Naturally occurring dog model for juvenile dermatomyositis. The genetic factors contributing to the development of juvenile dermatomyositis (DM) are poorly defined. Juvenile DM, characterized by a skin rash and progressive muscle weakness, is the most common of the inherited childhood inflammatory myopathies. The long-term goal of this proposal is to facilitate the discovery of genetic factors involved in the development of DM in human populations. A spontaneous, inflammatory myopathy of domestic dogs, also termed dermatomyositis, is clinically, histologically, and immunologically similar to human juvenile DM, and is the only animal model for the disease. Dogs offer numerous advantages for the study of complex traits. Dog breeds are genetically isolated populations, each of which has experienced founder effects, population bottlenecks, and/or popular sire effects, resulting in significant homogeneity. Large litter sizes and a short gestational period yield many more informative meiosis than do human families, and unlike other model organisms, dogs share our environment, have a high level of medical surveillance, and receive regular vaccinations. These factors both enhance the probability that inherited abnormalities will be recognized, and at the same time, enhance their relevance to human health. The overall objective of this proposal is to exploit the homogeneity of the dog model to identify genetic factors that influence the development of DM. The hypothesis here is that DM in dogs is governed by multiple loci with strong effects, and is based on both our own preliminary data, and findings from other investigations into the genetics of canine autoimmune diseases. This hypothesis will be tested by pursuing two specific aims: 1) identify genomic regions associated with canine dermatomyositis, and 2) investigate class II dog leukocyte antigens (DLA) for association with dermatomyositis. Under the first aim, a panel of 127,000 SNPs will be genotyped in DM- affected and control Shetland sheepdogs and used in a case/control analysis to identify genomic regions associated with canine DM. Under the second aim, three-locus haplotypes will be determined for the DLA class II loci, DRB1, DQA1, and DQB1, and assessed for association with DM in dogs. The DLA region is known to be poorly covered by the SNP panel used in Aim 1 and thus must be examined separately.
Both aims have been established as feasible in the applicant's hands. The proposed research will identify genetic factors that are important to disease pathogenesis in a dog model for DM and provide candidate genes that may play a role in disease development in human forms of DM. This approach is innovative because it utilizes a naturally occurring dog model of disease to better understand the complex genetic factors that contribute to DM.
The proposed research is relevant to public health because the identification of genetic factors important in a dog model for dermatomyositis (DM) will provide insight into the disease pathogenesis of human juvenile DM. A deeper knowledge of the genetic basis for DM will ultimately lead to new methods for earlier diagnosis, improved therapies, and a better prognosis for affected children.
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