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

虽然类风湿性关节炎有明显的遗传基础，但一种破坏性的关节炎 尽管高达1%的成年人口受到这种疾病的困扰，但我们对基因的理解仍然不完整。 从20世纪70年代中期的S到2007年，只有两个RA易感基因座被确认 毫不含糊地；在过去的一年里，我们已经识别和验证了另外两个基因 精神错乱。然而，三个关键问题是：(1)我们不知道确切的原因突变在 每个基因座，(2)我们还没有所有RA突变的完整目录，以及(3)我们 不了解这些等位基因是如何扰乱人类免疫细胞致病的。这个 这项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 影响临床发病前利用遗传学预测类风湿性关节炎风险的长期目标 并开发新的治疗方法。为了实现我们的目标，我们提出了三个具体的 目标：具体目标1：确定两个新发现的常见原因突变 RA易感基因座。我们最近发现了两个新的类风湿性关节炎易感基因 位于染色体9q33(包括TRAF1基因)和6q23(包括TNFAIP3)。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，并定义最准确的一组假定的因果突变 在超过5,000个RA病例对照样本中的每个基因座。具体目标2：搜索 TRAF1和TNFAIP3基因罕见的蛋白质编码突变 增加类风湿性关节炎风险(与常见突变无关)。我们将再次使用状态- 最先进的测序技术(Solexa)。在这里，我们将寻找罕见的DNA变异 在类风湿性关节炎患者中比在对照组中更常见的情况，通过对 500例RA患者和500例正常对照TRAF1和TNFAIP3基因编码区的研究特定的 目的3：测试常见和罕见的RA易感性突变的功能 假设驱动的实验。我们将生成关于预测的假设 常见和罕见变量(目标1和2)的功能，并在 相关的免疫组织类型(例如，单核细胞和B细胞)。这将提供洞察力 这些等位基因如何导致类风湿性关节炎。 实现这些目标将使我们朝着我们的最终目标取得实质性进展 完全了解所有类风湿性关节炎基因突变--遗传学之前的必要步骤 可以转化为临床护理。此外，这种方法也将适用于其他RA 随着易感基因的识别，这些易感基因也会出现。

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.