Understanding the Increased Risk of Childhood Acute Lymphoblastic Leukemia in Latinos
了解拉丁裔儿童儿童急性淋巴细胞白血病风险增加
基本信息
- 批准号:10615852
- 负责人:
- 金额:$ 64.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-01 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:AccountingAcute Lymphocytic LeukemiaAdmixtureAmericasAwarenessCaliforniaCesarean sectionCessation of lifeChildChildhoodChildhood Acute Lymphocytic LeukemiaChildhood LeukemiaCytomegalovirus InfectionsDataEnvironmental ExposureEnvironmental Risk FactorEpidemiologyEthnic OriginEtiologyEuropeanExhibitsFaceFutureGATA3 geneGene ExpressionGene FrequencyGeneral PopulationGeneticGenetic Predisposition to DiseaseGenetic RiskGenetic VariationGenomeGenomic SegmentGoalsGuatemalaHeritabilityHumanImmuneImmune responseImmunological ModelsIncidenceInfectionInferiorKnowledgeLatinoLatino PopulationLinkage DisequilibriumMalignant Childhood NeoplasmMalignant NeoplasmsMapsMeta-AnalysisModelingMorbidity - disease rateNative American AncestryNative AmericansNatural SelectionsNatureOutcomePediatric Oncology GroupPlayPopulationPreventionQuantitative Trait LociRecording of previous eventsReportingRiskRisk AssessmentRisk FactorsRoleSaint Jude Children&aposs Research HospitalSample SizeSurvivorsSusceptibility GeneTestingTexasTreesUnited StatesVariantVulnerable PopulationsWeightadmixture mappingcase controlcausal variantdisorder preventionepidemiology studyethnic disparitygenetic risk assessmentgenetic risk factorgenetic variantgenome wide association studygenome-widehigh riskimprovedin uteroinsightmodifiable risknovelpolygenic risk scorerisk mitigationrisk predictionrisk stratificationrisk varianttranscriptometranscriptomics
项目摘要
ABSTRACT
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and, despite advances in treatment, it
is still one of the leading causes of childhood death in the United States (US), and survivors face significant
lifelong treatment-related morbidities. Children of Latino ethnicity have the highest and fastest-increasing risk of
ALL in the US, and have lower survival than non-Latino whites; however, this ethnic disparity in incidence and
outcome is not fully understood. Elucidating the increased risk of ALL in Latino children may reveal novel insights
in the etiology of ALL in both Latino and non-Latino populations, and may highlight potential avenues for disease
prevention. We hypothesize that germline genetic variation plays an essential role in the increased ALL risk in
Latinos, that this risk is imparted via Native American ancestry, and that ALL risk alleles were selected in Native
Americans during European colonization of the Americas due to their beneficial effects on immune response to
new infections. We have assembled the largest ever case-control set of childhood ALL in Latinos, including over
5,400 cases and 27,000 controls from three independent studies in California, plus studies in Texas, Children’s
Oncology Group/St. Jude Children’s Research Hospital, and Guatemala. In our first aim, we will perform three
complementary approaches to discover novel common risk loci associated with childhood ALL: i) a genome-
wide association study (GWAS) meta-analysis, ii) admixture mapping to capitalize on the recently admixed
nature of Latino genomes, and iii) a transcriptome-wide association study to identify novel loci and to pinpoint
causal genes at known and novel risk regions. In our second aim, we will characterize the genetic variants in
terms of their association with local Native American ancestry and whether they exhibit evidence of directional
natural selection on the Native American branch of the human population tree. We will also characterize the
aggregate effects of common variants on childhood ALL risk and how this varies by ethnicity, via comprehensive
modeling of polygenic risk scores (PRS) for ALL in Latinos and in non-Latino whites. Finally, we will incorporate
our genetic findings into epidemiologic analyses, by accounting for common (PRS) genetic variants in ALL risk
models for immune-related risk factors in Latinos and non-Latino whites, including cesarean delivery and in utero
cytomegalovirus infection, both of which have shown stronger effects on ALL risk in Latinos and are potentially
modifiable risk factors. The results of this study will shed light on the etiology of childhood ALL in general and of
the increased risk of ALL in Latino children, which will help to alleviate this ethnic disparity and may inform future
approaches for childhood leukemia prevention.
