Sex and racial/ethnic differences in B-ALL genomics

B-ALL 基因组学中的性别和种族/民族差异

• 批准号: 10555358
• 负责人: Michael E Scheurer
• 金额: $ 15.5万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10555358
• 关键词: 12 year old; Acute Lymphocytic Leukemia; Administrative Supplement; Admixture; Adult; African; African American; African ancestry; Age; Award; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocytes; Behavior; Biological; Birth Weight; CD34 gene; Candidate Disease Gene; Case-Control Studies; Cessation of life; Characteristics; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Childhood Precursor B Lymphoblastic Leukemia; Clinical; Clinical Data; Complex; Confidence Intervals; DNA; Data; Diagnosis; Disease; Environment; Environmental Risk Factor; Etiology; European; Exhibits; Exposure to; Female; Funding; Future; Genes; Genetic; Genetic Models; Genome; Genomics; Goals; Hematopoietic; Hematopoietic stem cells; Heritability; Hormonal; Human; In Vitro; Incidence; Inherited; Investigation; Knowledge; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Maternal Age; Modeling; Molecular; Newborn Infant; Odds Ratio; Parents; Patients; Perinatal; Prevalence; Prevention strategy; Process; Puberty; Quantitative Trait Loci; Relapse; Research; Risk; Risk Factors; Role; Sampling; Sex Chromosomes; Sex Differences; Single Nucleotide Polymorphism; Source; Techniques; Time; Tissues; Umbilical cord structure; Variant; X Chromosome; admixture mapping; autosome; base; caucasian American; differential expression; disorder risk; ethnic difference; experience; gene environment interaction; genetic variant; genome wide association study; genome-wide; genomic data; genomic locus; genotypic sex; immune function; in silico; male; minority children; parent grant; public health relevance; racial and ethnic; racial difference; risk variant; sex; stem cells; trait; young adult

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.

项目概要 长期以来，人们就知道具有大量非洲血统的儿童 B- 患病率只有一半或更少。 细胞急性淋巴细胞白血病（B-ALL）的发病率高于其他大陆血统的儿童。 尽管 AA 儿童更多地接触许多假定的因果环境，但其发病率较低 B-ALL 的危险因素高于白人儿童 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 ALL 的发病率显着增加 300% 12岁时，男性的过量可能取决于性别差异与生殖系疾病的关系。 常染色体和 X 染色体的遗传学、免疫功能的性别差异和/或激素 全基因组关联研究 (GWAS) 建立的常见遗传变异。 不完全解释 AA 儿童中 B-ALL 的缺陷，表明尚未发现的遗传因素 很少有研究可以通过性别进行 GWAS 检测。 行政补充，标题为“非洲裔美国人急性淋巴细胞白血病的混合分析” 儿童：ADMIRAL 研究”(R01 CA239701)，包括现有的 DNA 样本和 930 B-ALL 数据 AA 血统的患者将在我们正在进行的剩余项目年份中积累约 600 个样本。 在聚集的患者组中进行混合作图，以检测新的遗传位点和新的变异 已确定与 B-ALL 发生相关的位点 此外，我们正在检查关联的混合物。 将在诊断和生存时对候选基因/变异进行功能评估。 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。 对来自父母 R01 的患有 B-ALL 的 AA 儿童进行 GWAS，我们将扩大我们的分析范围以包括 X 染色体，通常被排除在 GWAS 之外，作为该奖项的一部分，我们将生成一个新的染色体来源。 使用脐带造血干细胞获取健康 AA 儿童的基因组数据，我们将用它来绘制图谱 每个性别的性别差异表达数量性状基因座，从而减少了我们对疾病的搜索空间- 相关基因座，并增强我们在患有 B-ALL 的 AA 男性和女性中识别生物学相关基因座的能力。 研究结果将与我们目前正在 AA 儿童中观察到的结果结合起来，作为 我们的另一项资助研究可能会通过揭示来解答一个长期存在的谜团。 可能解释 AA 男性 B-ALL 发病率增加的关键基因或基因座。 种系 SNV 与儿童 ALL 之间的关联将使我们能够确定生物学机制 导致观察到的 AA B-ALL 发病率存在性别差异。