Genetics of Juvenile Idiopathic Arthritis

描述(由申请人提供)：本申请涉及广泛的挑战领域(08)基因组学和特定挑战主题，08-AR-101：风湿、皮肤和肌肉骨骼疾病现有队列的基因分型。这些研究将利用现有的临床队列来创建一个广泛共享的数据资源，而这个数据资源目前在这个重要的疾病领域是缺失的，我们将向所有研究人员提供这一资源。这项工作的直接结果将是向基因型和表型数据库(DBGaP)提交一个大型的基因-表型数据库，其中包括&gt；3000例青少年特发性关节炎(JIA)病例。这个数据库将允许我们的合作工作组和其他人进行分析项目，以确定导致疾病风险的基因位点。这些数据集还将提供从我们自己的新的方法学分析方法中得出的结果，这些方法的目的是确定JIA的遗传风险因素。贾樟柯是导致儿童后天残疾的头号原因，每1000名儿童中就有一名患有这种疾病。最近的报告，包括我们自己的报告，已经发现了多个亚型炎症性关节炎(例如，血清阳性的成人类风湿性关节炎、全身性JIA、多关节JIA)常见的基因变异。这些基因可能代表了易患关节炎的“总开关”，与其他影响表型亚型的基因协同作用。该项目试图通过对大量表型良好的人群进行基因分型来阐明JIA的遗传基础。因此，在我们具体目标的第一阶段，我们建议在从大费城地区和合作的国际中心招募的1500例JIA病例的发现队列中，定义具有证据的JIA候选区域。这个队列中大约50%的人已经进行了基因分型，这笔资金将使我们能够通过对700多个额外样本进行全基因组关联(GWA)分析来扩大这个数据集(所有样本都已经在手中)，使用基于高密度单核苷酸多态(SNP)的设计来跟踪60万个潜在的多态。在第二阶段，我们将通过对招募到其他合作地点的表型良好的JIA病例的另外1000个现有样本进行选择性基因分型，来复制我们的发现。该数据库将与来自8,000多个基因分型对照的匹配样本进行对比，我们预计其中至少有4,000个是完美匹配的。我们假设，全基因组范围的个体SNPs、SNP单倍型或CNV与JIA的关联将识别易患JIA的候选危险基因和结构变异。这个挑战项目将创造或保留4个就业机会，并将购买美国制造的产品。幼年特发性关节炎(JIA)是儿童获得性残疾的头号原因。我们的项目试图确定重要的基因，当这些基因改变时，会使儿童处于JIA的高危状态，进而建议使用新的药物靶点来改善这些儿童的结果。

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (08) Genomics and specific Challenge Topic, 08-AR-101: Genotyping of Existing Cohorts in Rheumatic, Skin, and Musculoskeletal Diseases. These studies will utilize existing clinical cohorts to create a broadly shared data resource that is currently missing in this important disease area and we will make this resource available to all researchers. The immediate result of the work will be submission of a large genotype-phenotype dataset, consisting of >3,000 cases of Juvenile Idiopathic Arthritis (JIA), to the Database of Genotypes and Phenotypes (dbGaP). This database will allow our collaborative working group and others to pursue analytical projects that will identify genetic loci contributing to disease risk. The datasets will also provide access to results derived from our own new methodological analytical approaches aimed at the identification of genetic risk factors for JIA. JIA is the #1 cause of acquired disability in children, afflicting one in every one thousand children. Recent reports, including our own, have identified genetic variants common to multiple subtypes of inflammatory arthritis (e.g., seropositive adult rheumatoid arthritis, systemic JIA, polyarticular JIA). These genes could represent "master switches" predisposing to arthritis in general, in concert with other genes that contribute to phenotypic subtype. This project seeks to elucidate the genetic underpinnings of JIA by genotyping a large well-phenotyped population. Accordingly, in Stage 1 of our Specific Aim, we propose to define JIA candidate regions with evidence for association in a discovery cohort of 1,500 JIA cases recruited from the greater Philadelphia area and collaborating international centers. Approximately 50% of this cohort is already genotyped and this funding will enable us to augment this dataset by whole genome-wide association (GWA) analyses of over 700 additional samples (all of which are already in-hand), using a high-density single nucleotide polymorphism (SNP)-based design to track 600,000 potential polymorphisms. In Stage 2, we will replicate our findings by selective genotyping of an additional 1,000 existing samples from well-phenotyped JIA cases recruited to other collaborating sites. This database will be leveraged against matched samples from a collection of over 8,000 genotyped controls, from which we expect at least 4,000 to be a perfect match. We hypothesize that the association of genome-wide individual SNPs, SNP haplotypes, or CNVs with JIA will identify candidate risk genes and structural variants that predispose to JIA. This Challenge project will create or retain 4 jobs and will buy American-made products. Juvenile idiopathic arthritis (JIA) is the #1 cause of acquired disability in children. Our project seeks to identify important genes that, when altered, put a child at high-risk for JIA, in turn suggesting new targets for drugs to improve outcomes for these children.