Segmental chromosome sharing in affected relatives with Juvenile Arthritis

描述（由申请人提供）：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着数十万儿童。尽管JIA遗传易感性的证据很强，但迄今为止，在确定影响JIA易感性的基因位点方面取得的成功有限。大多数先前的研究都集中在与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名受JIA影响的儿童。我们建议在这些大谱系中研究JIA的远亲个体，以验证JIA的远亲儿童在JIA易感性变异周围区域会表现出扩展的血统认同（IBD）共享的假设。我们提出以下具体目标。目的1：在扩展的多重家系中识别和表征JIA的远亲儿童。使用UPDB，我们将确定额外的扩展谱系，其中创始人的后代患JIA的风险明显更高。我们将选择200例彼此有远亲关系的JIA病例。使用我们的大型无自身免疫对照队列，我们将同样从一组单独的非jia家系中确定100个远亲未受影响的对照个体。目的2：在扩展的多重家系中，确定JIA病例中过度IBD共享所揭示的候选基因组区域。我们将使用Affymetrix 6.0 Array对来自扩展多重JIA家系的200例远亲感染病例和100例远亲未感染对照进行约900K个常见单核苷酸多态性（snp）的基因分型。我们将使用得到的基因型来识别与对照相比，病例对之间IBD共享度大于预期的基因组区域。我们将从这些IBD区域中生成候选基因组区域列表，以便在Aim 3中进行后续验证。目标3：在一项包含1000例JIA病例和1000例匹配对照的独立病例对照研究中，验证目标2中确定的高优先级候选基因组区域。我们将使用Illumina GoldenGate检测技术，在特定目标2中鉴定出的具有过度IBD共享区域的高优先级变异进行基因分型，这些变异是在一个特征明确的独立队列中发现的，该队列由无亲缘关系的JIA儿童组成，以及一大批与种族匹配的无自身免疫的健康对照。我们的建议建立在现有的JIA病例和对照的特征良好的队列，以及几个有多个JIA患儿的多代大家庭的基础上，以确定与JIA易感性相关的基因。我们认为，将高密度基因型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JIA相关变异有助于提高对JIA病理生理的认识，提高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.