Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication




Journal article


Diabetes Care

Publication Date





169 - 177


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