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Diabetes Care. 2019 Sep 26. pii: dc190803. doi: 10.2337/dc19-0803. [Epub ahead of print]

Genetic Variants Predisposing Most Strongly to Type 1 Diabetes Diagnosed Under Age 7 Years Lie Near Candidate Genes That Function in the Immune System and in Pancreatic β-Cells.

Author information

1
JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, University of Oxford, Oxford, U.K. jinshaw@well.ox.ac.uk.
2
JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, University of Oxford, Oxford, U.K.
3
JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, University of Oxford, Oxford, U.K. jatodd@well.ox.ac.uk.

Abstract

OBJECTIVE:

Immunohistological analyses of pancreata from patients with type 1 diabetes suggest distinct autoimmune islet β-cell pathology between those diagnosed at <7 years (<7 group) and those diagnosed at age ≥13 years (≥13 group), with both B- and T-lymphocyte islet inflammation common in children in the <7 group, whereas B cells are rare in the ≥13 group. Based on these observations, we sought to identify differences in genetic susceptibility between these prespecified age-at-diagnosis groups to inform on the etiology 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 and 55 non-HLA loci had significantly stronger effect sizes in the <7 group compared with the ≥13 group, using genotype data from 27,071 individuals (18,485 control subjects and 3,121 case subjects diagnosed at <7 years, 3,757 at 7-13 years, and 1,708 at ≥13 years).

RESULTS:

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

CONCLUSIONS:

A subset of type 1 diabetes-associated variants are more prevalent in children diagnosed under the age of 7 years and are near candidate genes that act in both pancreatic β- and immune cells.

PMID:
31558544
DOI:
10.2337/dc19-0803

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