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）基因组学和特定的挑战主题，08-AR-101：风湿性、皮肤和肌肉骨骼疾病中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，这是目前在这一重要疾病领域缺失的，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）提交一个大型基因型-表型数据集，包括> 3，000例幼年特发性关节炎（JIA）病例。该数据库将使我们的合作工作组和其他人能够进行分析项目，以确定导致疾病风险的遗传位点。这些数据集还将提供从我们自己的新方法分析方法中获得的结果，这些方法旨在识别JIA的遗传风险因素。JIA是儿童获得性残疾的头号原因，每1000名儿童中就有一名受到影响。最近的报告，包括我们自己的，已经确定了炎症性关节炎的多种亚型共同的遗传变异（例如，血清阳性成人类风湿性关节炎、全身性JIA、多关节JIA）。这些基因可以代表“主开关”诱发关节炎一般，在音乐会与其他基因，有助于表型亚型。该项目旨在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，在我们的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1,500例JIA病例的发现队列中，用相关证据定义JIA候选区域。该队列中大约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多个额外样本的全基因组关联（GWA）分析（所有这些样本都已经在手）来扩大这一数据集，使用基于高密度单核苷酸多态性（SNP）的设计来跟踪60万个潜在的多态性。在第二阶段，我们将通过选择性基因分型另外1,000个现有的样本复制我们的发现，这些样本来自其他合作地点招募的表型良好的JIA病例。该数据库将与来自8，000多个基因型对照的匹配样本进行比对，我们预计其中至少有4，000个是完全匹配的。我们假设全基因组单个SNP、SNP单倍型或CNVs与JIA的关联将识别易患JIA的候选风险基因和结构变异。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。我们的项目旨在确定重要的基因，当改变时，使儿童处于JIA的高风险中，从而为药物提供新的靶点，以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.