An exploratory association analysis of the insulin gene region with diabetes mellitus in two dog breeds

Samoyeds and Australian Terriers are the two dog breeds at highest risk (>10 fold) for diabetes mellitus in the United States. It is unknown if the INS gene is involved in the pathophysiology of diabetes in Samoyeds and Australian Terriers. It was hypothesized that the INS gene region provides a common genetic causality for diabetes in Samoyeds and Australian Terriers. We conducted a two-stage genetic association study involving both breeds. In the discovery stage (Stage 1), Samoyeds with and without diabetes were compared in the frequencies of 447 tagging single nucleotide polymorphisms (SNPs) within 2.5Mb up- and down-stream of the INS gene on the Illumina CanineHD BeadChip. SNPs yielding a p-value <0.005 were selected for further followup. In the validation stage (Stage 2), Australian Terriers with and without diabetes were compared in the SNPs genotyped by the Affymetrix GeneChip Canine Genome 2.0 Array and within 1Mb up- and down-stream of the selected SNPs from Stage 1. Two SNPs that were in high linkage disequilibrium (LD, r2=0.7) were selected from Stage 1. In Stage 2, among the 76 SNPs examined, 5 were significantly associated with diabetes after Bonferroni's correction for multiple comparisons. Three of these 5 SNPs were in complete LD (r2=1 for all associations) and the two remaining SNPs were in moderate LD (r2=0.4). In conclusion, an association between the INS gene region and diabetes was suggested in two dog breeds of different clades. This region could have importance in diabetes in other breeds or in canine diabetes at large.