Dissection of two rheumatoid arthritis risk loci from genome-wide studies

全基因组研究中两个类风湿性关节炎风险位点的剖析

• 批准号: 7845683
• 负责人: ROBERT M PLENGE
• 金额: $ 39.65万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7845683
• 关键词: 3' Untranslated Regions; 9q33; Address; Adult; Alleles; Amino Acid Sequence; Amino Acids; Area; Arthritis; Arts; B-Lymphocytes; Biological Process; Cataloging; Catalogs; Cells; Chromosomes; Clinical; Code; Collection; Correlation Studies; DNA; DNA Sequence; Data; Development; Diagnosis; Disease; Disease Pathway; Dissection; Elements; Exons; Frameshift Mutation; Gene Frequency; Gene Mutation; Genes; Genetic; Genetic Variation; Genotype; Goals; HLA-DRB1; Histocompatibility Testing; Human; Human Genome; Immune; In Vitro; Individual; Inherited; Investigation; Length; Link; Linkage Disequilibrium; Logistic Regressions; Lymphocyte; Maps; Measures; Messenger RNA; Methods; Mononuclear; Mutate; Mutation; PTPN22 gene; Pathogenesis; Pathway interactions; Patient Care; Peptide Sequence Determination; Peripheral; Phenotype; Population; Predisposition; Protein Isoforms; Proteins; Proxy; Rheumatoid Arthritis; Risk; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Susceptibility Gene; Symptoms; TNF receptor-associated factor 1; Technology; Testing; Translating; Variant; base; bone; case control; clinical care; disease-causing mutation; gene function; genetic analysis; genetic variant; genome wide association study; improved; insight; novel; novel therapeutics; peripheral blood; public health relevance; research study; theories

DESCRIPTION (provided by applicant): While there is a clear inherited basis to rheumatoid arthritis, a destructive arthritis that afflicts up to 1% of the adult population, our genetic understanding remains incomplete. From the mid-1970's until 2007, only two RA susceptibility loci had been confirmed unequivocally; over the last year, we have identified and validated two additional gene loci. However, three key issues are: (1) we do not know the exact causal mutation at each locus, (2) we do not yet have a complete catalogue of all RA mutations, and (3) we do not understand how these alleles perturb human immune cells to cause disease. The goal of this proposal is to address these three key issues. Importantly, these key issues impact the long-term goal of using genetics to predict risk of RA prior to clinical onset and to develop new therapeutics. To accomplish our goals, we proposed three Specific Aims: Specific Aim 1: Identify the common causal mutations two newly identified RA susceptibility gene loci. We have recently identified two new RA susceptibility loci on chromosomes 9q33 (includes TRAF1 the gene) and 6q23 (includes TNFAIP3). We will use state-of-the-art sequencing technology (Solexa) to identify all known genetic variants within these loci, and define the most accurate set of putative causal mutations at each locus in more than 5,000 RA case-control samples. Specific Aim 2: Search for rare protein coding mutations in the TRAF1 and TNFAIP3 genes that also contribute to RA risk (independent of common mutations). We will again use state-of- the-art sequencing technology (Solexa). Here, we will search for rare DNA variants that are more commonly observed in RA cases than in controls by re-sequencing the coding regions of TRAF1 and TNFAIP3 in 500 RA cases and 500 RA controls. Specific Aim 3: Test the function of common and rare RA susceptibility mutations using hypothesis-driven experiments. We will generate hypotheses about the predicted function of common and rare variants (Aims 1 and 2), and test these hypotheses in a relevant immune tissue type (e.g., mononuclear and B-cells). This will provide insight into how these alleles cause RA. Completing these Aims will provide substantial progress towards our ultimate goal of a complete understanding of all RA genetic mutations - a necessary step before genetics can be translated to clinical care. Moreover, this approach will be applicable to other RA susceptibility genes as they are identified. PUBLIC HEALTH RELEVANCE: A long-term goal of understanding the genetic basis of rheumatoid arthritis is to improve care of patients with this common and debilitating disease. In theory, identifying specific pieces of DNA ("alleles") should aid in diagnosing a treatable condition either prior to onset of symptoms, or early in the course of disease before bone destruction occurs. In addition, genetics should provide insight into important steps of the disease pathway, allowing for the development of new therapies that target these pathways in at-risk individuals.

描述（由申请人提供）：虽然类风湿关节炎有明确的遗传基础，但我们对遗传的理解仍然不完整，类风湿关节炎是一种折磨高达1%的成年人的破坏性关节炎。从20世纪70年代中期到2007年，只有两个类风湿性关节炎易感位点得到明确确认；在过去的一年里，我们已经确定并验证了另外两个基因位点。然而，三个关键问题是：(1)我们不知道每个位点的确切因果突变，(2)我们还没有所有RA突变的完整目录，(3)我们不了解这些等位基因是如何扰乱人类免疫细胞导致疾病的。本提案的目标是解决这三个关键问题。重要的是，这些关键问题影响了在临床发病前使用遗传学预测RA风险和开发新疗法的长期目标。为了实现我们的目标，我们提出了三个具体目标：具体目标1：确定常见的因果突变两个新发现的RA易感基因位点。我们最近在染色体9q33（包括TRAF1基因）和6q23（包括TNFAIP3基因）上发现了两个新的RA易感位点。我们将使用最先进的测序技术（Solexa）来识别这些基因座内所有已知的遗传变异，并在5000多个RA病例对照样本中定义每个基因座上最准确的假定因果突变集。特异性目标2：寻找TRAF1和TNFAIP3基因中罕见的蛋白质编码突变，这些基因也会导致RA风险（独立于常见突变）。我们将再次使用最先进的测序技术（Solexa）。在这里，我们将通过重新测序500例RA病例和500例RA对照中TRAF1和TNFAIP3的编码区，寻找在RA病例中比在对照组中更常见的罕见DNA变异。具体目标3：使用假设驱动实验测试常见和罕见RA易感性突变的功能。我们将产生关于常见和罕见变异的预测功能的假设（目标1和2），并在相关的免疫组织类型（例如，单核细胞和b细胞）中测试这些假设。这将有助于深入了解这些等位基因是如何引起类风湿性关节炎的。完成这些目标将为我们完全了解所有类风湿性关节炎基因突变的最终目标提供实质性的进展，这是遗传学转化为临床护理之前的必要步骤。此外，该方法将适用于其他类风湿性关节炎易感基因的鉴定。公共卫生相关性：了解类风湿关节炎遗传基础的长期目标是改善对这种常见且使人衰弱的疾病患者的护理。从理论上讲，识别特定的DNA片段（“等位基因”）应该有助于在症状出现之前或在骨骼破坏发生之前的疾病早期诊断出可治疗的疾病。此外，遗传学应该提供对疾病途径的重要步骤的见解，允许开发针对高危个体的这些途径的新疗法。