Type 1 diabetes, previously known as insulin-dependent diabetes mellitus, is a common chronic T-cell-mediated disease in which there is selective autoimmune destruction of the insulin-producing β cells of the pancreas. Although the mechanisms underlying this process are not fully understood, type 1 diabetes occurs as a result of complex interactions between multiple genes (reviewed in references 1–3) and environmental influences, which may both promote and protect against disease. Type 1 diabetes clusters in some families, but with no distinct pattern of inheritance. The concordance rates in monozygotic twins for type 1 diabetes can reach 50%, compared to 6% for dizygotic twins. The sibling recurrence risk ratio (λs) (risk to siblings ÷ risk to general population) value for type 1 diabetes is 15 (6.0 ÷ 0.4 or 6% ÷ 0.4%), and twin studies suggest that 80% to 85% of familial aggregation is accounted for by genes. Type 1 diabetes has been noted to coexist with other autoimmune diseases—notably, Graves’ disease and coeliac disease—in certain families, implying the involvement of common autoimmune pathways.
Improved understanding of the so-called ‘allelic architecture’ (the identity of disease-associated gene variants, their frequencies, and size of the risk conferred by each variant) and biological pathways involved in type 1 diabetes is expected to facilitate the identification of new therapeutic targets for the development of new treatments. DNA biomarkers could also assist risk prediction at a population level. This is clinically relevant since individuals can survive with only 20% intact β-cell mass, and the time to reach this level of destruction can be considerably delayed in some individuals, offering a window of opportunity for intervention therapy. Furthermore, clinical trials should be improved by only focusing on those patients at highest risk of developing type 1 diabetes.
Early prediction, improved treatments, and, ultimately, prevention of type 1 diabetes are major goals because incidence rates are increasing. A recent study by the EURODIAB Study Group, involving 20 population-based registries across 17 European countries, has assessed incidence trends in children diagnosed with type 1 diabetes under the age of 15 between 1989 and 2003: an overall increase of 3.9% per year was reported, and, in the under 5 age group, an increase of 5.4% per year was observed (4).
Constitutional mismatch repair deficiency as a differential diagnosis of neurofibromatosis type 1: consensus guidelines for testing a child without malignancy
