Necrotizing meningoencephalitis of Pug Dogs associates with dog leukocyte antigen class II and resembles acute variant forms of multiple sclerosis

School of Natural Sciences and Mathematics, Indiana University East, Richmond, IN 47374, USA.
Tissue Antigens (Impact Factor: 2.14). 08/2010; 76(2):110-8. DOI: 10.1111/j.1399-0039.2010.01484.x
Source: PubMed


Necrotizing meningoencephalitis (NME) is a disorder of Pug Dogs that appears to have an immune etiology and high heritability based on population studies. The present study was undertaken to identify a genetic basis for the disease. A genome-wide association scan with single tandem repeat (STR) markers showed a single strong association near the dog leukocyte antigen (DLA) complex on CFA12. Fine resolution mapping with 27 STR markers on CFA12 further narrowed association to the region containing DLA-DRB1, -DQA1 and, -DQB1 genes. Sequencing confirmed that affected dogs were more likely to be homozygous for specific alleles at each locus and that these alleles were linked, forming a single high risk haplotype. The strong DLA class II association of NME in Pug Dogs resembles that of human multiple sclerosis (MS). Like MS, NME appears to have an autoimmune basis, involves genetic and nongenetic factors, has a relatively low incidence, is more frequent in females than males, and is associated with a vascularly orientated nonsuppurative inflammation. However, NME of Pug Dogs is more aggressive in disease course than classical human MS, appears to be relatively earlier in onset, and involves necrosis rather than demyelination as the central pathobiologic feature. Thus, Pug Dog encephalitis (PDE) shares clinical features with the less common acute variant forms of MS. Accordingly, NME of Pug Dogs may represent a naturally occurring canine model of certain idiopathic inflammatory disorders of the human central nervous system.

