Naturally occurring dog model for inherited autoinflammatory diseases in children

自然发生的儿童遗传性自身炎症性疾病的狗模型

• 批准号: 8085932
• 负责人: DANIKA L BANNASCH
• 金额: $ 18.99万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-10 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8085932
• 关键词: Affect; Biological Models; Biopsy; Bone Pain; Breeding; Canis familiaris; Caring; Characteristics; Child; Childhood; Chromosomes, Human, Pair 12; Chronic; Clinical; Code; DNA Databases; Diarrhea; Disease; Environment; Fever; Gene Targeting; Genes; Genetic; Genome; Genomics; Genotype; HLA Antigens; Haplotypes; Histocompatibility Antigens Class II; Home environment; Human; Human Genome; Immune System Diseases; Inbreeding; Individual; Infectious Agent; Inflammation; Inherited; Investigation; Lesion; Link; Linkage Disequilibrium; Lytic; Maps; Medical; Metabolism; Modeling; Molecular; Mutation; Natural Immunity; Nature; Organ Size; Osteomyelitis; Pathology; Population Heterogeneity; Recurrence; Risk Factors; Rodent Model; Sampling; Scanning; Single Nucleotide Polymorphism; Skin; Staging; Swelling; Syndrome; TNF gene; Time; Work; base; bone; dog genome; expectation; gastrointestinal sign; gene environment interaction; genetic risk factor; genome wide association study; long bone; public health relevance; response; soft tissue

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.

描述（由申请人提供）：主要出现在儿童中的几种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) 是一种常见于儿童的自身炎症性疾病，其中涉及的确切基因尚不清楚。此外，这种疾病相对不常见，并且发生在遗传多样化的人群中，这使得遗传研究变得困难。自身炎症性疾病的啮齿动物模型已经开发出来，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 (HOD)，发生在年轻的威玛猎犬和爱尔兰雪达犬身上。临床症状包括间歇性高热、骨痛和受影响骨骼上的软组织肿胀。狗和儿童在射线照片或骨活检中都存在多灶性溶骨性病变，它们还可能出现胃肠道症状，例如腹泻和皮肤病变，例如脓疱病。这两种疾病都是在没有可检测到的传染源的情况下发生的，并且已知都有遗传基础。 我们建议鉴定与 HOD 相关的遗传位点作为人类遗传性自身炎症综合征（特别是 CRMO）的模型。狗的 HOD 作为模型有几个优点：1）纯种狗具有广泛的连锁不平衡，大约是人类的 20 倍 - 因此，使用很少的个体和标记就可以实现狗基因组中相关基因座的鉴定； 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性自身炎症危险因素，使得这些遗传危险因素在狗身上比在人类身上更容易被追踪到； 3）狗与人类环境共存，使用自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，4）狗的器官大小和新陈代谢与人类更相似，其基因组更接近人类基因组。 威玛猎犬的初步结果表明，HOD 与特定的犬主要组织相容性复合体 (MHC) II 类单倍型（狗白细胞抗原，DLA-DRB1）相关。先天免疫基因 C4 和 TNF-α 是 HOD 的有趣候选基因，也在犬 12 号染色体上的该区域中发现。我们假设与 DRB1 相关的基因中的突变是 HOD 的分子原因。因此，初步研究将针对与 DLA 相关的基因。来自 DLA 区域的一组 153 个编码单核苷酸多态性 (SNP) 标记将用于从我们的 DNA 样本数据库中扫描受​​影响和未受影响的威玛猎犬和爱尔兰塞特犬。如果在 DLA 中发现特定关联，将进行进一步研究以确定所涉及的基因。如果受影响狗的 DLA 中未发现关联，则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品种内的长 LD 进行初始关联，而这两个品种之间的短 LD 将用于任何公认关联的精细绘制。 公众健康相关性：肥厚性骨营养不良 (HOD) 是狗的一种自身炎症综合征，类似于儿童中出现的一种称为慢性复发性多灶性骨髓炎 (CRMO) 的疾病。我们建议使用狗模型来了解狗中与这种疾病有关的基因，并期望这些相同的基因可能在儿童疾病中发挥重要作用。

项目成果

Genome-wide association mapping in dogs enables identification of the homeobox gene, NKX2-8, as a genetic component of neural tube defects in humans.

• DOI: 10.1371/journal.pgen.1003646
• 发表时间: 2013
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Safra N;Bassuk AG;Ferguson PJ;Aguilar M;Coulson RL;Thomas N;Hitchens PL;Dickinson PJ;Vernau KM;Wolf ZT;Bannasch DL
• 通讯作者: Bannasch DL