摘要
急性淋巴细胞性白血病(ALL)是最常见的儿童癌症,尽管治疗取得了进展,但它
仍然是美国儿童死亡的主要原因之一,幸存者面临着重大的
终生与治疗相关的疾病。拉丁裔儿童患癌症的风险最高,增长最快。
都在美国,存活率低于非拉丁裔白人;然而,这种发病率和
结果还没有完全弄清楚。阐明拉美裔儿童ALL风险增加可能会揭示新的见解
在拉丁裔和非拉丁裔人群中ALL的病因学方面,并可能突出潜在的致病途径
预防。我们假设,生殖系遗传变异在增加的所有风险中起重要作用。
拉美人,这种风险是通过美洲原住民的祖先遗传的,并且所有的风险等位基因都是在原住民中选择的
美国人在欧洲殖民美洲期间,由于他们对免疫反应的有益影响
新的感染。我们已经收集了有史以来最大的儿童病例对照集合,所有人都是拉丁裔,包括
5,400例病例和27,000名对照,来自加利福尼亚州的三项独立研究,以及德克萨斯州的研究,儿童
肿瘤学小组/圣犹大儿童研究医院和危地马拉。在我们的第一个目标中,我们将执行三个
发现与儿童ALL相关的新的共同危险基因的互补方法:i)基因组-
广泛关联研究(GWAS)荟萃分析,II)混合映射,以利用最近混合的
拉丁裔基因组的性质,以及iii)一项转录组范围的关联研究,以确定新的基因座并精确定位
已知和新风险区域的因果基因。在我们的第二个目标中,我们将描述
他们与当地美洲原住民祖先的联系以及他们是否表现出方向性的证据
人类种群树中美洲原住民分支上的自然选择。我们还将描述
共同变异对儿童ALL风险的综合影响,以及这种影响如何因种族而异,通过
拉丁裔和非拉丁裔白人所有人的多基因风险分数(PR)模型。最后,我们将把
通过考虑所有风险中的常见(PR)基因变异,将我们的基因发现纳入流行病学分析
拉丁裔和非拉丁裔白人的免疫相关危险因素模型,包括剖腹产和宫内分娩
巨细胞病毒感染,这两种病毒对拉丁裔的所有风险都显示出更强的影响,并有可能
可更改的风险因素。这项研究的结果将有助于揭示儿童ALL的一般病因学和
拉美裔儿童患ALL的风险增加,这将有助于缓解这种种族差距,并可能为未来
预防儿童白血病的方法。
项目成果
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Adam De Smith其他文献
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{{ truncateString('Adam De Smith', 18)}}的其他基金
Understanding the Increased Risk of Childhood Acute Lymphoblastic Leukemia in Latinos
了解拉丁裔儿童儿童急性淋巴细胞白血病风险增加
- 批准号:
10440966 - 财政年份:2022
- 资助金额:
$ 64.06万 - 项目类别:
Understanding the Increased Risk of Childhood Acute Lymphoblastic Leukemia in Latinos
了解拉丁裔儿童儿童急性淋巴细胞白血病风险增加
- 批准号:
10629825 - 财政年份:2022
- 资助金额:
$ 64.06万 - 项目类别:
Genetic determinants of lymphocyte traits and risk of acute lymphoblastic leukemia in children with Down syndrome
唐氏综合症儿童淋巴细胞特征和急性淋巴细胞白血病风险的遗传决定因素
- 批准号:
10700064 - 财政年份:2022
- 资助金额:
$ 64.06万 - 项目类别:
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Backtracking Leukemia-Typical Somatic Alterations in Cord Blood at Single-cell Resolution
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