Genetics of GI Disease
World Small Animal Veterinary Association World Congress Proceedings, 2007
Edward J. Hall, MA, VetMB, PhD, DECVIM-CA, MRCVS
Department of Clinical Veterinary Science, University of Bristol
Langford, Bristol, England

There are almost no simple genetic defects identified that are known to cause GI disease in dogs and cats. Selective cobalamin deficiency in Giant schnauzers and Border collies is the only one that is well characterized.1 The cobalamin receptor is a complex of the proteins cubilin and amnionless (AMN), called the cubam complex The disease is an autosomal recessive inherited trait, and genetic analysis has demonstrated a mutation at the AMN locus.2 A genetic test is now available from the University of Pennsylvania.

In most other diseases where a genetic basis is suspected, often based on breed predisposition, the problem is likely to be multifactorial with potentially multiple gene involvement and modulation by environmental factors. Indeed, simple infectious diseases may mimic genetic disease if infection follows family lines.

Infectious Inheritance?

The existence of breed-specific intestinal diseases in dogs and cats is suggestive of an underlying genetic cause for each disease. However, gastrointestinal (GI) diseases can have an infectious aetiology, and suspected inherited diseases could simply be due to infection transmitted between relatives.

Gastric Carcinoma

Gastric carcinoma in dogs is markedly over-represented in collies, especially Rough collies, suggesting a genetic predisposition. Yet in humans, gastric Helicobacter infection, which can lead to a spectrum of disease ranging from gastritis and ulcers to mucosal lymphoma and gastric carcinoma, most commonly follows infection from the mother. Thus passage of a pathogenic strain of Helicobacter from dam to pup as the initiating cause of gastric carcinoma in dogs cannot be ruled out. Whilst the pathogenicity of Helicobacter in dogs may be debated, transmission of Demodex from dam to pups is accepted in veterinary dermatology, and similar transmission of Helicobacter may be possible.

Histiocytic Ulcerative Colitis (HUC)

More conclusive proof of 'infectious heredity' comes from the recent recognition that HUC is associated with infection with an atypical adherent and invasive E. coli (AIEC).3 This unusual form of bowel inflammation has been reported almost exclusively in Boxers with just two reports of HUC in an ancestrally related breed, the French bulldog, and recent cases in a Mastiff, an Alaskan malamute, and a Dobermann pinscher. The disease is restricted to the colon, and the colitis is characterized by accumulations of periodic acid Schiff (PAS) positive macrophages, although a mixed inflammatory response with T cells and IgG plasma cells is actually present. The disease is rare and sporadic and for many years it was hypothesized that it was infectious in nature, although attempts at disease transmission failed. Recently the condition has been reported to be sensitive to enrofloxacin,4 suggesting an infectious aetiology, and molecular techniques have now identified an AIEC as the likely causative agent.

Nevertheless, it is not yet clear whether infection with AIECs is merely related to opportunity (e.g., infection from the bitch in the perinatal period) or whether there is actually a genetic susceptibility to infection.

Parvovirus

Susceptibility to parvovirus infection is recognised in certain breeds such as the Rottweiler, Dobermann, English Springer spaniel and American pit bull terrier, and inadequacies in the immune response, which may be inherited, are suggested.5

German Shepherd Enteropathies

As well as an inherited predisposition to exocrine pancreatic insufficiency, German shepherd dogs (GSDs) are prone to a number of chronic enteropathies. EPI is not strictly a GI disease, but heritability has been demonstrated in Rough collies as well as GSDs, and surveys have shown that these breeds plus the Chow Chow and Cavalier King Charles spaniel are clearly predisposed to EPI.

Antibiotic-Responsive Diarrhoea (ARD)

The syndrome of ARD (also known as small intestinal bacterial overgrowth) is seen most commonly as an idiopathic problem in young, large-breed dogs, and especially in the German shepherd dog.

Inflammatory Bowel Disease (IBD)

Although the intestinal inflammation in idiopathic IBD is believed to be due to a loss of tolerance to the normal enteric flora, there appears to be a breed predisposition that may reflect breed differences in the function of the mucosal immune system. The condition is particularly reported in the German shepherd as well as the Shar pei, two breeds where there is mounting circumstantial evidence of an immune defect. Both lymphoplasmacytic and eosinophilic enteritis are recognised in GSDs.

For a long time the predisposition of the GSD to a variety of intestinal diseases has focused on suspected inherited IgA deficiency, although conflicting evidence concerning serum IgA concentrations in GSDs exists in the literature. However, serum concentrations do not reflect mucosal IgA secretion,6 and evidence of reduced faecal concentrations, and reduced secretion in intestinal explant cultures, despite increased IgA plasma cell numbers, have been reported.7-8 However, no changes in the expression of the polymeric immunoglobulin receptor (pIgR), IgA alpha chain or J chain have been found.9

Recently it has been shown that dogs can express at least four allotypes of IgA. Intriguingly all GSDs examined so far express just variant C.10 Variations in the products of these allotype genes occur in the antibody hinge region. This could potentially influence the ability of the IgA molecules to bind antigens and their susceptibility to proteolysis, and hence their efficacy in immune exclusion of luminal antigens.

Dogs with ARD show similar changes in cytokine mRNA expression to lymphoplasmacytic enteritis, but with no gross histological evidence of inflammation and a predominance of IgA plasma cell expression.7 As the average age of GSDs with IBD is much older than those with ARD, it has been speculated that ARD occurs first, and that prolonged stimulation by the intestinal flora in genetically predisposed individuals ultimately causes IBD.

