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

• Published in: Diabetes care Vol. 43; no. 1; pp. 169 - 177
• Main Authors: Inshaw, Jamie R.J., Cutler, Antony J., Crouch, Daniel J.M., Wicker, Linda S., Todd, John A.
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.01.2020
• Subjects: Adolescent; Adult; Age; Age of Onset; Alleles; Autoantibodies - genetics; Autoantibodies - immunology; Beta cells; Case-Control Studies; Child; Child, Preschool; Children; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - diagnosis; Diabetes Mellitus, Type 1 - epidemiology; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Etiology; Female; Genes; Genetic diversity; Genetic Predisposition to Disease; Genetic variance; Genotype; Genotypes; Haplotypes; Histocompatibility antigen HLA; Humans; Immune system; Immune System - metabolism; Infant; Infant, Newborn; Insulin-Secreting Cells - immunology; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Interleukin 1; Interleukin 10; Interleukin 2 receptors; Islets of Langerhans - immunology; Islets of Langerhans - metabolism; Loci; Lymphocytes; Lymphocytes T; Male; Medical diagnosis; Middle Aged; Pancreas; Pathophysiology/Complications; Polymorphism, Genetic; Regression analysis; Regression models; Research design; Young Adult
• ISSN: 0149-5992; 1935-5548; 1935-5548
• DOI: 10.2337/dc19-0803

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