Association of a dog leukocyte antigen class II haplotype with hypoadrenocorticism in Nova Scotia Duck Tolling Retrievers

Abstract

Canine hypoadrenocorticism (Addison's disease) is due to a deficiency of corticosteroids and mineralocorticoids produced by the adrenals. Although this is a relatively uncommon disease in the general dog population, some breeds, including the Nova Scotia Duck Tolling Retriever (NSDTR), are at increased risk for developing hypoadrenocorticism. A prior study has shown that the increased risk is due to a heritable component. This potentially lethal disorder is hypothesized to have an autoimmune etiology, thus the aim of this study was to determine whether genetic susceptibility to hypoadrenocorticism in NSDTRs is associated with genes of the canine major histocompatibility complex [MHC; dog leukocyte antigen system (DLA)]. Samples were collected from NSDTRs diagnosed with hypoadrenocorticism and healthy siblings or country-matched controls. The DLA class II alleles and haplotypes were determined and compared between cases and controls. We found seven different haplotypes of which the haplotype DLA-DRB1*01502/DQA*00601/DQB1*02301 was significantly more prevalent in the diseased dogs (P = 0.044). In addition, these affected dogs also were more likely to be homozygous across the DLA class II region than the control dogs (OR = 6.7, CI = 1.5-29.3, P = 0.011). We also found that homozygous dogs, regardless of their haplotype, tended to have earlier disease onset compared with heterozygous dogs. These data indicate a limited MHC diversity in North American NSDTRs and suggest that the MHC may play a role in the development of hypoadrenocorticism in the NSDTR, supporting the autoimmune origin of the disease.

Lymphocyte Subsets in the Adrenal Glands of Dogs With Primary Hypoadrenocorticism

“…This finding is consistent with the association of MHC class II genes and canine AD 1,8,11 , as certain CD4+ T cell subsets (T fh cells) directly interact with MHC class II molecules on the surface of dendritic cells. 10 It is also consistent with what is believed to occur in the adrenal glands of human patients with AD.…”

Expanded dog leukocyte antigen (DLA) single nucleotide polymorphism (SNP) genotyping reveals spurious class II associations

“…This diverse group of diseases includes type I diabetes mellitus of the Samoyed dog and Cairn and Tibetan terriers (Kennedy et al, 2006a, 2007c; Catchpole et al, 2008), immune-hemolytic anemia (Kennedy et al, 2006b), systemic lupus erythematosus-related disease complex (Wilbe et al, 2009) and hypoadrenocorticism (Hughes et al, 2010) in Nova Scotia duck tolling retrievers, anal furunculosis in German shepherd dogs (Kennedy et al, 2008), necrotizing meningoencephalitis (NME) of Pug dogs (Greer et al, 2010), autoimmune lymphocytic thyroiditis (Wilbe et al, 2010) and Vogt-Koyanagi-Harada-like syndrome of the Akita (Angles et al, 2005a). …”

Dog Leukocyte Antigen Class II–Associated Genetic Risk Testing for Immune Disorders of Dogs: Simplified Approaches Using Pug Dog Necrotizing Meningoencephalitis as a Model

“…A Vogt-Koyanagi-Harada-like syndrome of Akita dogs has a strong association with certain alleles and allele combinations of DLA class II genes, 1 as does autoimmune hemolytic anemia, 20 immune arthritis, 28 hypothyroidism in several breeds, 25,26,38 type I diabetes mellitus in Samoyed dogs and Cairn and Tibetan Terriers, 23 anal furunculosis of German Shepherd Dogs, 5 and systemic lupus erythematosus-related complex of Nova Scotia Tolling Retrievers. 37 Necrotizing meningoencephalitis (NME) of Pug dogs 10 and Addison disease in Nova Scotia Duck Tolling Retrievers 12 have been recently added to this growing list. Dog leukocyte antigen class II associations have also been described for visceral leishmaniasis 30 in domestic dogs in Spain and for generalized demodicosis in Boxer, Argentinean Mastiff, and mixed-breed dogs in Argentina.…”