Browsing by Subject "DLA"

Sort by: Order: Results:

Now showing items 1-3 of 3
  • Gershony, Liza C.; Belanger, Janelle M.; Short, Andrea D; Le, Myly; Hytönen, Marjo K.; Lohi, Hannes; Famula, Thomas R; Kennedy, Lorna J; Oberbauer, Anita M. (BioMed Central, 2019)
    Abstract 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.
  • Gershony, Liza C.; Belanger, Janelle M.; Hytönen, Marjo K.; Lohi, Hannes; Oberbauer, Anita M. (2019)
    Symmetrical lupoid onychodystrophy (SLO) is characterized by inflammation of the nail bed and nail sloughing that causes affected dogs considerable pain. Disease etiology remains unclear, although an autoimmune component is suspected. A genome-wide association study on Bearded Collies revealed regions of association on canine chromosomes (CFA) 12 and 17. The large region of association on CFA12 likely consists of two smaller linked regions, both of which are also linked to the dog leukocyte antigen (DLA) class II genes. Dogs homozygous for the alternate allele at the top CFA12 SNP also carried two DLA class II risk haplotypes for SLO, and this locus explained most of the increased risk for disease seen throughout the CFA12 region of association. A stronger peak was seen on CFA17 when analysis was done solely on dogs that carried DLA class II risk haplotypes for SLO. The majority of SLO dogs carried a homozygous alternate genotype on CFA12 and at least one CFA17 risk haplotype. Our findings offer progress toward uncovering the genetic basis of SLO. While the contribution of the CFA17 region remains unclear, both CFA12 and CFA17 regions are significantly associated with SLO disease expression in the Bearded Collie and contain potential candidate genes for this disease.
  • Gershony, Liza C.; Belanger, Janelle M.; Hytönen, Marjo K.; Lohi, Hannes; Oberbauer, Anita M. (2021)
    In dogs, symmetrical lupoid onychodystrophy (SLO) results in nail loss and an abnormal regrowth of the claws. In Bearded Collies, an autoimmune nature has been suggested because certain dog leukocyte antigen (DLA) class II haplotypes are associated with the condition. A genome-wide association study of the Bearded Collie revealed two regions of association that conferred risk for disease: one on canine chromosome (CFA) 12 that encompasses the DLA genes, and one on CFA17. Case-control association was employed on whole genome sequencing data to uncover putative causative variants in SLO within the CFA12 and CFA17 associated regions. Genotype imputation was then employed to refine variants of interest. Although no SLO-associated protein-coding variants were identified on CFA17, multiple variants, many with predicted damaging effects, were identified within potential candidate genes on CFA12. Furthermore, many potentially damaging alleles were fully correlated with the presence of DLA class II risk haplotypes for SLO, suggesting that the variants may reflect DLA class II haplotype association with disease or vice versa. Strong linkage disequilibrium in the region precluded the ability to isolate and assess the individual or combined effect of variants on disease development. Nonetheless, all were predictive of risk for SLO and, with judicious assessment, their application in selective breeding may prove useful to reduce the incidence of SLO in the breed.