4.8 Article

Transcriptional networks in at-risk individuals identify signatures of type 1 diabetes progression

Journal

SCIENCE TRANSLATIONAL MEDICINE
Volume 13, Issue 587, Pages -

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.abd5666

Keywords

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Funding

  1. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, HHSN267200700014C]
  2. National Institute of Allergy and Infectious Diseases (NIAID) [U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, HHSN267200700014C]
  3. Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) [U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, HHSN267200700014C]
  4. National Institute of Environmental Health Sciences (NIEHS) [U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, HHSN267200700014C]
  5. Centers for Disease Control and Prevention (CDC) [U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, HHSN267200700014C]
  6. JDRF [U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, HHSN267200700014C]
  7. NIH/NCATS [UL1 TR000064, UL1 TR001082]
  8. Wellcome Trust Senior Investigator award [200871/Z/16/Z]
  9. Beit Foundation [10406/Z/14/Z, 10406/Z/14/A]
  10. National Institutes for Health Research Biomedical Research Centre (Cambridge) [10406/Z/14/A]
  11. Wellcome Trust [10406/Z/14/Z, 10406/Z/14/A]
  12. Wellcome Trust [200871/Z/16/Z] Funding Source: Wellcome Trust

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Research shows that early and longitudinal changes in gene expression play a significant role in the progression of type 1 diabetes, informing the immunopathology and facilitating prediction of the disease course.
Type 1 diabetes (T1D) is a disease of insulin deficiency that results from autoimmune destruction of pancreatic islet. cells. The exact cause of T1D remains unknown, although asymptomatic islet autoimmunity lasting from weeks to years before diagnosis raises the possibility of intervention before the onset of clinical disease. The number, type, and titer of islet autoantibodies are associated with long-term disease risk but do not cause disease, and robust early predictors of individual progression to T1D onset remain elusive. The Environmental Determinants of Diabetes in the Young (TEDDY) consortium is a prospective cohort study aiming to determine genetic and environmental interactions causing T1D. Here, we analyzed longitudinal blood transcriptomes of 2013 samples from 400 individuals in the TEDDY study before both T1D and islet autoimmunity. We identified and interpreted age-associated gene expression changes in healthy infancy and age-independent changes tracking with progression to both T1D and islet autoimmunity, beginning before other evidence of islet autoimmunity was present. We combined multivariate longitudinal data in a Bayesian joint model to predict individual risk of T1D onset and validated the association of a natural killer cell signature with progression and the model's predictive performance on an additional 356 samples from 56 individuals in the independent Type 1 Diabetes Prediction and Prevention study. Together, our results indicate that T1D is characterized by early and longitudinal changes in gene expression, informing the immunopathology of disease progression and facilitating prediction of its course.

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