Whilst the importance of intestinal bacteria in driving intestinal inflammation is possible, it seems likely that inherent abnormalities in an individual's intestinal immune system may influence the manifestation and persistence of the inflammation. The NOD2/CARD15 bacterial peptidoglycan recognition gene is implicated in the susceptibility to human Crohn's disease,11-13 and the search for similar mutations or differences in Toll-like receptor expression in GSDs has begun.

Basenji Enteropathy

This condition is characterized by severe lymphoplasmacytic enteritis and hypergammaglobulinaemia.14,15 Originally this condition was termed Immunoproliferative Small Intestinal Disease (IPSID) because it resembled a condition seen in humans of primarily Mediterranean origin. However the human condition is associated with alpha heavy-chain disease and a predisposition to lymphoma. Alpha heavy-chain disease is not present in affected Basenjis but they may be predisposed to lymphoma.

Gluten-Sensitive Enteropathy (GSE)

Small intestinal disease, induced by the presence of dietary wheat gluten and related cereal peptides, has been clearly documented in Irish setter dogs.16 The condition resembles GSE (coeliac disease) in humans in whom there is an underlying genetic predisposition: there is an association with the MHC class II haplotype HLA-DQω2, and the development of anti-gliadin antibodies that cross-react with the self-antigen, tissue transglutaminase. In Irish setters it is also a familial condition with an autosomal recessive mode of inheritance. However, intestinal damage and clinical signs are less marked and, unlike human coeliac disease, there is no relationship with major histocompatibility genes DQA and DQB, nor any similarity in the pathogenesis.17 The line of affected setters from which these dogs were originally bred has been eliminated but the disease may affect other dog breeds, although it has not been reported in cats.

Protein-losing Enteropathy (PLE) and Nephropathy (PLN)

This is a clinical syndrome so far unique to the Soft Coated Wheaten terrier (SCWT), characterized by signs of a PLE and/or a PLN. Signs of PLE tend to develop at a younger age than PLN, and a genetic basis is likely and, although the mode of inheritance is not yet clear, pedigree analysis has demonstrated a common male ancestor.18 The disease is probably immune-mediated given the presence of inflammatory cell infiltration. A potential role for food hypersensitivity has been suggested, since affected dogs have demonstrated adverse reactions during provocative food trials, with alterations in antigen-specific faecal IgE concentrations.

Lymphangiectasia

Marked dilatation and dysfunction of intestinal lymphatics is the hallmark of intestinal lymphangiectasia and breed-specific disease is likely to be a primary disorder rather than secondary to lymphatic obstruction. It is usually limited to the intestine although concurrent chylothorax may occur and although usually considered a congenital abnormality, clinical signs are not usually present from birth. The development of associated lipogranulomatous lymphangitis, superimposed on the congenital abnormalities is one potential explanation for it being a progressive disorder. The disease is most commonly seen in small terrier breeds (e.g., Yorkshire, Maltese), Rottweilers and the Norwegian Lundehund,19 suggesting a genetic predisposition.

Intestinal Neoplasia

The development of intestinal neoplasia is likely to depend on an inter-relationship between genetic and environmental factors such as the diet and commensal bacterial flora. The mechanisms of intestinal neoplasia development in dogs and cats is not known, but a colon cancer model is well developed in humans.20

Acquisition of several genetic alterations drives the progression of normal intestinal epithelium to colonic carcinoma. The genetic modifications include:

 Activation of oncogenes including ras by point mutation

 Inactivation of tumour-suppressor genes such as p53, DCC and APC by point mutation or deletion

 Mutations of DNA mismatch repair genes

 DNA hypomethylation

As the number of mutations increases the disease progresses from a benign polyp to cancer. However, a number of environmental carcinogens may act at different stages in this model, causing somatic mutations. Other factors, such as dietary constituents, may stimulate the rate of cell turnover and act as promoters.

References

1.  Fordyce HH, et al. J Sm Anim Pract 2000;41:407.

2.  He Q, et al. Mamm Genome 2003;14:758

3.  Simpson KW, et al. Infect Immun 2006;74:4778

4.  Davies DR, et al. Aust Vet J 2004;82:58.

5.  Houston DM, et al. J Am Vet Med Assoc 1996;208:542.

6.  German AJ, et al. Vet Immunol Immunopath 1998;64:107.

7.  German AJ, et al. J Vet Intern Med 2001;15:14.

8.  German AJ, et al. Vet Immunol Immunopath 2000;76:25.

9.  Peters IR, et al. Am J Vet Res 2005;66:11.

10. Peters IR, et al. Immunogenetics 2004;56:254.

11. Inohara N, et al. J Biol Chem 2003;278:5509.

12. Hisamatsu T, et al. Gastroenterol 2003;124:993.

13. Jergens AE, et al. Am J Vet Res 1996;57:697.

14. Breitschwerdt EB, et al. JAAHA 1980;16:551.

15. Lothrop Jr CD, et al. Proceedings of the 15th ACVIM Forum, 1997 p. 662.

16. Hall EJ, Batt RM. Am J Vet Res 1990;51:978 & 983

17. Garden OA, et al. Am J Vet Res 2000;61:462.

18. Littman MP, et al. J Vet Intern Med 2000;14:68.

19. Kolbjornsen O, et al. APMIS 1994;102:647.

20. Rustgi AK, Podolsky DK. Sleisenger & Fordtran's Gastrointestinal and Liver Disease, 1998, 49-65.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Edward J. Hall, MA, VetMB, PhD, DECVIM-CA, MRCVS
University of Bristol
Bristol, England


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