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，影响美国和世界各地数十万儿童。尽管有强有力的证据表明JIA的遗传易感性，但迄今为止，在确定影响JIA易感性的基因座方面的成功是有限的。大多数先前的研究集中在JIA无关个体的病例对照研究。我们使用犹他州人口数据库（JIA B）一个独特的家谱数据库，确定了几个多代家庭，其中有4至13个受影响的儿童与JIA。我们建议在这些大型家系中研究JIA的远亲个体，以检验这一假设，即JIA的远亲儿童将表现出扩展的血统认同（IBD），在易患JIA的变异周围地区共享。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描述JIA的远亲儿童。使用CIBB，我们将确定额外的扩展谱系，其中创始人有一个显着更高的风险有后代与JIA。我们将选择200例JIA病例，这些病例彼此之间有远亲关系。使用我们的大队列自身免疫免费控制，我们将同样确定100个远缘相关的未受影响的控制个人从一组单独的非JIA家系。目的2：确定候选基因组区域，揭示了过度IBD共享JIA病例在扩展的多重家系。我们将使用Affysse6.0 Array对来自扩展的多重JIA家系的200例远缘受累病例和100例远缘未受累对照进行~ 900 K常见单核苷酸多态性（SNP）基因分型。我们将使用得到的基因型来鉴定与对照组相比，病例对之间IBD共享比预期更高的基因组区域。我们将从这些IBD区域中生成候选基因组区域的列表，用于目标3中的后续验证。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，在Aim 2中确定了高优先级候选基因组区域。我们将使用Illumina GoldenGate检测试剂盒对特定目标2中确定的IBD过度共享区域中的高优先级变体进行基因分型，该区域由JIA无关儿童和一大组与种族匹配的无自身免疫的健康对照组成。我们的建议是建立在现有的良好的特点与JIA和对照组的病例队列，以及几个大的多代家庭与多个受影响的儿童与JIA，以确定与JIA易感性相关的基因。我们相信，应用高密度基因型数据和现代分析方法的家族性病例JIA提供了一个创新的方法来识别遗传变异诱发JIA。识别JIA相关变异将提高对JIA病理生理学的认识，并改善JIA的诊断和治疗。

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.