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).

项目摘要/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，并研究遗传血统的影响 在拉丁裔人群中所有人的风险。在过去的几十年中，全球的发病率都在增加 和国家规模。尽管在所有人群中都存在这种增加，但发病率，较差的预后和 拉丁裔儿童中的并发症比非拉丁裔的同行高得多。以前的文献 已经确定了所有风险的免疫，遗传和进化病因。特别是美国原住民 由于拉丁美洲的进化史，血统与所有人的风险增加有关。而 拉丁美洲人之间的风险差异很明显，文献的发展和应用中存在差距 计算方法来研究各种和混合种群中复杂疾病的遗传风险。 鉴于大约有80％的研究对象在已发表的广泛基因组关联研究中是欧洲的 下降，我们对所有遗传学的理解可能具有有限的外部有效性和概括性。 该拟议的项目旨在将拉丁美洲人的所有风险升高的病因结合起来，并添加到工具中 用于混合种群的遗传研究。使用3000多例病例和9000个对照 基于病例对照和临床试验研究，兰吉女士将实施和开发基因发现方法 针对混合种群量身定制，以鉴定与所有人相关的新风险基因座和因果基因。鉴于 总体假设，即增加具有特定人群风险的美国原住民血统的副本 等位基因将与所有人的风险呈正相关，Langie女士将实施一种GWAS的形式，包括 该模型中的局部血统估计并产生特定于祖先的效应大小（AIM 1A）。此外，她 将进行混合映射，并专门测试美国原住民血统对所有风险的影响 局部和跨基因组（AIM 1B）。然后，她将执行多民族精细映射和基因优先级 已知和新颖的分析（从AIM1发现）风险所有基因座都有提名合理的生物学候选者 下游功能和药理研究（AIM 2）。最后，她将开发一种新方法 结合了混合映射研究的不同研究设计以改进这两者的混合图映射 当前设计的功能和鲁棒性（AIM 3）。