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: 8259526
• 负责人: ROBERT M PLENGE
• 金额: $ 38.17万
• 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/8259526
• 关键词: 3' Untranslated Regions; 9q33; Address; Adult; Alleles; Amino Acid Sequence; Amino Acids; Area; Arthritis; 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; research study; theories

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.

虽然类风湿性关节炎有明确的遗传基础， 尽管有1%的成年人患有这种疾病，但我们对遗传的理解仍然不完整。 从20世纪70年代中期到2007年，只有两个RA易感基因位点得到了确认 在过去的一年里，我们已经确定并验证了另外两个基因， 的位点然而，三个关键问题是：（1）我们不知道确切的因果突变， 每个位点，（2）我们还没有一个完整的目录，所有RA突变，（3）我们 不明白这些等位基因是如何扰乱人类免疫细胞而导致疾病的。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 影响在临床发作前使用遗传学预测RA风险的长期目标 and to develop发展new新therapeutics疗法.为了实现我们的目标，我们提出了三个具体的建议。 目的：具体目的1：确定两个新发现的常见致病突变 RA易感基因位点。我们最近发现了两个新的RA易感基因座 在染色体9 q33（包括TRAF 1基因）和6 q23（包括TNFAIP 3）上。我们 将使用最先进的测序技术（Solexa）来识别所有已知的基因， 这些基因座内的变异，并确定最准确的一组推定的因果突变 在超过5,000个RA病例对照样本中的每个位点。目标2：寻找 TRAF 1和TNFAIP 3基因中罕见的蛋白质编码突变， 导致RA风险（独立于常见突变）。我们将再次使用国家- 最先进的测序技术（Solexa）。在这里，我们将寻找罕见的DNA变异 在RA病例中比对照组更常见， TRAF 1和TNFAIP 3编码区的500例RA病例和500例RA对照。具体 目的3：检测常见和罕见RA易感突变的功能， 假设驱动的实验我们将对预测的 常见和罕见变异的功能（目的1和2），并在一个 相关免疫组织类型（例如，单核细胞和B细胞）。这将提供洞察力 这些等位基因是如何导致风湿性关节炎的 完成这些目标将为我们实现 全面了解所有RA基因突变-遗传学之前的必要步骤 可以转化为临床护理。此外，这种方法将适用于其他RA 易感基因，因为它们被识别。