I was interested to read the papers by Bishop and others 2010 and Furrow and others 2012 giving conflicting results of genetic studies looking at SPINK 1 mutations in Miniature Schnauzers with pancreatitis and equally interested to read the authors' letters to the editor in the May/June 2013 issue of the Journal of Veterinary Internal Medicine. I would like to add another possible explanation for the conflicting results.
In human medicine, it has long been recognized that SPINK 1 mutations are not sufficient alone to cause pancreatitis but only do so if there are concurrent environmental or genetic risk factors. The reason for this has recently been demonstrated in studies showing that, at least in humans and rodents, SPINK1 is only expressed at very low levels in normal acinar cells. Its expression is up-regulated as a protective measure in the context of active pancreatic inflammation. This is an interesting observation which has not been investigated in dogs to date. However, if it is extrapolated to this species, it might provide some explanation for differing results in different studies. SPINK1 mutations in humans become most clinically relevant when they occur concurrently with other mutations predisposing to increased trypsin activation. The phenomenon of genetic epistasis, whereby the effect of one gene modifies the effect of another, is increasingly recognized as important in chronic pancreatitis in humans, which usually is a complex multigenic disease. The severe trypsin mutations causing hereditary pancreatitis in humans are so marked that they produce disease alone without concurrent SPINK1 mutations, although they are still susceptible to environmental modification. However, if SPINK1 mutations occur concurrently with other milder mutations such as mild CFTR mutations, the risk of pancreatitis is increased. To quote LaRush and Whitcomb 2011, ‘It is critical to note that although the individual risk of pancreatitis among either SPINK1 or CTFR single mutation carriers is 2-4 fold, carrier frequency is 2-5% each and 99% of carriers are healthy. However, with concurrent multiple SPINK1/CFTR variants the risk is synergistic, mutation specific and healthy carriers of multiple mutations are exceptionally rare'.
Another recently published study has demonstrated a variety of CFTR variants in dogs both with and without pancreatitis, with no apparent effect on disease occurrence. It would be interesting to study the effects of combined CFTR and SPINK1 mutations in dogs. I hope that these conflicting studies in dogs will drive larger studies in the future investigating not one, but multiple, genes in dogs both with and without pancreatitis and in more than one breed before we draw definitive conclusions.