Association of a common dog leucocyte antigen class II haplotype with canine primary immune‐mediated haemolytic anaemia

Abstract

Immune-mediated haemolytic anaemia (IMHA) is the commonest immune-mediated disease of the dog, representing a major health concern to this species. The aim of this investigation was to determine whether genetic susceptibility to IMHA is associated with genes of the canine major histocompatibility complex (MHC; dog leucocyte antigen system, DLA). Samples were collected from 108 dogs with primary idiopathic, Coombs' positive IMHA. This diseased population was subdivided on the basis of Coombs' test results into two groups: 1) dogs with dominant warm-reactive immunoglobulin (Ig) G haemagglutinins and (2) dogs with an additional or dominant cold-reactive IgM haemagglutinin. The DLA class II alleles and haplotypes of the diseased population were characterised, and these data were compared with those derived from a breed-matched control cohort and a much larger group of DLA-typed dogs. Two haplotypes were increased in the patient group: DLA-DRB1*00601/DQA1*005011/DQB1*00701 (in the group with warm-reactive IgG haemagglutinins only) and DLA-DRB1*015/DQA1*00601/DQB1*00301 (in both groups, but more so in the group with cold-reactive IgM haemagglutinins). One haplotype, DLA-DRB1*001/DQA1*00101/DQB1*00201, was decreased in the total patient group, but this decrease was limited to the warm-reactive IgG haemagglutinins group, and it was actually increased in the cold-reactive IgM haemagglutinins group. A second haplotype, DLA-DRB1*015/DQA1*00601/DQB1*02301, was also decreased in the total patient group, and this decrease was found in both subgroups. In addition, all haplotypes carrying DLA-DRB1*001 were significantly increased in the cold-reactive IgM haemagglutinins group. When the overall patient group was divided on the basis of individual breeds with more than six animals represented, each of the haplotypes could be shown to be implicated in one of the breeds. Thus, it was apparent that different breeds had different MHC associations with canine IMHA, which is similar to the observation that different human ethnic groups can have different HLA associations with the same immune-mediated disease.

Canine idiopathic immune-mediated haemolytic anaemia: a review with recommendations for future research

“…Odds ratios or hazard rates attributed to breed are higher than those conferred by DLA haplotype suggesting that the risk for IMHA cannot be explained solely by the DLA haplotype (Klag et al 1993;Miller et al 2004;Kennedy et al 2006;McAlees 2010). Several other genes are involved in the immune response cluster in the MHC region and show strong linkage disequilibrium with MHC genes (Horton et al 2004).…”

“…In case of Bichon frise, Finnish spitz, Miniature Pinscher, and the Rough-coated Collie, the author acknowledged that the numbers of dogs with this breed with IMHA may have been too low in study to accurately assess risk on IMHA. The risks associated with a specific DLA haplotype differed between breeds (Kennedy et al 2006). OR, Odds Ratio; HR, Hazard Ratio; and -, not reported.…”

“…The recognition of foreign proteins or selfproteins by the major histocompatibility complex (MHC) proteins is one of the key events in the development of immune-mediated disease (McDevitt 2000). Canine IMHA is associated with both susceptible and protective dog leucocyte antigen (DLA) haplotypes which, interestingly, are associated with different effects in specific breeds (Kennedy et al 2006; Table 1). The presence of autoreactive T-cells in dogs with IMHA supports the view that MHC molecules are candidate susceptibility genes for IMHA (Corato et al 1997).…”

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.…”

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

“…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.…”