- To develop innovative, miniaturized high throughput methods for large scale determination of genetic and immune markers of susceptibility to type 1 diabetes mellitus.
- To undertake training of researchers and technicians from laboratories setting up these methods, and to promote technology transfer, standardization and quality control programmes.
- To apply this technology in support of the EURODIAB TIGER and ENDIT concerted actions, in order (a) to examine the distribution of diabetes susceptibility genes in relation to the incidence across Europe, (b) to examine interactions between genetic susceptibility and immune activation and (c) to improve risk assessment for recruitment into intervention trials.
Type 1 (insulin dependent) diabetes mellitus typically presents in childhood, and the highest known incidence of the disease is found in Europe. Irreversible loss of pancreatic beta cells results from an autoimmune process that appears to be initiated early in life as the result of an interaction between genetic susceptibility and environmental factors. There is a long pre-clinical prodrome, characterized by the presence of circulating autoantibodies against islet antigens, and intervention to modulate the disease process at this stage appears increasingly possible. Investigation of the interactions between genetic susceptibility, autoantibodies and potential environmental determinants promises increased understanding of the aetiology and pathogenesis of the disease. It also offers the opportunity to refine risk assessment to identify individuals likely to benefit from interventions to delay or prevent the clinical onset of disease.
Testing on the scale required to undertake such studies must be cheap, simple and easily applied. Assays need to be performed on dried blood spots or mouth swabs and non-radioactive methods need to be developed to enable widespread transfer of assay technology. Genetic susceptibility is polygenic. A total genome screen has confirmed that the main locus is encoded by the major histocompatibility complex on chromosome 6p21 (IDDM1), which with a lesser effect in the insulin gene region on chromosome 11p15 (IDDM2) accounts for some 50% of the susceptibility. The aim is to develop semi-automated methods for IDDM1 and IDDM2 typing using the PCR- based Taq polymerase 5' nuclease assay. Measurement of islet cell antibodies (ICA) are the gold standard for risk assessment during the pre-clinical disease phase, is difficult to standardize or to apply in non-specialist centres. Identification glutamic acid decarboxylase (GAD) and protein tyrosine phosphatase IA-2 as islet antigens has allowed these to be cloned and incorporated into simple radio-ligand assays that promise to overcome the limitations of ICA measurement whilst retaining high sensitivity. It is planned to adapt such antibody assays and use them in conjunction with IDDM1 and IDDM2 typing to develop a screening test for type 1 diabetes that can be performed on a single blood spot. Training, quality assurance schemes and technology transfer will permit dissemination of these methods across Europe and will prepare the way for large scale studies and, ultimately, for cost-effective, practicable strategies for population screening.