide

Abstract Type 1 diabetes arises from the autoimmune destruction of insulin-producing beta-cells of the pancreas, resulting in dependence on exogenously administered insulin to maintain glucose homeostasis. In this study, our aim was to identify genetic risk factors that contribute to progression from islet autoimmunity to clinical type 1 diabetes. We analyzed 6.8 million variants derived from whole genome sequencing of 160 islet autoantibody positive subjects, including 87 who had progressed to type 1 diabetes. The Cox proportional-hazard model for survival analysis was used to identify genetic variants associated with progression. We identified one novel region, 20p12.1 (TASP1; genome-wide P < 5 × 10–8) and three regions, 1q21.3 (MRPS21–PRPF3), 2p25.2 (NRIR), 3q22.1 (COL6A6), with suggestive evidence of association (P < 8.5 × 10–8) with progression from islet autoimmunity to type 1 diabetes. Once islet autoimmunity is initiated, functional mapping identified two critical pathways, response to viral infections and interferon signaling, as contributing to disease progression. These results provide evidence that genetic pathways involved in progression from islet autoimmunity differ from those pathways identified once disease has been established. These results support the need for further investigation of genetic risk factors that modulate initiation and progression of subclinical disease to inform efforts in development of novel strategies for prediction and intervention of type 1 diabetes.

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Genetic risk factors affecting mitochondrial function are associated with kidney disease in people with Type 1 diabetes

Diabetic Medicine ◽

10.1111/dme.12763 ◽

2015 ◽

Vol 32 (8) ◽

pp. 1104-1109 ◽

Cited By ~ 10

Author(s):

E. J. Swan ◽

R. M. Salem ◽

N. Sandholm ◽

L. Tarnow ◽

P. Rossing ◽

...

Keyword(s):

Risk Factors ◽

Type 1 Diabetes ◽

Kidney Disease ◽

Mitochondrial Function ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Factors Affecting

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Genetic risk factors for type 1 diabetes

The Lancet ◽

10.1016/s0140-6736(16)30582-7 ◽

2016 ◽

Vol 387 (10035) ◽

pp. 2331-2339 ◽

Cited By ~ 196

Author(s):

Flemming Pociot ◽

Åke Lernmark

Keyword(s):

Risk Factors ◽

Type 1 Diabetes ◽

Genetic Risk ◽

Genetic Risk Factors

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General population screening for childhood type 1 diabetes: is it time for a UK strategy?

Archives of Disease in Childhood ◽

10.1136/archdischild-2021-321864 ◽

2021 ◽

pp. archdischild-2021-321864

Author(s):

Rachel Elizabeth Jane Besser ◽

Sze May Ng ◽

John W Gregory ◽

Colin M Dayan ◽

Tabitha Randell ◽

...

Keyword(s):

Risk Factors ◽

Type 1 Diabetes ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Population Based ◽

Screening Strategy ◽

Smooth Transition ◽

Islet Autoantibodies ◽

Awareness Campaigns

Type 1 diabetes (T1D) is a chronic autoimmune disease of childhood affecting 1:500 children aged under 15 years, with around 25% presenting with life-threatening diabetic ketoacidosis (DKA). While first-degree relatives have the highest risk of T1D, more than 85% of children who develop T1D do not have a family history. Despite public health awareness campaigns, DKA rates have not fallen over the last decade. T1D has a long prodrome, and it is now possible to identify children who go on to develop T1D with a high degree of certainty. The reasons for identifying children presymptomatically include prevention of DKA and related morbidities and mortality, reducing the need for hospitalisation, time to provide emotional support and education to ensure a smooth transition to insulin treatment, and opportunities for new treatments to prevent or delay progression. Research studies of population-based screening strategies include using islet autoantibodies alone or in combination with genetic risk factors, both of which can be measured from a capillary sample. If found during screening, the presence of two or more islet autoantibodies has a high positive predictive value for future T1D in childhood (under 18 years), offering an opportunity for DKA prevention. However, a single time-point test will not identify all children who go on to develop T1D, and so combining with genetic risk factors for T1D may be an alternative approach. Here we discuss the pros and cons of T1D screening in the UK, the different strategies available, the knowledge gaps and why a T1D screening strategy is needed.

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