Page 28 - Copper-associated hepatitis in the Labrador retriever diagnosis, treatment and genetics

Chapter 1
intake on the expression of the disease phenotype is noticed; a same strong effect is seen in the Labrador retrievers. On the other hand, a change to a low copper diet in Bedlington terriers did not halt disease progression (personal communication Dr. R. Favier). In dogs, no neurological impairments have been noticed, although behavioral changes have been seen in Dobermanns, Labrador retrievers and Bedlington terriers. More research is needed in order to conclude if copper accumulation in brain may influence these behavioral changes.
In the search for new genes involved in copper metabolism, genome wide association studies in dog breeds with a high prevalence of copper toxicosis could make a valuable contribution. Unlike the heterogeneity of most human populations, the structure of dog breed populations is homogeneous, which is advantageous for unraveling the molecular genetics of complex diseases139; 140. For this reason, the dog was one of the first mammals of which the genome was sequenced to a high quality level141. As a consequence of breeding practices and population bottlenecks, linkage disequilibrium in the dog genome extends over distances that are up to 100 times longer than in the human genome and the number of haplotype variants in a breed is small141;142. This means that, relative to human studies, genotyping of a limited number of SNPs in small patient and control groups suffice for a genome wide association study (GWAS). For this purpose a 170K SNP array has been developed by Illumina in collaboration with the LUPA consortium131. Large LD-blocks in dogs may be a drawback in pinpointing the location of the gene of interest, however subsequent fine-mapping across breeds is an approach to overcome this problem143.
In addition to genetic homogeneity, the copper toxicosis phenotype within breeds is also much more homogeneous compared to, for example, WD phenotypes, which make a correct diagnosis more feasible. In dogs no biomarkers for copper status exist, therefore a liver biopsy is always needed to establish the diagnosis of copper toxicosis. This is beneficial for genetic studies, because a precise copper quantification as well as a careful histological description of the liver biopsy is often available. In addition, the availability of liver tissue opens the opportunity for transcriptomics and proteomics studies in order to gain insight in disease pathogenesis and the effect of gene
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