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 beta-Cells

OBJECTIVE Immunohistological analyses of pancreata from patients with type 1 diabetes suggest distinct autoimmune islet beta-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 beta-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 beta-cells (CTSH), showed evidence for stronger effects in the 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 beta- and immune cells.