Naturally occurring dog model for inherited autoinflammatory diseases in children

描述（由申请人提供）：几种主要表现在儿童身上的综合征与自身炎症反应有关。这种自身炎症反应的触发因素可能是环境因素，但其基础似乎是遗传因素。慢性复发性多灶性骨髓炎（CRMO）是一种发生在儿童身上的自身炎症性疾病，其确切的相关基因尚未明确。此外，这种疾病相对罕见，而且发生在基因多样化的人群中，这使得基因研究变得困难。啮齿类动物自身炎症性疾病的模型已经建立，但并不理想。一种与CRMO非常相似的疾病，称为肥厚性骨营养不良症（HOD），发生在年轻的威玛犬和爱尔兰塞特犬身上。临床症状包括间歇性热疗、骨痛和受影响骨骼的软组织肿胀。狗和儿童在x光片或骨活组织检查中都有多灶性溶解性骨病变，还可能出现腹泻等胃肠道症状和脓疱病等皮肤病变。这两种疾病都是在没有可检测到的传染原的情况下发生的，并且已知具有遗传基础。我们建议确定与HOD相关的基因位点，作为人类遗传性自身炎症综合征的模型，特别是CRMO。狗的HOD作为模型有几个优点：1)纯种狗有广泛的连锁不平衡，大约是人类的20倍-因此，狗基因组中相关位点的鉴定可以使用很少的个体和标记；2)由于近亲繁殖，威玛猎犬和爱尔兰塞特犬积累了具有强烈影响的遗传自身炎症风险因素，使得这些遗传风险因素在狗身上比在人身上更容易被追踪；(3)狗与人类环境共存，使用自己养的狗最终将有助于研究基因与环境的相互作用；与啮齿类动物模型相比，狗在器官大小和新陈代谢方面与人类更相似，其基因组更接近人类基因组。在威玛犬中的初步结果表明，HOD与一种特定的犬主要组织相容性复合体（MHC） II类单倍型（犬白细胞抗原，DLA-DRB1）有关。先天免疫基因C4和TNF-？在犬12号染色体的这个区域也发现了一个有趣的候选基因。我们假设与DRB1相关的基因突变是HOD的分子原因。因此，最初的研究将针对与DLA相关的基因。来自DLA区域的153个编码单核苷酸多态性（SNP）标记将用于扫描DNA样本数据库中受影响和未受影响的魏玛拉犬和爱尔兰塞特犬。如果在DLA中发现了特定的关联，将进行进一步的研究以确定所涉及的基因。如果在受影响犬的DLA中没有发现关联，将进行两阶段全基因组关联（GWA）研究。该GWA将利用威玛猎犬和爱尔兰塞特犬种之间的长LD进行初始关联，而两个品种之间的短LD将用于任何公认的关联的精细映射。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.