The genetics of type 1 diabetes

Although previous reports claim to have mapped one of the known genetic components to a polymorphism in close proximity to the insulin gene (INS) on chromosome 11p15.5, doubts have been raised regarding the true location of the aetiological variant. IT has been proposed that the mode of inheritance at this locus is one of the dominant protection and may be influenced by epigenetic modification. If genetic approaches are to further the goal of developing a preventive treatment for T1D and, hence, the serious side effects of current therapies by avoided, a greater understanding of the known loci, as well as localisation and characterisation of unidentified disease genes, is important. To this end, this thesis addresses some of the principal uncertainties surrounding the INS locus, as well as investigating DNA pooling as a means of identifying new disease loci. Contrary to previous studies of INS in T1D, it is found that i) the disease association of three polymorphisms in the region cannot currently be resolved from one another, ii) there is no significant evidence for epigenetic related modification of disease risk and iii) the mode of inheritance is not dominant protection, but may be better approximated by a multiplicative model. These findings have significant implications for the design and interpretation of both biological function and gene-gene interaction studies. In DNA pooling, the errors introduced into allele frequency measurements at each experimental stage are estimated, and predictions made about the likely effectiveness of different study designs. The finding, that greater efficiency is achieved by the formation of numerous small pools, rather than replication of large-pool formation or of later experimental stages, may help enable genome-wide and / or comprehensive candidate gene studies in the search for additional disease loci.