Content area
Full Text
That type 1 diabetes in humans and in animal models represents a complex genetic disease is universally accepted. Genetic dissection of type 1 diabetes in humans has typically entailed the collection of large numbers of individuals scored on the basis of the presence or absence of clinical disease (case/ control subjects). Statistically significant differences in allele frequencies distinguishing the affected subjects from control subjects are used to demonstrate associations. Human major histocompatibility complex (MHC) alleles, primarily but not exclusively within the class II sets of genes, are estimated to contribute up to 50% of genetic risk. Because of the strength of the MHC contribution and the genetic heterogeneity extant in humans, identification of non-MHC susceptibility loci by genome-wide association has required the accumulation of large numbers of case/control populations. Recent studies have identified up to 10 of such non-MHC susceptibility regions under conditions where multiple HLA haplotypes are segregating (1).
In the NOD mouse, the paramount role of the MHC was confirmed by the finding that almost all diabetic mice generated by outcross with diabetes-resistant strains were homozygous for the NOD's susceptibmty-conferring HS^sup g7^ MHC haplotype. Because inbred strains were used, linkage was ascertained by treating type 1 diabetes as a dichotomous trait, with diabetes susceptibility (Idd) genes identified by significant deviations from expected Mendelian ratios in the diabetic segregante. Initial segregation analyses in crosses in which H2^sup g7^ was also segregating only suggested effects of several non-MHC Idd genes. However, the true polygenic nature of type 1 diabetes in this model followed the generation of outcross partner strains congenie for NOD's susceptibility-conferring H2^sup g7^, such that only the non-MHC susceptibility modifiers segregated in a cross (2,3). By now, over 30 non-MHC murine loci have been identified, some of which (e.g., Ctla4, I12) represent likely orthologs for certain human non-MHC loci identified by genome-wide association (4). Because extensive genomic sequence information is available for NOD and outcross partner strains, geneticists can subdivide loci identified by linkage analysis across a broader genetic region and use high-density single nucleotide polymorphisms and polymorphic microsatellite markers to facilitate fine-mapping and candidate gene analysis.
Where does the rat figure into our understanding of type 1 diabetes genetic susceptibility? Consistent with the pivotal contributions of MHC in humans and NOD mice,...