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ObjectiveImmunohistological 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 methodsUsing 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).ResultsSix 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.ConclusionsA 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.

Original publication




Journal article


Diabetes care

Publication Date





169 - 177


JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, University of Oxford, Oxford, U.K.


Islets of Langerhans, Immune System, Humans, Diabetes Mellitus, Type 1, Genetic Predisposition to Disease, Autoantibodies, Case-Control Studies, Age of Onset, Genotype, Haplotypes, Polymorphism, Genetic, Alleles, Adolescent, Adult, Middle Aged, Child, Child, Preschool, Infant, Infant, Newborn, Female, Male, Insulin-Secreting Cells, Young Adult