MHC class II association study in eight breeds of dog with hypoadrenocorticism

Abstract

Canine hypoadrenocorticism is an endocrine disorder characterised by inadequate secretion of steroid hormones from the adrenal glands. Pathology results from immune-mediated destruction of the adrenal cortex, which is similar to that seen in the human Addison's disease. Both the canine and human diseases have similar clinical presentation, with the diagnosis based on performing a dynamic adrenocorticotropic hormone stimulation test. MHC class II has previously been associated with the human and canine diseases. In the current study, we conducted an MHC class II association study in eight breeds of dog with diagnoses of hypoadrenocorticism. We demonstrated significant differences in dog leukocyte antigen (DLA) haplotype frequencies in six of these breeds: Cocker spaniel, Springer spaniel, Labrador, West Highland white terrier (WHWT), Bearded collie, and Standard poodle. In the Springer spaniel, the DLA-DRB1*015:01--DQA1*006:01--DQB1*023:01 haplotype was significantly associated with disease risk (p = 0.014, odds ratio (OR) = 5.14) and showed a similar trend in the Cocker spaniel. This haplotype is related to one associated with hypoadrenocorticism in the Nova Scotia duck tolling retriever. Similar haplotypes shared between breeds were demonstrated, with DLA-DRB1*001:01--DQA1*001:01--DQB1*002:01 more prevalent in both affected Labrador (p = 0.0002, OR = 3.06) and WHWT (p = 0.01, OR = 2.11). Other haplotypes that have not previously been associated with the disease were identified. The inter-breed differences in DLA haplotypes associated with susceptibility to canine hypoadrenocorticism could represent divergent aetiologies. This could have implications for clinical diagnosis and future comparative studies. Alternatively, it may suggest that the gene of interest is closely linked to the MHC.

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.…”

Hypoadrenocorticism

“…Two disease associated loci on canine autosomes CFA 12 and 37, which are syntenic with the human DRB1 histocompatibility locus alleles HLA-DRB1*04 and DRB1*0301, have been identified in Portuguese Water dogs with hypoadrenocorticism (Chase et al, 2006). For example in the Springer and Cocker Spaniel the DLA-DRB1*015:01-DQA1*006-DQB1*023:01 haplotype is significantly associated with disease risk (Massey et al, 2013). For example in the Springer and Cocker Spaniel the DLA-DRB1*015:01-DQA1*006-DQB1*023:01 haplotype is significantly associated with disease risk (Massey et al, 2013).…”

Evaluation of a DLA-79 allele associated with multiple immune-mediated diseases in dogs

“…We also accessed the protein-coding genes from ImmunoBase version 1.7 (www.immunobase.org) and included these in our analysis (Parkes et al 2013). After developing a preliminary list of candidate genes based upon the frequency of association with human autoimmune disease, we cross-referenced our findings with genes that have been implicated in canine immune-mediated diseases including IMHA, T1D, and systemic lupus erythematosus (Wilbe et al 2009; Wilbe et al 2010c; Pedersen et al 2012a; Pedersen et al 2012b; Massey et al 2013a; Catchpole et al 2013; Short et al 2013). We ultimately selected 15 of these genes for targeted resequencing, which represented the maximum number of genes that could be covered within a 500 Kb capture region.…”

“…Analysis of this network of genes has led to the theory that an accumulated burden of genetic variants causes an underlying predisposition to multiple immune-mediated diseases (Cotsapas et al 2011; Gregersen et al 2012; Cotsapas and Hafler 2013). Some of these genes, such as the Major Histocompatibility Complex (MHC) class II genes, PTPN22, and CTLA4, have been associated with specific canine immune-mediated diseases (Kennedy et al 2006b; Kennedy et al 2006a; Short et al 2010; Greer et al 2010; Barber et al 2011; Massey et al 2013b; Massey et al 2013a; Catchpole et al 2013; Short et al 2013; Schrauwen et al 2014), but the importance of broader gene networks across multiple immune-mediated diseases is not well understood in dogs.…”