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:10440966
- 负责人:
- 金额:$ 74.6万
- 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 PopulationLeadLightLinkage DisequilibriumMalignant Childhood NeoplasmMalignant NeoplasmsMeta-AnalysisModelingMorbidity - disease rateNative American AncestryNative AmericansNatural SelectionsNatureOutcomePediatric Oncology GroupPlayPopulationPreventionQuantitative Trait LociRecording of previous eventsReportingRiskRisk FactorsRoleSaint Jude Children&aposs Research HospitalSample SizeSurvivorsSusceptibility GeneTestingTexasTreesUnited StatesVariantVulnerable PopulationsWeightadmixture mappingcase controlcausal variantdisorder preventionepidemiology studyethnic disparitygenetic risk assessmentgenetic 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
急性淋巴细胞白血病(ALL)是最常见的儿科癌症,尽管治疗取得了进展,
仍然是美国儿童死亡的主要原因之一,幸存者面临着巨大的风险。
终身治疗相关的发病率。拉丁裔儿童有最高和最快的风险增加,
所有在美国,并有较低的生存率比非拉丁裔白人;然而,这种种族差异的发病率和
结果并不完全清楚。阐明拉丁美洲儿童ALL风险增加可能揭示新的见解
在拉丁裔和非拉丁裔人群中ALL的病因学中,并可能突出疾病的潜在途径
预防我们假设生殖系遗传变异在急性淋巴细胞白血病风险增加中起重要作用,
拉丁美洲人,这种风险是通过美洲原住民血统传递的,并且所有风险等位基因都是在原住民中选择的。
在欧洲殖民美洲期间,由于其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病例对照组的儿童ALL在拉丁美洲,包括超过
来自加州三项独立研究的5,400例病例和27,000例对照,加上德克萨斯州的研究,儿童医院
肿瘤组/圣裘德儿童研究医院和危地马拉。在我们的第一个目标,我们将执行三个
发现与儿童ALL相关的新的常见风险基因座的补充方法: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
拉丁美洲人基因组的性质,和iii)一个转录组范围内的关联研究,以确定新的基因座,并查明
已知和新的风险区域的致病基因。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定向的证据,
自然选择在人类种群树的美洲土著分支上。我们还将描述
通过综合分析,常见变异对儿童ALL风险的总体影响以及这种影响如何因种族而异
拉丁美洲人和非拉丁美洲白人ALL的多基因风险评分(PRS)建模。最后,我们将
通过解释ALL风险中的常见(PRS)遗传变异,将我们的遗传发现纳入流行病学分析
拉丁美洲人和非拉丁美洲白人中免疫相关风险因素的模型,包括剖宫产和子宫内
巨细胞病毒感染,这两种病毒都对拉丁美洲人的ALL风险有更强的影响,
可改变的风险因素。这项研究的结果将阐明儿童ALL的一般病因,
拉丁裔儿童ALL的风险增加,这将有助于缓解这种种族差异,并可能为未来的研究提供信息。
预防儿童白血病的方法。
项目成果
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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:
10615852 - 财政年份:2022
- 资助金额:
$ 74.6万 - 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:
$ 74.6万 - 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:
$ 74.6万 - 项目类别:
Backtracking Leukemia-Typical Somatic Alterations in Cord Blood at Single-cell Resolution
以单细胞分辨率回溯脐带血中白血病典型体细胞改变
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10459501 - 财政年份:2021
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Backtracking Leukemia-Typical Somatic Alterations in Cord Blood at Single-cell Resolution
以单细胞分辨率回溯脐带血中白血病典型体细胞改变
- 批准号:
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Backtracking Leukemia-Typical Somatic Alterations in Cord Blood at Single-cell Resolution
以单细胞分辨率回溯脐带血中白血病典型体细胞改变
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10063853 - 财政年份:2019
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