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Browsing by Author "Furrow, Eva"

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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.