Several syndromes, mainly manifested in children, have been linked to an autoinflammatory response. The triggers for such autoinflammatory responses may be environmental, but the underpinnings appear to be genetic in nature. Chronic Recurrent Multifocal Osteomyelitis (CRMO) is one such autoinflammatory disease seen in children where the exact genes involved are poorly defined. Furthermore, the disorder is relatively uncommon and occurs in a genetically diverse population, making genetic studies difficult. Rodent models for autoinflammatory diseases have been developed, but are not ideal. A disease that appears very similar to CRMO, and called hypertrophic osteodystrophy (HOD), occurs in young Weimaraner and Irish Setter dogs. Clinical signs consist of intermittent hyperthermia, bone pain, and soft tissue swellings over affected bones. Both dogs and children have multifocal lytic bone lesions present on radiographs or bone biopsies and they may also present with gastrointestinal signs such as diarrhea and skin pathologies such as pustulosis. Both diseases occur in the absence of detectable infectious agents and are known to have a genetic basis. We propose to identify genetic loci associated with HOD as a model of human inherited autoinflammatory syndromes, and in particular CRMO. HOD in dogs has several advantages as a model: 1) pure breed dogs have extensive linkage disequilibrium, approximately 20 times as long as humans - therefore, identification of associated loci in the dog genome can be achieved using very few individuals and markers;2) Weimaraner and Irish Setter dogs have accumulated genetic autoinflammatory risk factors with strong effects due to inbreeding practices, allowing these genetic risk factors to be more easily traced in dogs than in humans;3) dogs cohabitate the human environment and using owned dogs will eventually facilitate the investigation of gene-environment interactions;and compared to rodent models, 4) the dog is more similar to humans in organ size and metabolism and its genome is closer to the human genome. Preliminary results in Weimaraner dogs suggest that HOD is associated with a specific canine major histocompatibility complex (MHC) class II haplotype (dog leukocyte antigen, DLA-DRB1). The innate immunity genes C4 and TNF-?, intriguing candidates for HOD, are also found in this region on canine chromosome 12. We hypothesize that a mutation in a gene linked to DRB1 is the molecular cause of HOD. Therefore, initial studies will target genes associated with the DLA. A panel of 153 coding single nucleotide polymorphism (SNP) markers from the DLA region will be used to scan affected and non-affected Weimaraner and Irish Setter dogs from our database of DNA samples. If a specific association is found in the DLA, further studies will be conducted to identify the gene that is involved. If no associations are found in the DLA of affected dogs, a two-stage genome wide association (GWA) study will be performed. This GWA will take advantage of the long LD within the Weimaraner and the Irish Setter breeds for initial association, while the short LD between the two breeds will be utilized for fine mapping of any recognized associations.
Hypertrophic Osteodystrophy (HOD) is an autoinflammatory syndrome in dogs that mimics a disease seen in children called Chronic Recurrent Multifocal Osteomyelitis (CRMO). We propose to use the dog model to understand the genes involved in this disease in dogs with the expectation that these same gene might be important in the childhood disease.
