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Specific type 1 diabetes risk genes underpin age-at-diagnosis and indicate joint defects in immunity, beta-cell fragility and responses to viral infections in early-onset disease

View ORCID ProfileJamie R.J. Inshaw, Antony J. Cutler, Daniel J.M. Crouch, Linda S. Wicker, John A. Todd
doi: https://doi.org/10.1101/577304
Jamie R.J. Inshaw
JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, University of Oxford, United Kingdom
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  • For correspondence: jinshaw@well.ox.ac.uk jatodd@well.ox.ac.uk
Antony J. Cutler
JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, University of Oxford, United Kingdom
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Daniel J.M. Crouch
JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, University of Oxford, United Kingdom
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Linda S. Wicker
JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, University of Oxford, United Kingdom
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John A. Todd
JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, University of Oxford, United Kingdom
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  • For correspondence: jinshaw@well.ox.ac.uk jatodd@well.ox.ac.uk
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Abstract

Objective Immunohistological analyses of pancreata from patients with type 1 diabetes suggest a stratification of islet pathology of both B and T lymphocyte islet inflammation common in children diagnosed at <7 years (<7 group), whereas B cells are rare in those diagnosed age ≥13 (≥13 group). Based on these observations, we sought to identify differences in genetic susceptibility between these age-at-diagnosis groups, to inform on the aetiology of the most aggressive form of type 1 diabetes that initiates in the first years of life.

Research Design and Methods Using multinomial logistic regression models, we tested if known type 1 diabetes loci (17 within the HLA region and 55 non-HLA regions) had significantly stronger effect sizes in the <7 group compared to the ≥13 group, using genotype data from 27,075 individuals (18,488 controls, 3,109 cases diagnosed at <7, 3,754 at 7-13 and 1,724 at ≥13).

Results Six HLA haplotypes/classical alleles and seven non-HLA regions, one of which functions specifically in beta cells (GLIS3), and the other six likely affecting key T cell (IL2RA, IL10, SIRPG, IKZF3, THEMIS), thymus (THEMIS) and B cell development/functions (IKZF3, IL10) or in both immune and beta cells (CTSH) had stronger effects in the <7 group.

Conclusions In newborn children with the greatest load of certain risk alleles, dysregulated response of immune and beta cells to environmental stresses such as virus infection, combine to cause a rapid loss of insulin production, driving down the age of type 1 diabetes diagnosis.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 18, 2019.
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Specific type 1 diabetes risk genes underpin age-at-diagnosis and indicate joint defects in immunity, beta-cell fragility and responses to viral infections in early-onset disease
Jamie R.J. Inshaw, Antony J. Cutler, Daniel J.M. Crouch, Linda S. Wicker, John A. Todd
bioRxiv 577304; doi: https://doi.org/10.1101/577304
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Specific type 1 diabetes risk genes underpin age-at-diagnosis and indicate joint defects in immunity, beta-cell fragility and responses to viral infections in early-onset disease
Jamie R.J. Inshaw, Antony J. Cutler, Daniel J.M. Crouch, Linda S. Wicker, John A. Todd
bioRxiv 577304; doi: https://doi.org/10.1101/577304

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