Genome-Wide Association Study of Childhood Leukemia by Hispanic Status

按西班牙裔身份划分的儿童白血病全基因组关联研究

• 批准号: 8471006
• 负责人: Xiaomei Ma
• 金额: $ 156.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8471006
• 关键词: Accounting; Acute Lymphocytic Leukemia; African American; Algorithms; Alleles; American; Archives; Birth; Birth Order; Birth Records; Birth Weight; Blood; California; Case-Control Studies; Characteristics; Child; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Coupled; Custom; Data; Development; Dimensions; Disease; Dose; Down Syndrome; Ensure; Ethnic Origin; Ethnic group; Etiology; European; Exposure to; Fetal Growth; Funding; Gender; Genes; Genetic Predisposition to Disease; Genetic Risk; Genome; Genomics; Genotype; Gestational Age; Goals; Growth; Hereditary Disease; Hispanics; Incidence; Infant; Ionizing radiation; Link; Malignant Neoplasms; Measures; Meta-Analysis; Neonatal; Not Hispanic or Latino; Odds Ratio; Only Child; Parental Ages; Phase; Population; Population Study; Pregnancy; Process; Public Health; Publishing; Race; Reporting; Research; Risk; Risk Factors; Role; Sample Size; Sampling; Single Nucleotide Polymorphism; Spottings; Time; United States; United States National Institutes of Health; Validation; Vulnerable Populations; base; case control; design; ethnic difference; genetic risk factor; genetic variant; genome wide association study; improved; in utero; leukemia; leukemogenesis; neoplasm registry; parity; population based; programs; response; screening

DESCRIPTION (provided by applicant): Although acute lymphoblastic leukemia (ALL) is the most common malignancy in children (0 - 14 years), there are few known risk factors. In the United States, Hispanic children have higher incidence of ALL than any other ethnic/racial groups; they have 1.3 times of the risk for ALL than non-Hispanic white children. Two small genome-wide association studies (GWAS) recently identified 2-3 genetic risk factors for childhood ALL, but only in European white populations with non-population based ascertainment. High birth weight and other markers of fetal growth have been consistently linked to an increased risk of childhood ALL in most studies, and Hispanics appear to have accelerated fetal growth early on during pregnancy. In the current application, we seek to significantly advance leukemia research by clarifying the roles of genetic susceptibility and fetal growth in the etiology of childhood ALL in a large population-based sample of Hispanics and non-Hispanic whites in California, using high dimension arrays specifically designed for the two ethnic groups. We will (1) link California birth records with California Cancer Registry data (1988 - 2008) to assemble a population-based case-control study with an unprecedented size (4,000 cases and 4,000 controls, about half of which will be Hispanics and half non-Hispanic whites); (2) obtain the archived neonatal dried blood spots of all cases and controls from the California Department of Public Health; (3) genotype the study population with custom Affymetrix whole genome arrays designed for the California population, with optimized designs for Hispanics and non-Hispanic whites separately; (4) use data from these cases and controls to identify distinct and shared genetic risk alleles for Hispanics and non-Hispanic whites; and (5) validate top GWAS hits in the California Childhood Leukemia Study (an ongoing NIH-funded case-control study with a separate and distinct subject ascertainment, >1000 cases, > 1000 controls, approximately half of which will be Hispanics and half non- Hispanic whites) and in a Brazilian childhood leukemia study with Latin American cases (n = 200) and controls (n = 400). In addition, we will utilize data on the characteristics of all births in California during 1988 - 2008 to develop an algorithm to predict birth weight based on factors such as gestational age, gender, birth order, parental race, parental Hispanic status, and parental ages, and calculate a proportion of expected birth weight (PEBW) for all cases and controls (n = 8000) by dividing their actual observed birth weight by the expected birth weight derived from the algorithm. Subsequently, we will determine whether the PEBW or birth weight is associated with (i) childhood ALL, (ii) the top GWAS hits, and (iii) the SNPs in genes potentially related to fetal growth, in Hispanics and non-Hispanic whites separately. Given the unprecedented sample size, especially the large number of Hispanics included, and ethnic-specific genotyping panels with great genome coverage, this study will clarify the role of genetic susceptibility in childhood ALL, the mechanism involving fetal growth, and in the process identify potential reasons for the puzzling ethnic difference in disease incidence.

描述（由申请人提供）：虽然急性淋巴细胞白血病（ALL）是儿童（0 - 14岁）最常见的恶性肿瘤，但已知的危险因素很少。在美国，西班牙裔儿童的ALL发病率高于其他任何族裔/种族群体；他们患ALL的风险是非西班牙裔白人儿童的1.3倍。两项小型全基因组关联研究（GWAS）最近确定了儿童ALL的2-3个遗传风险因素，但仅在欧洲白人人群中进行了非群体确定。在大多数研究中，高出生体重和胎儿生长的其他标志一直与儿童ALL风险增加有关，西班牙裔似乎在怀孕早期就加速了胎儿生长。在当前的应用中，我们试图通过明确遗传易感性和胎儿生长在加利福尼亚西班牙裔和非西班牙裔白人儿童ALL病因学中的作用来显著推进白血病研究，使用专门为这两个种族设计的高维阵列。我们将(1)将加州出生记录与加州癌症登记数据（1988 - 2008）联系起来，以空前规模（4000例病例和4000例对照，其中约一半为西班牙裔白人，一半为非西班牙裔白人）进行基于人群的病例对照研究；(2)从加州公共卫生部获得所有病例和对照病例的新生儿干血斑档案；(3)采用为加州人群设计的Affymetrix全基因组阵列对研究人群进行基因分型，并分别对西班牙裔和非西班牙裔白人进行优化设计；(4)利用这些病例和对照的数据，确定西班牙裔和非西班牙裔白人不同的和共有的遗传风险等位基因；(5)验证加州儿童白血病研究（一项正在进行的美国国立卫生研究院资助的病例对照研究，具有独立和独特的受试者确定，1000例病例，1000例对照，其中约一半为西班牙裔白人，一半为非西班牙裔白人）和巴西儿童白血病研究中拉丁美洲病例（n = 200）和对照（n = 400）的顶级GWAS结果。此外，我们将利用1988 - 2008年期间加州所有新生儿的特征数据，开发一种算法，根据胎龄、性别、出生顺序、父母种族、父母西班牙裔身份和父母年龄等因素预测出生体重，并通过将实际观察到的出生体重除以算法得出的预期出生体重，计算出所有病例和对照组（n = 8000）的预期出生体重（PEBW）的比例。随后，我们将分别在西班牙裔和非西班牙裔白人中确定PEBW或出生体重是否与(i)儿童ALL， （ii） GWAS命中数最高，以及（iii）可能与胎儿生长相关的基因snp相关。考虑到前所未有的样本量，尤其是大量的西班牙裔人，以及具有很大基因组覆盖率的种族特异性基因分型面板，本研究将阐明遗传易感性在儿童ALL中的作用，涉及胎儿生长的机制，并在此过程中确定令人费解的疾病发病率种族差异的潜在原因。