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Browsing by Subject "dogs"

Now showing 1 - 2 of 2
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    Metabolic and Genetic Determinants of Urolithiasis in a Natural Canine Model
    (2014-06) Furrow, Eva
    Calcium oxalate (CaOx) kidney stones are a common health problem across the world. There is a substantial inherited component to CaOx stone risk, but susceptibility genes have largely evaded identification. The goal of this thesis was to use the dog as a natural model to ascertain metabolic and genetic risk factors for urolithiasis. Cystine and urate stones have previously been reported to have shared susceptibility genes between dogs and people. This thesis demonstrated that 2,8-dihydroxyadenine urolithiasis provides a third example of stone disease with a shared genetic basis between the species. It is likely that there are also overlapping genetic risk factors for CaOx urolithiasis. Prior to initiating genetic investigations into CaOx urolithiasis, three canine breeds were evaluated for metabolic disturbances associated with stone risk. Each of the breeds was shown to have idiopathic hypercalciuria, the trait underlying stone risk in people. Two breeds were subsequently selected for genome-wide association studies. Three unique susceptibility loci were identified. This supports a polygenic basis for CaOx stone risk in dogs. All three loci harbor plasma membrane transporter genes. One locus on CFA37 was selected for variant discovery using whole genome next-generation sequencing. No putative causal mutations were identified in coding sequence for the positional genes, but markers in and near the top candidate gene, SLC39A10, were associated with disease in a large cohort. SLC39A10 encodes a plasma membrane metal ion transporter. Several metals have been debated as potential triggers of stone formation. Genotype for the SLC39A10 risk haplotype was found to correlate with urinary strontium and calcium levels, as well as stone risk. This provides evidence that dogs with the SLC39A10 risk haplotype may have a functional mutation in the gene that directly or indirectly alters handling of strontium and/or calcium. Though no coding variants were found in SLC39A10, the mutation could reside within a regulatory region of the gene. Future sequencing and expression studies are planned to further evaluate SLC39A10 and genes within the other risk loci for a role in CaOx urolithiasis.
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    Novel insights into Addison's disease in dogs
    (2023-05) Treeful, Amy
    Addison’s disease is a dangerous hormone deficiency found in humans and dogs. Studies in humans support a complex autoimmune etiology, however evidence in studies in dogs is sparse. The work summarized in this dissertation was conducted to evaluate contributions from each of the three main types of risk factors of a complex autoimmune disease to developing AD in dogs; immunological, genetic, and environmental risk factors. Firstly, the immunological study tested the hypothesis that similar to humans with AD, dogs with AD have anti-adrenocortical autoantibodies. Several different immunoassays were performed to screen IgGs from three dog breeds predisposed to AD (Standard Poodles, Portuguese Water Dogs, and English Cocker Spaniels) for autoantibodies to adrenal antigens. Two different, mostly non-overlapping positive results were found in Western blots; IgGs from dogs with AD often had antibodies to a 42kDa band or to a 75kDa band. However, inconsistent replicability made it difficult to form definitive conclusions. Results from other immunoassays were also either inconclusive or negative. Secondly, the genetic study tested the hypothesis that certain MHC Class II genes and/or haplotypes are associated with AD in dogs from a breed with elevated risk of developing AD, Standard Poodles. Sanger sequencing of exon 2 of MHC class II haplotypes allowed for the identification of two sex-specific associations. Thirdly, an online survey study was used to compare the frequencies of certain environmental exposures and lifestyle factors between dogs with and without AD in a study cohort consisting of dogs from two high risk breeds, Standard Poodles and Portuguese Water Dogs. The variable with the highest effect size associated with AD was spay (odds ratio 2.5, 95% CI [1.4-3.5]) and neutering (odds ratio 6.0, 95% CI [2.6-13.9]). A lack of consistent positive results in the immunology study can be interpreted several different ways; 1) technical issues prevented autoantibodies from being detected, 2) AD in dogs from the breeds in this study is not immune-mediated, or 3) AD is primarily T-cell mediated and there are no autoantibodies. Results from the genetic and survey study suggest that sex hormones play a role in influencing susceptibility to AD in dogs. However, these results are correlational and future studies are needed to determine whether these associations can be explained by molecular mechanisms.