Relationship Between Mutations of the Pancreatic Secretory Trypsin Inhibitor Gene and Pancreatitis in Miniature Schnauzers and Dogs of Other Breeds
Anecdotal evidence suggests that Miniature Schnauzers (MS) are predisposed to pancreatitis. We have previously reported the identification of 3 mutations (2 exonic mutations: N20K, N25T and 1 intronic mutation: IVS3+26-27ins(T)33-39,15_61dup11) of the pancreatic secretory trypsin inhibitor gene (PSTI) in MS. In humans, multiple mutations of the PSTI gene have been linked to hereditary pancreatitis. Therefore, the aim of this study was to evaluate the prevalence of mutations in the PSTI gene in a population of MS and dogs of other breeds, and to determine whether the presence of these mutations is associated with pancreatitis.
A total of 4 groups of dogs were enrolled in this study: 55 MS with pancreatitis, 13 dogs of other breeds with pancreatitis, 40 healthy MS, and 17 healthy dogs of other breeds. Diagnosis of pancreatitis was based on a combination of clinical signs suggestive of pancreatitis and a serum cPLI concentration above the cut-off value for pancreatitis. A complete history and clinical findings were recorded for each dog. Serum and whole blood were obtained from each dog. DNA was extracted from whole blood and PCR was performed to amplify the 3 regions of the gene with the previously reported mutations, using specific primers. PCR products were purified and sequenced directly by automated cycle sequencing. Sequences were compared with the published canine genome project sequence for this gene and also among the 4 groups of dogs. Proportions of dogs with mutations of the PSTI gene were compared among groups using a Fisher's exact test and odds ratios (OR) with their 95% confidence intervals (CI) were calculated.
The 2 exonic mutations were always linked and were commonly present in all 4 groups of dogs studied. The intronic mutation was found only in MS (46 of 55 MS with pancreatitis and 25 of 40 healthy MS). Additionally, this mutation was always linked to the first 2 mutations. Of the MS with pancreatitis, 35/55 (63.6%) were homozygous for the intronic mutation compared to 16/40 (40.0%) of healthy MS (OR = 2.625; p = 0.0366; 95% CI: 1.135-6.069). However, being heterozygous for the intronic mutation was not significantly associated with pancreatitis (p = 0.4765).
Results of this study suggest that this intronic mutation is unique to MS. The 2 exonic mutations were found in both MS and dogs of other breeds and probably represent single nucleotide polymorphisms (SNPs). MS that were homozygous for the intronic mutation were significantly more likely to have pancreatitis than MS that were heterozygous or did not have the mutation. Due to the fact that the intronic mutation was present in both healthy and diseased MS, we hypothesize that pancreatitis in MS is likely multi-factorial. Further studies are in progress to determine the role of this mutation and other risk factors in the development of pancreatitis in MS.