Type 1 (insulin-dependent) diabetes mellitus is one of the most common chronic disease in children and young adults. Because of its associated risk of long-term complications and premature death type 1 diabetes therefore h represents a major public health problem. Type 1 diabetes develops on the basis of genetic susceptibility and exposure to unknown non-genetic determinants, with an immune response leading to destruction of the insulinproducing cells of the pancreas. Evidence is accumulating that the disease is potentially preventable, but the development and implementation of future preventive measures at the population level require precise individual risk assessment in different populations. Such information is not yet available. EURODIAB ACE (1992-1995) was established as a Concerted Action under the BIOMED 1 Programme with the aims to characterize the geographical distribution of childhood-onset type 1 diabetes in Europe and to provide the framework for research into the aetiology of the disease. The achievements of EURODIAB ACE include the, demonstration of a more than 10-fold dmerence in risk of type 1 diabetes across Europe, which demonstrates that Europe represents a unique setting for research into the aetiology of type 1 diabetes.
The proposal is built upon the achievements of EURODIAB ACE. We propose to correlate the frequency of genes conferring high risk of type 1 diabetes with the incidence (risk) and immune markers of the disease in European D populations. Furthermore, we want to investigate possible heterogeneity by relating gender and age at disease onset to genetic and immune markers in different European populations. Interactions between a non-genetic candidate $ determinant, namely Coxsackie B virus infections and genetic and immune markers, notably antibodies to glutamic acid decarboxylase (GADA) will be investigated in the search for different causal mechanisms of type 1 diabetes in different European populations.
The proposal will take advantage of the existing registration network of new (incident) cases of type 1 diabetes which will provide the prospective epidemiological sampling framework of probands and their families for intensive genetic and immune markers. With the inclusion of new participating centres the EURODIAB TIGER networkr comprises 44 centres from 28 European nations, covering 25-30% of all European children and producing about 2800, new cases of childhood-onset type 1 diabetes annually. in addition, some 1350 new cases with onset in the age .
group 15-29 years will be registered annually from 12 centres. From selected centres, characterized by different levels of population risk of type 1 diabetes, about 2000 cases and their nuclear family members, totalling about 8000 individuals, will be sampled for detailed investigations. Leading expert laboratories in advanced molecular genetics and immunology will provide laboratory support, organized in the proposed Centralized Facility, PARADIGM, as; submitted in a parallel application. This collaboration ensures that the newest technology will be available in largescaled international epidemiological investigations like EURODIAB TIGER.
The deliverables of the proposal include new scientific information on the individual risk and causation of type 1 diabetes and its geographical distribution which cannot be achieved elsewhere. The proposal implements newest advances in molecular genetics and immune marker technology which, by built-in programmes of training and technology transfer will be made accessible for participating centres. Accordingly, EURODIAB TIGER will maintainand further develop an internationally unmatched resource for further genetic epidemiological research in type 1 diabetes, with future perspectives of screening and assessment of individual disease risk for preventive purposes a t the general population level.