Research objectives and content
Insulin-dependent or type 1 diabetes mellitus (IDDM) is a multifactorial complex disease. Whole genome screens for regions associated to IDDM have revealed at least 20 regions which show positive linkage to IDDM including the proterminal region of chromosome 6q (IDDM8). The disease determinants have now been identified for two regions, the MHC locus (IDDM1) and the insulin region (IDDM2), through linkage disequilibrium mapping and haplotype analysis. Recently, evidence for linkage of IDDM to chromosome 6q97 (IDDM8) has been confirmed. The objective of this project is therefore to localize and identify the IDDM determinant on chromosome 6q27. The region showing strong evidence of linkage to disease will be physically cloned, and microsatellites will be isolated for linkage disequilibrium fine mapping. This will narrow down the region of interest to 100-200kb. In this region all polymorphism and genes will be identified, and subsequent linkage disequilibrium and haplotype analysis of these polymorphism in large numbers of families will allow identification of candidate mutations for functional analyses.
Training content (objective, benefit and expected impact)
I already have experience in genetics of human disease, but this is limited to diseases with high penetrance mutations. The fellowship will allow me to obtain a thorough training in the genetics of a complex multifactorial disease in which the genes have reduced penetrance, thereby making the identification and cloning of these genes much more challenging. Since common multifactorial diseases cause the greatest mortality and morbidity, and since a better understanding of basic disease mechanisms is an essential step in the prevention of these diseases, the results of this project are expected to make a significant impact on our understanding of pathogenesis of type I diabetes.
Links with industry / industrial relevance (22)
Oxford University has signed a research and license agreement with Merck & Co. Inc. (a US company) and the Wellcome Trust which covers the terms and conditions governing the research programme in connection with which this TMR fellowship is being submitted, and under which all results are joint owned by Merck and the Wellcome Trust (but can be used for further research by the University). This collaboration will enable high throughput DNA sequencing and computer analysis of chromosome regions associated with type I diabetes, and will facilitate a better and direct exploitation of disease genes towards the ultimate goal of prevention of the disease.