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）：主要在儿童中表现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性的。慢性复发性多灶性骨髓炎（CRMO）是一种见于儿童的自身炎症性疾病，其中涉及的确切基因定义不清。此外，这种疾病相对罕见，并且发生在遗传多样性的人群中，使得遗传研究变得困难。已经开发了用于自身炎性疾病的啮齿动物模型，但并不理想。一种与CRMO非常相似的疾病，称为肥大性骨营养不良（HOD），发生在年轻的威玛犬和爱尔兰塞特犬中。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。犬和儿童在X线片或骨活检中均存在多灶性溶骨性病变，它们也可能存在胃肠道体征，如腹泻和皮肤病理学，如脓疱病。这两种疾病都是在没有可检测到的感染因子的情况下发生的，并且已知具有遗传基础。 我们建议确定与HOD相关的遗传基因座作为人类遗传性自身炎症综合征的模型，特别是CRMO。1）纯种狗具有广泛的连锁不平衡，大约是人类的20倍-因此，可以使用非常少的个体和标记来实现狗基因组中相关基因座的鉴定; 2）由于近亲繁殖，魏玛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风险因子，使这些遗传风险因素在狗中比在人类中更容易追踪; 3）狗与人类环境同居，并且使用拥有的狗最终将促进基因-环境相互作用的调查;与啮齿动物模型相比，4）狗在器官大小和代谢方面与人类更相似，其基因组更接近人类基因组。 在威玛犬的初步结果表明，HOD是与一个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-DRB 1）。先天免疫基因C4和TNF-？，HOD的有趣候选者也在犬12号染色体上的该区域中发现。我们假设与DRB 1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。一组153编码单核苷酸多态性（SNP）标记从DLA区域将被用来扫描受影响和未受影响的威玛和爱尔兰塞特犬从我们的数据库的DNA样本。如果在DLA中发现特定的关联，将进行进一步的研究以确定涉及的基因。如果在受影响犬的DLA中未发现关联，则将进行两阶段全基因组关联（GWA）研究。这个GWA将利用威马和爱尔兰塞特犬品种内的长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。 公共卫生关系：肥大性骨营养不良（HOD）是一种犬的自身炎症综合征，类似于儿童慢性复发性多灶性骨髓炎（CRMO）。我们建议使用狗模型来了解狗中参与这种疾病的基因，期望这些相同的基因在儿童疾病中可能是重要的。

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