Journal of Heredity Advance Access published online on July 4, 2007
Journal of Heredity, doi:10.1093/jhered/esm048
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Analysis of Candidate Susceptibility Genes in Canine Diabetes
From the Centre for Integrated Genomic Medical Research, Stopford Building, The University of Manchester, Manchester M13 9PT, UK (Short, Kennedy, and Ollier); the Royal Veterinary College, London, UK (Catchpole); Veterinary Faculty, The University of Liverpool, Liverpool, UK (Barnes); the WALTHAM Centre for Pet Nutrition, Freeby Lane, Leicestershire, UK (Fretwell and Jones); and the School of Epidemiology and Health Sciences, Stopford Building, The University of Manchester, Manchester, UK (Thompson)
Address correspondence to A. D. Short at the address above, or e-mail: andrea.short{at}manchester.ac.uk.
Canine diabetes is a complex genetic disease of unknown aetiology. It affects 0.005–1.5% of the canine population and shows a clear breed predisposition with the Samoyed being at high risk and the Boxer being at low risk of developing the disease. Canine diabetes is considered to be a disease homologue for human type 1 diabetes (T1D). It results in insulin deficiency as a consequence of autoimmune destruction of islet ß-cells in the pancreas and is believed to be mediated by Th1 cytokines (IFN
, TNF
, and IL-2). A number of genes have been associated with type 1 diabetes in humans, including the human leukocyte antigen region, the insulin variable number tandem repeat, PTPN22, CTLA4, IL-4, and IL-13. As yet, these genes have not been evaluated in canine diabetes. In this study, 483 cases of canine diabetes and 869 controls of known breed were analyzed for association with IFN, IGF2, IL-10, IL-12ß, IL-6, insulin, PTPN22, RANTES, IL-4, IL-1 and TNF. Minor allele frequencies were determined for these genes in each breed. These data were used for comparative analyses in a case–control study, and clear associations with diabetes were identified in some breeds with certain alleles of candidate genes. Some associations were with increased susceptibility to the disease (IFN, IL-10, IL-12ß, IL-6, insulin, PTPN22, IL-4, and TNF), whereas others were protective (IL-4, PTPN22, IL-6, insulin, IGF2, TNF). This study demonstrates that a number of the candidate genes previously associated with human T1D also appear to be associated with canine diabetes and identifies an IL-10 haplotype which is associated with diabetes in the Cavalier King Charles Spaniel. This suggests that canine diabetes is an excellent comparative and spontaneously occurring disease model of human T1D.
This paper was delivered at the 3rd International Conference on the Advances in Canine and Feline Genomics, School of Veterinary Medicine, University of California, Davis, CA, August 3–5, 2006.