Specific type 1 diabetes risk genes underpin age-at-diagnosis and indicate joint defects in immunity, beta-cell fragility and responses to viral infections in early-onset disease

Background Immunohistological analyses of pancreata from patients with autoimmune type 1 diabetes (T1D) suggest a stratification of islet pathology of both B and T lymphocyte islet inflammation common in children diagnosed under age 7 years, whereas B cells are rare in those diagnosed age ≥13. Based on these observations, we would expect to see genetic susceptibility differences between these age-at-diagnosis groups at the population level. Moreover, these genetic susceptibility differences could inform us on the aetiology of this most aggressive form of T1D that initiates in the first years of life.

Methods Using multinomial logistic regression models we tested if the known T1D loci (17 within the human leucocyte antigen (HLA) region and 55 others, non HLA regions) had significantly stronger effect sizes in the <7 group compared to the ≥13 group, using genotype data from 26,991 individuals (18,400 controls, 3,111 T1D diagnosed <7 years of age, 3,759 at 7-13 and 1,721 at ≥13).

Findings Six associations of the HLA class II and I genes had stronger effects in the <7 group, and seven non-HLA regions, one of which functions specifically in beta cells (GLIS3), and the other six likely affecting key T cell (IL2RA, IL10, SIRPG), thymus (PTPRK) and B cell development/functions (IKZF3, IL10) or in both immune cells and beta cells (CTSH).

Interpretation In newborn children with the greatest load of certain HLA and non-HLA risk alleles, inherited variants in immune and beta cells, and their inherent disregulated response to environmental stresses such as virus infection, combine to cause a rapid loss of insulin production, thereby driving down the age at which T1D is diagnosed.