DLA class II risk haplotypes for autoimmune diseases in the bearded collie offer insight to autoimmunity signatures across dog breeds

Abstract

BackgroundPrimary hypoadrenocorticism (Addison’s disease, AD) and symmetrical lupoid onychodystrophy (SLO) are two clinical conditions with an autoimmune etiology that occur in multiple dog breeds. In man, autoimmunity is associated with polymorphisms in immune-related genes that result in a reduced threshold for, or defective regulation of, T cell activation. The major histocompatibility complex (MHC) class II genes encode molecules that participate in these functions, and polymorphisms within these genes have been associated with autoimmune conditions in dogs and humans. Bearded collies have a relatively high prevalence of autoimmune diseases, particularly AD and SLO. Our study assessed the relationship between particular MHC (dog leukocyte antigen, DLA) class II haplotypes and the two autoimmune diseases most common in this breed. Moreover, five unrelated breeds at increased risk for AD were studied for comparative purposes and analyzed in the context of extant literature.ResultsA single DLA class II three-locus haplotype, determined by sequence-based typing, was associated with increased risk for AD (DLA-DRB1*009:01/DQA1*001:01/DQB1*008:02) in bearded collies. Comparative analysis with the five additional breeds showed limited allele sharing, with DQA1*001:01 and DQB1*002:01 being the only alleles observed in all breeds. A distinct three-locus risk haplotype (DLA-DRB1*001:01/DQA1*001:01/DQB1*002:01) was associated with AD in the West Highland white terrier and Leonberger. Two different risk haplotypes were associated with increased risk for SLO in the bearded collie (DLA-DRB1*018:01/DQA1*001:01/DQB1*002:01 and DLA-DRB1*018:01/DQA1*001:01/ DQB1*008:02).ConclusionTwo-locus DQ haplotypes composed of DLA-DQA1*001:01 in association with DLA-DQB1*002:01 or DLA-DQB1*008:02 make up the four risk haplotypes identified in the present study and are also found in other risk haplotypes previously associated with diabetes mellitus and hypothyroidism across different dog breeds. Our findings build upon previously published data to suggest that this two-locus (DQ) model serves as a good indicator for susceptibility to multiple organ-specific autoimmune diseases in the canine population. However, it is also clear that additional loci are necessary for actual disease expression. Investigation of affected and unaffected dogs carrying these predisposing DQ haplotype signatures may allow for the identification of those additional genetic components that determine autoimmune disease expression and organ specificity.Electronic supplementary materialThe online version of this article (10.1186/s40575-019-0070-7) contains supplementary material, which is available to authorized users.

Dog leucocyte antigen (DLA) class II haplotypes and risk of canine diabetes mellitus in specific dog breeds

“…However, because it was only identified in only 2% of controls and the 95% CI is very wide (0–0.95), this association should be interpreted with caution and further investigated in a larger cohort of WHWTs. A similar observation was made by a study of DLA class II haplotypes in AD [ 42 ]: the same haplotype (001:01--001:01--036:01) was identified solely in the control population of WHWTs (0 cases; 6 controls). However, this may be due to the WHWT control population being much larger than the case population in that study (43 cases; 166 controls).…”

“…In this breed, DLA haplotype 1 (001:01--001:01--002:01) was found to be associated with increased risk of DM (OR = 1.59, 95% CI = 1.02–2.47), which suggests that this particular DLA-type might play a role in the pathogenesis of beta cell loss/dysfunction in this breed. This DLA haplotype has previously been associated with increased risk of hypothyroidism in Gordon Setters [ 41 ] as well as primary hypoadrenocorticism (Addison’s disease; AD) in WHWT and Leonberger breeds [ 42 ]. Notably, both hypothyroidism associated with lymphocytic thyroiditis and primary hypoadrenocorticism are considered to have an autoimmune basis and demonstrate breed differences in susceptibility [ 43 , 44 ].…”

“…For example, in human T1D, polymorphisms at positions 56 and 57 of the DQB chain are associated with either disease susceptibility or resistance, according to the amino acid changes in the peptide binding groove [ 48 ]. It has been suggested that many risk haplotypes associated with organ-specific autoimmune disease in dogs carry either DQA1*001:01--DQB1*002:01 or DQA1*001:01--DQB1*008:02 haplotypes [ 42 ]. The first of these DQ haplotypes is present in haplotype 1 in this study (001:01--001:01--002:01), associated with DM in the Labrador Retriever, however, the second was not present in any haplotypes associated with DM in any of the 12 breeds in the present study.…”

Polymorphisms in the CTLA4 promoter sequence are associated with canine hypoadrenocorticism

“…In dogs, genetic susceptibility to hypoadrenocorticism has been evidenced through breed predispositions and further revealed by pedigree analyses [21][22][23][24][25][26]. More focussed dissection of underlying genetic factors has shown dog leukocyte antigen (DLA) class II variation to be significantly associated with hypoadrenocorticism [5,[27][28][29]. Whilst the significance of these findings have been contested [30,31] it is the case that fine mapping techniques have confirmed MHC associations in human studies as well as revealing further associations and the importance of epistasis [32].…”

Novel Locus Associated with Symmetrical Lupoid Onychodystrophy in the Bearded Collie

“…A genome-wide association study (GWAS) subsequently identified a region of association on canine chromosome (CFA) 12 (12:555,475-3,775,420) that includes the DLA class II genes in English and Gordon Setters [4]. Recently, a study by our laboratory has confirmed the association of two dog leukocyte antigen (DLA) class II risk haplotypes with SLO in the Bearded Collie [12]. Combined, these findings support an autoimmune etiology for SLO.…”