Abstract
BackgroundOne strategy to help identify susceptibility genes for complex, multifactorial diseases is to map disease loci in a representative animal model of the disorder. The nonobese diabetic (NOD) mouse is a model for human type 1 diabetes. Linkage and congenic strain analyses have identified several NOD mouse Idd (insulin dependent diabetes) loci, which have been mapped to small chromosome intervals, for which the orthologous regions in the human genome can be identified. Here, we have conducted re-sequencing and association analysis of six orthologous genes identified in NOD Idd loci: NRAMP1/SLC11A1 (orthologous to Nramp1/Slc11a1 in Idd5.2), FRAP1 (orthologous to Frap1 in Idd9.2), 4-1BB/CD137/TNFRSF9 (orthologous to 4-1bb/Cd137/Tnrfrsf9 in Idd9.3), CD101/IGSF2 (orthologous to Cd101/Igsf2 in Idd10), B2M (orthologous to B2m in Idd13) and VAV3 (orthologous to Vav3 in Idd18).ResultsRe-sequencing of a total of 110 kb of DNA from 32 or 96 type 1 diabetes cases yielded 220 single nucleotide polymorphisms (SNPs). Sixty-five SNPs, including 54 informative tag SNPs, and a microsatellite were selected and genotyped in up to 1,632 type 1 diabetes families and 1,709 cases and 1,829 controls.ConclusionNone of the candidate regions showed evidence of association with type 1 diabetes (P values > 0.2), indicating that common variation in these key candidate genes does not play a major role in type 1 diabetes susceptibility in the European ancestry populations studied.
Highlights
One strategy to help identify susceptibility genes for complex, multifactorial diseases is to map disease loci in a representative animal model of the disorder
The other causative gene(s) in the known Idd regions controlling type 1 diabetes susceptibility in the nonobese diabetic (NOD) mouse could determine susceptibility in humans, even though this depends on the frequency of susceptibility alleles in human populations, which affects statistical power, and that the correct candidate gene has been chosen from the Idd interval
A multi-locus test was used to evaluate the association between type 1 diabetes and the tag SNPs due to linkage disequilibrium (LD) with one or more causal variants [17]
Summary
One strategy to help identify susceptibility genes for complex, multifactorial diseases is to map disease loci in a representative animal model of the disorder. Type 1 diabetes is a common, multifactorial disease believed to be caused in a proportion of cases by an autoimmune destruction of pancreatic β-cells by an inflammatory infiltrate comprising T lymphocytes, dendritic cells and macrophages This process results from a complex interaction between genetic and environmental risk factors. The other causative gene(s) in the known Idd regions controlling type 1 diabetes susceptibility in the NOD mouse could determine susceptibility in humans, even though this depends on the frequency of susceptibility alleles in human populations, which affects statistical power, and that the correct candidate gene has been chosen from the Idd interval. In contrast to studies in humans based on linkage, the localisation of a type 1 diabetes locus to a specific chromosome region in the mouse genome using congenic strain breeding defines with certainty a set of genes, one or more of which is definitely a susceptibility gene [3,4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
