Abstract
Canine hypoadrenocorticism is believed to be an immune-related condition. It is rare in the overall dog population but shows a breed-related predisposition with Standard poodles and Portuguese water dogs having a greater prevalence of the condition. It shares many similarities with human primary adrenal insufficiency and is believed to be a naturally occurring, spontaneous model for the human condition. Short haplotype blocks and low levels of linkage disequilibrium in the human genome mean that the identification of genetic contributors to the condition requires large sample numbers. Pedigree dogs have high linkage disequilibrium and long haplotypes within a breed, increasing the potential of identifying novel genes that contribute to canine genetic disease. We investigated 222 SNPs from 42 genes that have been associated or may be implicated in human Addison's disease. We conducted case-control analyses in 3 pedigree dog breeds (Labrador retriever: affected n = 30, unaffected = 76; Cocker Spaniel: affected n = 19, unaffected = 53; Springer spaniel: affected n = 26, unaffected = 46) and identified 8 associated alleles in genes COL4A4, OSBPL9, CTLA4, PTPN22, and STXBP5 in 3 pedigree breeds. Association with immune response genes PTPN22 and CTLA4 in certain breeds suggests an underlying immunopathogenesis of the disease. These results suggest that canine hypoadrenocorticism could be a useful model for studying comparative genetics relevant to human Addison's disease.
Highlights
Adrenal insufficiency is a clinical condition in which pathology or functional defects of the adrenal cortex result in inadequate secretion of corticosteroid hormones
A diagnosis of canine hypoadrenocorticism can be problematic, and it is suspected that some affected dogs die or are euthanazed before a diagnosis is made
There is currently no adrenal autoantibody test for hypoadrenocorticism in dogs and histopathological evidence points to an immune-mediated destruction of the adrenal cortex, it is possible that the disease is more heterogeneous in nature and that some breeds may not have autoimmune involvement
Summary
Adrenal insufficiency is a clinical condition in which pathology or functional defects of the adrenal cortex result in inadequate secretion of corticosteroid hormones. Dogs suffer from hypoadrenocorticism with adrenal pathology (destruction of the cortical layers and infiltration by lymphocytes and plasma cells) and clinical presentation similar to human autoimmune Addison’s disease (Boujon 1994; Peterson et al 1996; Feldman and Nelson 2004; Thompson et al 2007; Adissu et al 2010). While the dog may not be an ideal animal model for laboratory investigations, the spontaneous nature of hypoadrenocorticism in this species (including atrophy of the adrenal cortex) and the breed structure of the dog population make canine hypoadrenocorticism a potential model for the identification of susceptibility genes, which could be further investigated as candidate genes in human Addison’s disease. A candidate gene study of canine hypoadrenocorticism was undertaken in three dog breeds to help resolve the heterogeneity of the condition in the dog population and to determine whether human Addison’s disease and canine hypoadrenocorticism share similar susceptibility genes
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