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).

项目概要/摘要 该提案的总体目标是采用和完善最先进的基因发现方法来揭示 急性淋巴细胞白血病 (ALL) 风险的遗传病因并调查遗传血统的影响 拉丁裔人群患 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，但发病率、较差的预后和 拉丁裔儿童的并发症明显高于非拉丁裔儿童。以前的文献 已确定 ALL 风险的免疫学、遗传和进化病因。具体来说，美洲原住民 由于拉丁美洲的进化历史，血统与 ALL 风险增加有关。虽然 拉丁美洲人之间的风险差异很明显，在开发和应用方面的文献仍存在差距 研究不同和混合人群中复杂疾病遗传风险的计算方法。 鉴于已发表的全基因组关联研究中大约 80% 的研究对象来自欧洲 由于血统，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。 该拟议项目旨在同时解决拉丁裔 ALL 风险升高的病因并增加工具 用于混合人群的遗传研究。使用来自大量人群的 3000 多个病例和 9000 个对照 - 兰吉女士将基于病例对照和临床试验研究实施和开发基因发现方法 针对混合人群量身定制，以确定与 ALL 相关的新风险位点和致病基因。鉴于 总体假设是，越来越多的美洲原住民血统存在着特定人群的风险 等位基因与 ALL 风险呈正相关，Langie 女士将实施一种 GWAS 形式，其中包括 估计模型中的当地血统并产生特定于血统的效应大小（目标 1A）。此外，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（目标 1B）。然后，她将进行多种族精细绘图和基因优先排序 对已知和新的（从 Aim1 发现的）风险所有位点进行分析，以提名合理的生物候选者 下游功能和药理学研究（目标 2）。最后，她将开发一种新方法 混合映射，结合了混合映射研究的不同研究设计，以改进两者 当前设计的功能和稳健性（目标 3）。