Sex and racial/ethnic differences in B-ALL genomics

项目摘要 长期以来，人们一直知道，有大量非洲血统的儿童的出生率是B- 细胞急性淋巴细胞白血病（B-ALL）比其他大陆血统的儿童。此外，委员会认为， AA儿童的发病率较低，尽管他们有更多的暴露于许多有害的环境因素， 比白色儿童更易患B-ALL。然而，即使在AA儿童中，我们仍然观察到30%的过量 与所有年龄段的女性相比，男性的ALL发病率显著增加了300 在12岁的时候男性过度可能取决于性别差异与种系疾病的相关性 常染色体和X染色体上的遗传学，免疫功能的性别差异，和/或激素 差异通过全基因组关联研究（GWAS）建立的常见遗传变异 不能完全解释AA儿童B-ALL的缺陷，表明未发现的遗传因素 因子可以通过混合映射来检测。很少有研究按性别研究GWAS。父R 01 行政补充，题为“非洲裔美国人急性淋巴细胞白血病的混合物分析 儿童：ADMIRAL研究”（R 01 CA 239701），包括930例B-ALL的现有DNA样本和数据 具有AA血统的患者，并将在剩余的项目年内累积约600份样本。我们正在进行 在患者集合组中进行混合作图，以检测新的遗传基因座和新的变异， 与B-ALL发生相关的基因座。此外，我们还在研究 在诊断和存活时具有临床特征。将对候选基因/变体进行功能评价 通过计算机和体外技术。对于行政补充，我们将进行性别分层 来自父母R 01的B-ALL AA儿童的GWAS，我们将扩展我们的分析以包括X 染色体，这通常被排除在GWAS之外。作为这个奖项的一部分，我们将产生一个新的来源， 使用脐带造血干细胞的健康AA儿童的基因组数据，我们将使用这些数据来绘制 性别差异表达的数量性状基因座，从而减少了我们对疾病的搜索空间， 相关基因座，并增加我们的权力，以确定生物学相关基因座AA男性和女性与B-ALL。 调查结果将被放置在我们目前正在生成的AA儿童中观察到的背景下， 我们另一项资助的研究这项拟议中的研究可能会通过揭示一个长期存在的谜团， 可能解释AA男性中B-ALL发病率增加的关键基因或位点。识别性别差异 生殖系SNV和儿童ALL之间的联系将使我们能够确定生物学机制， 导致观察到的AA B-ALL发生率的性别差异。

Project Summary 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. Moreover, AA children have lower incidence despite having greater exposure to many putatively causal environmental risk factors for B-ALL than do white children. However, even within AA children, we still observe a 30% excess incidence of ALL among males compared to females at all ages and a remarkable 300% increased incidence at 12 years of age. The male excess may depend on sex-varying associations with the disease for germline genetics on the autosomes and the X chromosome, sex differences in immune function, and/or hormonal differences. Common genetic variants established by genomewide association studies (GWAS) incompletely explain the deficit of B-ALL in AA children, suggesting undiscovered contributing genetic factors may be detected by admixture mapping. Few studies examine GWAS by sex. The parent R01 of this Administrative Supplement, titled “Admixture analysis of acute lymphoblastic leukemia in African American children: the ADMIRAL Study” (R01 CA239701), includes existing DNA samples and data for 930 B-ALL patients with AA ancestry and will accrue ~600 samples over the remaining project years. We are conducting 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 are examining 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. For the Administrative Supplement, we will conduct sex-stratified GWAS in AA children with B-ALL from the parent R01 and we will expand our analyses to include the X chromosome, which is generally excluded from GWAS. As part of this Award, we will generate a new source of genomic data from healthy AA children using umbilical cord hematopoietic stem cells, which we will use to map sex-differential expression quantitative trait loci for each sex thereby decreasing our search space for disease- relevant loci and increase our power to identify biologically relevant loci in AA males and females with B-ALL. Findings will be placed in context to those observed in AA children that we are currently generating as part of our other funded research. The proposed research will potentially answer a long-standing mystery by revealing critical genes or loci that may explain increased incidence of B-ALL in AA males. Identifying sex-varying associations between germline SNVs and childhood ALL will allow us to identify biologic mechanisms contributing to the observed sex differences in AA B-ALL incidence.