Segmental chromosome sharing in affected relatives with Juvenile Arthritis

患有幼年关节炎的受影响亲属的节段染色体共享

• 批准号: 8725933
• 负责人: SAMPATH PRAHALAD
• 金额: $ 38.04万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-17 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8725933
• 关键词: 16 year old; Accounting; Affect; Alleles; Arthritis; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biological Assay; Candidate Disease Gene; Case-Control Studies; Child; Childhood; Chromosomes; Chronic; Chronic Childhood Arthritis; Clinical; Complex; DNA; Data; Databases; Diagnosis; Disease; Ethnic Origin; Etiology; Exhibits; Experimental Designs; Family; Functional disorder; Genealogy; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Goals; HLA Antigens; Hand; Heritability; Individual; International; Knowledge; Lead; Link; Parents; Phenotype; Population Database; Predisposition; Relative (related person); Research Personnel; Rheumatology; Risk; Role; Single Nucleotide Polymorphism; Staging; Surveys; Testing; United States; Utah; Validation; Variant; arthropathies; base; case control; chronic pain; cohort; density; design; genetic pedigree; genetic variant; genome wide association study; high risk; improved; innovation; insight; interest; novel; success

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.

描述（由申请人提供）：少年特发性关节炎（JIA）是最常见的童年关节病，影响了美国和世界各地数十万儿童。尽管对JIA的遗传易感性的证据很强，但成功地识别影响JIA易感性的基因座一直受到限制。大多数先前的研究都集中在jia无关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，其中有四到13个受影响的JIA儿童。我们建议在这些大型的血统中研究与JIA的远距离相关的人，以检验以下假设：与JIA相关的遥远儿童将通过下降（IBD）在易于JIA的变种的区域中表现出扩展的身份（IBD）。我们提出以下特定目标。 AIM 1：在延长的多重谱系中识别和表征与JIA相关的儿童。使用UPDB，我们将确定其他扩展的血统，其中创始人的后代与JIA的风险显着更高。我们将选择200例与JIA相互遥远相关的案例。使用我们大量的自身免疫自由控制群体，我们将同样从单独的非JIA谱系中识别出100个遥远的无影响的对照个体。 AIM 2：确定候选基因组区域，如延长的多重谱系中的JIA案例中过度共享所揭示的。我们将使用来自扩展的多重jia giedigrees的200例远距离影响的病例和100个远距离相关的不受影响的对照组中，将Affymetrix 6.0阵列与〜900K 〜900K公共单核苷酸多态性（SNP）一起使用。与对照对相比，我们将使用所得的基因型鉴定基因组区域的IBD共享大于预期的IBD。我们将从这些IBD区域内生成候选基因组区域的列表，以在AIM 3中进行后续验证。AIM3：在AIM 2中确定的高优先级候选候选基因组区域，对1000个JIA病例的同类群体进行了独立的病例对照研究，并验证了1000个JIA病例和1000个匹配的对照组。我们将使用Illumina Goldengate测定法进行基因型的高优先级变体，在特定目标2中鉴定出过度的IBD共享的区域中，在具有良好特定的独立的无关儿童的JIA和大量的自身免疫自由健康的自由健康对照组中，与种族相匹配。我们的提案建立在现有良好特征的JIA和控制案件的案例上，以及几个具有多个患有JIA的儿童的大型多代家族，以识别与JIA敏感性相关的基因。我们认为，将高密度基因型数据和现代分析方法应用于JIA的家族病例，为鉴定易感JIA的遗传变异提供了创新的方法。与JIA相关的变体的鉴定将改善对JIA的病理生理学的理解，并改善JIA的诊断和治疗。

项目成果

Profiling anti-cyclic citrullinated peptide antibodies in patients with juvenile idiopathic arthritis.

• DOI: 10.1186/1546-0096-10-29
• 发表时间: 2012-08-29
• 期刊: Pediatric rheumatology online journal
• 作者: Tebo AE;Jaskowski T;Davis KW;Whiting A;Clifford B;Zeft A;McNally B;Hill HR;Bohnsack J;Prahalad S
• 通讯作者: Prahalad S