Exploring the Impact of Genetic Ancestry on Acute Lymphoblastic Leukemia Risk in Latino Populations

探索遗传血统对拉丁裔人群急性淋巴细胞白血病风险的影响

• 批准号: 10607300
• 负责人: Jalen Langie
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607300
• 关键词: 20 year old; Acute Lymphocytic Leukemia; Address; Admixture; African American population; African ancestry; Alleles; Biological; Birth Order; CEBPE gene; Cesarean section; Child; Clinical Trials; Complex; Computing Methodologies; Coupled; Cytomegalovirus Infections; Development; Diagnosis; Disease; Disparity; Disparity in diagnosis; Ethnic Population; Etiology; European; European ancestry; Exclusion; Exposure to; GATA3 gene; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genetic Screening; Genetic study; Genome; Goals; Hispanic; Immune; Immune response; Immunologics; Incidence; Individual; Investigation; Knowledge; Latin America; Latino; Latino Population; Link; Literature; Malignant Childhood Neoplasm; Malignant Neoplasms; Maps; Medicine; Methodology; Methods; Modeling; Modernization; Native American Ancestry; Native Hawaiian; Pathogenesis; Population; Population Heterogeneity; Prevention; Prognosis; Public Health; Publishing; Recording of previous events; Recurrence; Relapse; Research; Research Design; Resolution; Risk; Risk Factors; Siblings; Study Subject; Testing; United States; Variant; Work; admixture mapping; cancer risk; case control; causal variant; control trial; design; follow-up; gene discovery; genetic architecture; genetic variant; genome wide association study; improved; in utero; insight; lens; leukemia; method development; mortality; multi-ethnic; novel; pathogenic microbe; pharmacologic; population based; precision medicine; racial disparity; risk variant; tool

PROJECT SUMMARY/ABSTRACT The overarching goal of this proposal is to employ and refine state-of-the-art gene discovery methods to uncover the genetic etiology of Acute Lymphoblastic Leukemia (ALL) risk and investigate the impact of genetic ancestry on risk of ALL in Latino populations. Over the past few decades, incidence of ALL has increased on both a global and national scale. While this increase is present in all populations, the rates of incidence, poorer prognosis, and complications are substantially higher in Latino children than their non-Latino counterparts. Previous literature has identified an immunological, genetic, and evolutionary etiology to ALL risk. Specifically, Native American ancestry, due to the evolutionary history of Latin America, is associated with increased risk of ALL. While the differences in risk among Latinos is evident, there remains a gap in the literature in development and application of computational methods to study the genetic risk of complex diseases in diverse and admixed populations. Given that approximately 80% of study subjects in published Genome Wide Association Studies are of European descent, our understanding of the genetics of ALL may have limited external validity and generalizability. This proposed project seeks to tandemly address the etiology of elevated ALL risk in Latinos and add to the tools for genetic studies in admixed populations. Using over 3000 cases and 9000 controls from large population- based case-control and clinical trial studies, Ms. Langie will implement and develop gene discovery methods tailored to admixed populations to identify novel risk loci and causal genes associated with ALL. Given the overarching hypothesis that increasing copies of Native American ancestry harboring population-specific risk alleles will be positively associated with risk of ALL, Ms. Langie will implement a form of GWAS that includes estimated local ancestry in the model and produces ancestry-specific effect sizes (Aim 1A). Furthermore, she will conduct admixture mapping and specifically test for the effect of Native American ancestry in ALL risk both locally and across the genome (Aim 1B). She will then perform multi-ethnic fine-mapping and gene-prioritization analysis at known and novel (discovered from Aim1) risk ALL loci to nominate plausible biological candidates for downstream functional and pharmacological investigations (Aim 2). Finally, she will develop a new method in admixture mapping that combines different study designs of admixture mapping studies to improve upon both the power and robustness of current designs (Aim 3).

项目总结/摘要 这项提案的首要目标是采用和改进最先进的基因发现方法， 急性淋巴细胞白血病（ALL）风险的遗传病因学，并调查遗传祖先的影响 拉丁裔人群中ALL的风险。在过去的几十年里，ALL的发病率在全球范围内都有所增加， 和全国规模。虽然这种增加存在于所有人群中，但其发病率，预后较差， 拉丁裔儿童的并发症明显高于非拉丁裔儿童。以往文献 已经确定了ALL风险的免疫学、遗传学和进化病因学。特别是美洲原住民 由于拉丁美洲的进化史，祖先与ALL风险增加有关。而 拉丁美洲人之间的风险差异是显而易见的，在开发和应用方面的文献中仍然存在差距 研究复杂疾病在不同和混合人群中遗传风险的计算方法。 鉴于已发表的全基因组关联研究中约80%的研究对象是欧洲人， 然而，我们对ALL遗传学的理解可能具有有限的外部有效性和普遍性。 该拟议项目旨在串联解决拉丁美洲人ALL风险升高的病因，并增加工具 用于混合种群的遗传研究。使用来自大量人群的3000多个病例和9000多个对照- 基于病例对照和临床试验研究，Langie女士将实施和开发基因发现方法 为混合人群量身定制，以确定与ALL相关的新风险基因座和致病基因。鉴于 总体假设，即越来越多的美洲原住民祖先的副本携带人口特异性风险 等位基因将与ALL风险呈正相关，Langie女士将实施一种形式的GWAS，包括 在模型中估计当地祖先，并产生祖先特异性效应量（目标1A）。而且她 将进行混合映射，并专门测试美洲原住民血统对ALL风险的影响， 局部和跨基因组（Aim 1B）。然后，她将进行多种族精细绘图和基因优先级排序 分析已知和新的（从Aim 1发现的）风险ALL基因座，以提名合理的生物学候选基因， 下游功能和药理学研究（目的2）。最后，她将开发一种新的方法， 混合物分布，结合了混合物分布研究的不同研究设计，以改善两者 当前设计的功效和稳健性（目标3）。