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

基本信息

批准号：
8288073
负责人：
Xiaomei Ma
金额：
$ 22.56万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
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/8288073
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 Screening procedure 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

项目摘要

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 发病率高于任何其他民族/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，但仅在欧洲白人群体中进行了非人群确定。在大多数研究中，高出生体重和其他胎儿生长标志物始终与儿童 ALL 风险增加相关，而西班牙裔似乎在怀孕早期加速了胎儿生长。在当前的应用中，我们专门使用高维阵列，明确了遗传易感性和胎儿生长在加利福尼亚州大量西班牙裔和非西班牙裔白人样本中儿童 ALL 病因学中的作用，从而显着推进白血病研究。专为两个民族设计。我们将 (1) 将加州出生记录与加州癌症登记数据（1988 - 2008 年）联系起来，以开展一项规模空前的基于人群的病例对照研究（4,000 例病例和 4,000 名对照组，其中大约一半是西班牙裔，一半是非裔美国人） - 西班牙裔白人）； (2) 从加州公共卫生部获取所有病例和对照的存档新生儿干血斑； (3) 使用专为加州人群设计的定制 Affymetrix 全基因组芯片对研究人群进行基因分型，并分别针对西班牙裔和非西班牙裔白人进行优化设计； (4) 使用这些病例和对照的数据来识别西班牙裔和非西班牙裔白人的独特和共有的遗传风险等位基因； (5) 验证加州儿童白血病研究（一项由 NIH 资助的正在进行的病例对照研究，具有单独且不同的受试者确定，> 1000 个病例，> 1000 个对照，其中大约一半是西班牙裔，一半是非裔），验证最热门的 GWAS 命中- 西班牙裔白人）以及一项针对拉丁美洲病例（n = 200）和对照（n = 400）的巴西儿童白血病研究。此外，我们将利用 1988 - 2008 年间加州所有出生婴儿的特征数据，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来预测出生体重，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，计算所有病例和对照 (n = 8000) 的预期出生体重 (PEBW) 比例。随后，我们将分别确定西班牙裔和非西班牙裔白人的 PEBW 或出生体重是否与 (i) 儿童 ALL、(ii) GWAS 热门命中以及 (iii) 与胎儿生长潜在相关的基因中的 SNP 相关。鉴于前所未有的样本量，特别是包含大量西班牙裔，以及基因组覆盖范围广的种族特异性基因分型小组，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，并在此过程中确定潜在的潜力。疾病发病率存在令人费解的种族差异的原因。