Type 1 Diabetes Genes in Rats: Few or Many?

  1. Edward H. Leiter
  1. From the Jackson Laboratory, Bar Harbor, Maine.
  1. Corresponding author: Edward H. Leiter, ehl{at}jax.org.

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 susceptibility-conferring H2g7 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 segregants. Initial segregation analyses in crosses in which H2g7 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 congenic for NOD's susceptibility-conferring H2g7, …

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