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Identification of novel genetic risk loci in Maltese dogs with necrotizing meningoencephalitis and evidence of a shared genetic risk across toy dog breeds.

ABSTRACT: Necrotizing meningoencephalitis (NME) affects toy and small breed dogs causing progressive, often fatal, inflammation and necrosis in the brain. Genetic risk loci for NME previously were identified in pug dogs, particularly associated with the dog leukocyte antigen (DLA) class II complex on chromosome 12, but have not been investigated in other susceptible breeds. We sought to evaluate Maltese and Chihuahua dogs, in addition to pug dogs, to identify novel or shared genetic risk factors for NME development. Genome-wide association testing of single nucleotide polymorphisms (SNPs) in Maltese dogs with NME identified 2 regions of genome-wide significance on chromosomes 4 (chr4:74522353T>A, p = 8.1×10-7) and 15 (chr15:53338796A>G, p = 1.5×10-7). Haplotype analysis and fine-mapping suggests that ILR7 and FBXW7, respectively, both important for regulation of immune system function, could be the underlying associated genes. Further evaluation of these regions and the previously identified DLA II locus across all three breeds, revealed an enrichment of nominal significant SNPs associated with chromosome 15 in pug dogs and DLA II in Maltese and Chihuahua dogs. Meta-analysis confirmed effect sizes the same direction in all three breeds for both the chromosome 15 and DLA II loci (p = 8.6×10-11 and p = 2.5×10-7, respectively). This suggests a shared genetic background exists between all breeds and confers susceptibility to NME, but effect sizes might be different among breeds. In conclusion, we identified the first genetic risk factors for NME development in the Maltese, chromosome 4 and chromosome 15, and provide evidence for a shared genetic risk between breeds associated with chromosome 15 and DLA II. Last, DLA II and IL7R both have been implicated in human inflammatory diseases of the central nervous system such as multiple sclerosis, suggesting that similar pharmacotherapeutic targets across species should be investigated.

SUBMITTER: Schrauwen I

PROVIDER: S-EPMC4231098 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCanine 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.MethodsThe 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.ResultsFive 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.ConclusionsNovel 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.

Project description:BackgroundThis study describes the presence and frequency of health traits among three populations of dogs traditionally used for sledding and explores their ancestry and breed composition as provided by the commercially available Embark dog DNA test. The three populations include the purebred Siberian Husky and the admixed populations of Alaskan sled dogs and Polar Huskies. While the Siberian Husky represents a well-established breed with extensive historical and health data, the Alaskan sled dog is less studied but has been the subject of nutritional, physiological, and genetic studies related to ancestry and performance. In contrast, the Polar Husky is a relatively obscure and rare group of dogs used for arctic exploration with very little-known information. The three populations were compared using Embark results, providing new insight into the health traits circulating within the populations and the potential ancestral linkage of the health traits between the sledding populations. Embark results are based upon 228,588 single-nucleotide polymorphisms (SNPs) spanning the canine genome, characterized using a custom-designed Illumina beadchip array.ResultsSpecifically, breed composition was summarized for the two admixed populations with most of the dogs being predominantly categorized as Alaskan husky- type dog or "Supermutt". Mitochondrial and Y chromosome haplogroups and haplotypes were found with Alaskan sled dogs carrying most of the haplogroups and types found in Siberian and Polar Huskies. Genomic principal component analysis reflected population structure corresponding to breed and substructure within the Alaskan sled dogs related to sprint or distance competition. Genetic markers associated with Alanine Aminotransferase activity, Alaskan Husky Encephalopathy, dilated cardiomyopathy, Collie eye anomaly, degenerative myelopathy, ichthyosis, and factor VII deficiency were identified in the populations of sledding breeds.ConclusionThese results provide a preliminary description of genetic characteristics found in sledding breeds, improving the understanding and care of working sled dogs.

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Identification of novel genetic risk loci in Maltese dogs with necrotizing meningoencephalitis and evidence of a shared genetic risk across toy dog breeds.

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