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

ABSTRACT: Background: Canine diabetes mellitus (DM) is a common endocrine disease in domestic dogs. A number of pathological mechanisms are thought to contribute to the aetiopathogenesis of relative or absolute insulin deficiency, including immune-mediated destruction of pancreatic beta cells. DM risk varies considerably between different dog breeds, suggesting that genetic factors are involved and contribute susceptibility or protection. Associations of particular dog leucocyte antigen (DLA) class II haplotypes with DM have been identified, but investigations to date have only considered all breeds pooled together. The aim of this study was to analyse an expanded data set so as to identify breed-specific diabetes-associated DLA haplotypes.

Methods: The 12 most highly represented breeds in the UK Canine Diabetes Register were selected for study. DLA-typing data from 646 diabetic dogs and 912 breed-matched non-diabetic controls were analysed to enable breed-specific analysis of the DLA. Dogs were genotyped for allelic variation at DLA-DRB1, -DQA1, -DQB1 loci using DNA sequence-based typing. Genotypes from all three loci were combined to reveal three-locus DLA class II haplotypes, which were evaluated for statistical associations with DM. This was performed for each breed individually and for all breeds pooled together.

Results: Five dog breeds were identified as having one or more DLA haplotype associated with DM susceptibility or protection. Four DM-associated haplotypes were identified in the Cocker Spaniel breed, of which one haplotype was shared with Border Terriers. In the three breeds known to be at highest risk of DM included in the study (Samoyed, Tibetan Terrier and Cairn Terrier), no DLA haplotypes were found to be associated with DM.

Conclusions: Novel DLA associations with DM in specific dog breeds provide further evidence that immune response genes contribute susceptibility to this disease in some cases. It is also apparent that DLA may not be contributing obvious or strong risk for DM in some breeds, including the seven breeds analysed for which no associations were identified.

SUBMITTER: Denyer AL

PROVIDER: S-EPMC7603736 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Denyer A L AL Massey J P JP Davison L J LJ Ollier W E R WER Catchpole B B Kennedy L J LJ

Canine medicine and genetics 20201031 1

<h4>Background</h4>Canine diabetes mellitus (DM) is a common endocrine disease in domestic dogs. A number of pathological mechanisms are thought to contribute to the aetiopathogenesis of relative or absolute insulin deficiency, including immune-mediated destruction of pancreatic beta cells. DM risk varies considerably between different dog breeds, suggesting that genetic factors are involved and contribute susceptibility or protection. Associations of particular dog leucocyte antigen (DLA) class ...[more]

PMID: 33292601

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Project description:Background:Primary 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. Results:A 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). Conclusion:Two-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.

Project description:JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50-60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR?=?0.42, p?=?7×10(-15)) and controls (OR?=?0.53, p?=?2×10(-5)). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR?=?1.63, p?=?0.006), and controls (OR?=?2.69, p?=?1×10(-5)). The German dataset confirmed these findings (OR?=?0.54, p?=?1×10(-4) and OR?=?1.58, p?=?0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention.

Dataset Information

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

Publications

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

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