Admixture analysis of acute lymphoblastic leukemia in African American children: the ADMIRAL Study

修改项目摘要/摘要部分 摘要 长期以来，人们一直知道，具有大量非洲血统的儿童的B细胞急性白血病发病率是非洲儿童的一半或更少。 淋巴母细胞白血病（B-ALL）比其他大陆血统的儿童。这是真的， 非洲国家与其他国家ALL发病率的国际比较，以及B-ALL发病率的比较 在美国，非裔美国人（AA）儿童与欧裔美国人（EA）儿童之间的差异。逆 非洲血统与B-ALL发病率的相关性独立于已确定的围产期风险因素， 这种疾病此外，AA儿童的发病率较低，尽管有更多的暴露于许多脓毒症 与EA儿童相比，B-ALL的因果环境危险因素。常见的遗传变异， 全基因组关联研究不能完全解释AA儿童B-ALL的缺陷，提示 未发现的起作用的遗传因子可以通过混合作图来检测。我们已经收集了现有的 930例AA血统B-ALL患者的DNA样本和数据，并将在一生中额外增加约590例 本项目我们将在聚集的患者组中进行混合作图，以检测新的遗传位点 以及与B-ALL发生相关的已建立基因座的新变异。此外，我们将检查混合物 与诊断和生存期的临床特征相关。候选基因/变体将在功能上是 通过计算机模拟和体外技术进行评价。这项研究可能会回答一个长期的问题- 通过揭示关键基因或位点来解释AA中B-ALL的相对缺陷， 给孩子们。此外，我们可能会发现基因或变异与更糟糕的特征， 在AA患者中的表现以及生存率更差，这将表明改善结局的途径 在AA儿童中。

Modified Project Summary/Abstract Section Abstract Children with substantial African ancestry have long been known to have half or less the rate of B-cell acute lymphoblastic leukemia (B-ALL) than do children with other continental ancestries. This is true both in international comparisons of rates of ALL in African nations to those elsewhere, and in comparing rate of B-ALL in African-American (AA) children to that in European-American (EA) children in the United States. The inverse association of African ancestry with incidence of B-ALL is independent of established perinatal risk factors for the disease. Moreover, AA children have lower incidence despite having greater exposure to many putatively causal environmental risk factors for B-ALL than do EA children. Common genetic variants established by genomewide association studies incompletely explain the deficit of B-ALL in AA children, suggesting undiscovered contributing genetic factors may be detected by admixture mapping. We have assembled existing DNA samples and data for 930 B-ALL patients with AA ancestry and will additionally accrue ~590 over the life of the project. We will conduct admixture mapping in the assembled group of patients to detect new genetic loci and new variants at established loci associated with occurrence of B-ALL. In addition, we will examine admixture in association with clinical characteristics at diagnosis and survival. Candidate genes/variants will be functionally evaluated through both in silico and in vitro techniques. The proposed research will potentially answer a long- standing mystery by revealing critical genes or loci that explain the comparative deficit of B-ALL in AA compared to EA children. In addition, we may uncover genes or variants associated with the worse characteristics at presentation in AA patients as well as with worse survival, which will indicate avenues for improving outcome among AA children.