Segmental chromosome sharing in affected relatives with Juvenile Arthritis

描述(申请人提供)：幼年特发性关节炎(JIA)，是最常见的儿童关节病，在美国和世界各地影响数十万儿童。尽管JIA遗传易感性的证据很强，但到目前为止，识别影响JIA易感性的基因座的成功还很有限。以前的大多数研究都集中在与JIA无关的个体的病例对照研究上。使用犹他州人口数据库(UPDB)，一个独特的家谱数据库，我们已经确定了几个多代家庭，其中有4到13名患有JIA的儿童。我们建议在这些大的家系中研究患有JIA的远亲个体，以检验这样的假设：患有JIA的远亲儿童将在易患JIA的变异体周围的区域表现出扩展的血统认同(IBD)。我们提出了以下具体目标。目的1：在扩大的多个家系中鉴定和鉴定远缘关系的JIA儿童。使用UPDB，我们将确定创始人有明显更高风险的后代患有JIA的其他扩展家系。我们将选择200例远缘关系的JIA病例。使用我们的大量无自身免疫对照，我们将类似地从一组单独的非JIA家系中识别100名远亲未受影响的对照个体。目的2：确定扩大多个家系中JIA患者过度分享IBD所揭示的候选基因组区域。我们将使用Affymetrix 6.0阵列对200例远缘JIA家系患者和100例远缘对照进行~900K常见单核苷酸多态(SNPs)的基因分型。我们将使用所得到的基因类型来识别与对照相比，病例对之间的IBD共享程度高于预期的基因组区域。我们将从这些IBD区域内生成候选基因组区域列表，用于随后在AIM 3中进行验证。目标3：在对1000例JIA病例和1000名匹配对照进行的独立病例对照研究中，验证在AIM 2中确定的高优先级候选基因组区域。我们将使用Illumina GoldenGate试验对特定目标2中确定的IBD过度共享区域的高优先级变异进行分型，研究对象为具有良好特征的无血缘关系的JIA儿童和一大群种族匹配的无自身免疫功能的健康对照儿童。我们的建议建立在现有的JIA和对照病例的特征良好的队列，以及几个有多个受JIA影响的儿童的大型多代家庭的基础上，以确定与JIA易感性相关的基因。我们认为，将高密度的基因数据和现代分析方法应用于家族性JIA病例，为鉴定易患JIA的遗传变异提供了一种创新的方法。发现与JIA相关的变异体有助于加深对JIA病理生理机制的认识，提高对JIA的诊断和治疗水平。

DESCRIPTION (provided by applicant): Juvenile idiopathic arthritis (JIA), is the most common childhood arthropathy which affects hundreds of thousands of children in the United States and around the world. Although the evidence for a genetic predisposition to JIA is strong, success in identifying loci that influence susceptibility to JIA has hitherto been limited. Most prior studies have focused on case-control studies of unrelated individuals with JIA. Using Utah Population Database (UPDB) a unique genealogy database, we have identified several multigenerational families in which there are four to thirteen affected children with JIA. We propose to study distantly related individuals with JIA in these large pedigrees to test the hypothesis that distantly-related children with JIA will exhibit extended identity by descent (IBD) sharing in regions surrounding variants which predispose to JIA. We propose the following specific aims. Aim 1: Identify and characterize distantly related children with JIA in extended multiplex pedigrees. Using the UPDB we will identify additional extended pedigrees where the founders have a significantly higher risk of having descendants with JIA. We will select 200 cases with JIA that are distantly related to each other. Using our large cohort of autoimmunity free controls, we will similarly identify 100 distantly-related unaffected control individuals from a separate set of non-JIA pedigrees. Aim 2: Identify candidate genomic regions as revealed by excessive IBD sharing among JIA cases in extended multiplex pedigrees. We will use the Affymetrix 6.0 Array to genotype ~900K common single nucleotide polymorphisms (SNPs) in 200 distantly-related affected cases from the extended multiplex JIA pedigrees, and the 100 distantly-related unaffected controls. We will use the resulting genotypes to identify genomic regions with greater-than-expected IBD sharing between pairs of cases as compared to pairs of controls. We will generate a list of candidate genomic regions from within these IBD regions for subsequent validation in Aim 3. Aim 3: Validate high priority candidate genomic regions identified in Aim 2 in an independent case-control study of a cohort of 1000 JIA cases and 1000 matched controls. We will use the Illumina GoldenGate assay to genotype high-priority variants in regions with excessive IBD sharing identified in specific aim 2 in a well-characterized independent cohort of unrelated children with JIA and a large group of autoimmunity free healthy controls matched for ethnicity. Our proposal builds on existing well characterized cohorts of cases with JIA and controls, as well as several large multigenerational families with multiple affected children with JIA to identify genes associated with JIA susceptibility. We believe that applying high density genotype data and modern analytical approaches to familial cases of JIA offers an innovative approach to the identification of genetic variants predisposing to JIA. Identification of variants associated with JIA will improve the understanding of the pathophysiology of JIA, and improve the diagnosis and treatment of JIA.