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    • "In the dog population as a whole, the DLA-DRB1*02001/DQA1*00401/DQB1*01303 haplotype is relatively common with a haplotype frequency of 6.2% amongst approximately 10,000 dogs from over 200 breeds tested (LJ Kennedy, unpublished data). The limited DLA class II haplotype diversity of the Hungarian Vizsla is typical of many other breeds studied [14], including the Pug dog [15]. "
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    ABSTRACT: A breed-specific polymyositis is frequently observed in the Hungarian Vizsla. Beneficial clinical response to immunosuppressive therapies has been demonstrated which points to an immune-mediated aetiology. Canine inflammatory myopathies share clinical and histological similarities with the human immune-mediated myopathies. As MHC class II associations have been reported in the human conditions we investigated whether an MHC class II association was present in the canine myopathy seen in this breed. 212 Hungarian Vizsla pedigree dogs were stratified both on disease status and degree of relatedness to an affected dog. This generated a group of 29 cases and 183 "graded" controls: 93 unaffected dogs with a first degree affected relative, 44 unaffected dogs with a second degree affected relative, and 46 unaffected dogs with no known affected relatives. Eleven DLA class II haplotypes were identified, of which, DLA-DRB1*02001/DQA1*00401/DQB1*01303, was at significantly raised frequency in cases compared to controls (OR = 1.92, p = 0.032). When only control dogs with no family history of the disease were compared to cases, the association was further strengthened (OR = 4.08, p = 0.00011). Additionally, a single copy of the risk haplotype was sufficient to increase disease risk, with the risk substantially increasing for homozygotes. There was a trend of increasing frequency of this haplotype with degree of relatedness, indicating low disease penetrance. These findings support the hypothesis of an immune-mediated aetiology for this canine myopathy and give credibility to potentially using the Hungarian Vizsla as a genetic model for comparative studies with human myositis.
    PLoS ONE 02/2013; 8(2):e56490. DOI:10.1371/journal.pone.0056490 · 3.23 Impact Factor
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    • "NME initially was identified in Pug dogs in the late 1960s (Cordy and Holliday 1989) and is known to have a strong familial association in this breed (Cordy and Holliday 1989; Greer et al. 2009). Studies of Pugs with NME suggest that there are likely multiple genes that contribute to disease phenotype (Greer et al. 2009) and a recent genome-wide study of simple tandem repeat markers in this breed identified regions of disease susceptibility within dog leukocyte antigen (DLA) class II, similar to major histocompatibility complex (MHC) loci previously identified in MS and other proposed autoimmune diseases (Greer et al. 2010). Purebred dog populations provide a unique opportunity for mapping genetic traits and recent technological developments have made it possible to leverage dogs as a model for the study of human genetic disease (Wilbe et al. 2010). "
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    ABSTRACT: Due to their unique population structure, purebred dogs have emerged as a key model for the study of complex genetic disorders. To evaluate the utility of a newly available high-density canine whole-genome array with >170,000 single nucleotide polymorphisms (SNPs), genome-wide association was performed on a small number of case and control dogs to determine disease susceptibility loci in canine necrotizing meningoencephalitis (NME), a disorder with known non-Mendelian inheritance that shares clinical similarities with atypical variants of multiple sclerosis in humans. Genotyping of 30 NME-affected Pug dogs and 68 healthy control Pugs identified 2 loci associated with NME, including a region within dog leukocyte antigen class II on chromosome 12 that remained significant after Bonferroni correction. Our results support the utility of this high-density SNP array, confirm that dogs are a powerful model for mapping complex genetic disorders and provide important preliminary data to support in depth genetic analysis of NME in numerous affected breeds.
    The Journal of heredity 08/2011; 102 Suppl 1(Suppl 1):S40-6. DOI:10.1093/jhered/esr048 · 2.09 Impact Factor
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    • "These results are in agreement with two previous publications: (1) a negative linkage analysis between Nova Scotia duck tolling retrievers with hypoadrenocorticism and the DLA class II region (Hughes et al., 2010); and (2) localization of NME of Pug dogs to the DLA region on cfa12 by a genome-wide association (GWA) study (Greer et al., 2010). Since the DLA-wide SNP panel assays the entire DLA region of 2.5 Mb containing 53 genes, including the MHC class II DRB1, DQA1 and DQB1 genes, for evidence of associations, it is unlikely that a true genetic association would be missed. "
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    ABSTRACT: The dog leukocyte antigen (DLA) system contains many of the functional genes of the immune system, thereby making it a candidate region for involvement in immune-mediated disorders. A number of studies have identified associations between specific DLA class II haplotypes and canine immune hemolytic anemia, thyroiditis, immune polyarthritis, type I diabetes mellitus, hypoadrenocorticism, systemic lupus erythematosus-related disease complex, necrotizing meningoencephalitis (NME) and anal furunculosis. These studies have relied on sequencing approximately 300 bases of exon 2 of each of the DLA class II genes: DLA-DRB1, DLA-DQA1 and DLA-DQB1. In the present study, an association (odds ratio=4.29) was identified by this method between Weimaraner dogs with hypertrophic osteodystrophy (HOD) and DLA-DRB1∗01501. To fine map the association with HOD, a genotyping assay of 126 coding single nucleotide polymorphisms (SNPs) from across the entire DLA, spanning a region of 2.5 Mb (3,320,000-5,830,000) on CFA12, was developed and tested on Weimaraners with HOD, as well as two additional breeds with diseases associated with DLA class II: Nova Scotia duck tolling retrievers with hypoadrenocorticism and Pug dogs with NME. No significant associations were found between Weimaraners with HOD or Nova Scotia duck tolling retrievers with hypoadrenocorticism and SNPs spanning the DLA region. In contrast, significant associations were found with NME in Pug dogs, although the associated region extended beyond the class II genes. By including a larger number of genes from a larger genomic region, a SNP genotyping assay was generated that provides coverage of the extended DLA region and may be useful in identifying and fine mapping DLA associations in dogs.
    The Veterinary Journal 08/2011; 189(2):220-6. DOI:10.1016/j.tvjl.2011.06.023 · 1.76 Impact Factor
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