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）：尽管急性淋巴细胞白血病（全部）是儿童中最常见的恶性肿瘤（0-14岁），但几乎没有已知的危险因素。在美国，西班牙裔儿童的发病率比任何其他种族/种族群体都更高。他们对所有人的风险是非西班牙裔白人儿童的1.3倍。两项小型基因组关联研究（GWAS）最近确定了儿童期的2-3个遗传风险因素，但仅在基于非人口的欧洲白人人群中。在大多数研究中，高出生体重和其他胎儿生长的标志一直与童年的风险增加有关，而西班牙裔似乎在怀孕期间早期就已经加速了胎儿生长。在当前的应用中，我们试图通过使用专门针对这两个种族设计的高维度阵列来阐明遗传易感性和胎儿生长在儿童期病因中的作用。我们将（1）将加州出生记录与加利福尼亚癌症登记处的数据（1988-2008）联系起来，以组装基于人群的病例对照研究，其大小是前所未有的（4,000例和4,000例对照，其中约有一半是西班牙裔和一半的非西班牙裔白人）；（2）获得加利福尼亚公共卫生部的所有病例和对照的所有病例的新生儿干血点；（3）基因型的研究人群具有为加利福尼亚人群设计的定制Affymetrix全基因组阵列，分别针对西班牙裔和非西班牙裔白人设计了优化的设计；（4）使用这些情况和对照组中的数据来识别西班牙裔和非西班牙裔白人的明显和共享的遗传风险等位基因； 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).此外，我们将利用有关1988年至2008年加利福尼亚州所有出生特征的数据来开发一种算法，以根据诸如胎龄，性别，性别，出生顺序，父母的性别，父母种族，父母西班牙裔状态以及父母的年龄以及预期的出生权重（PEBW）的比例（n = 8000）的体重来预测出生体重，以预测出生体重（胎龄，性别，出生阶段，父母的西班牙裔状态以及父母的体重（PEBW）的比例（n = 8000）算法。随后，我们将确定PEBW或出生体重是否与（i）童年全部相关，（ii）最高的GWAS命中以及（iii）基因中的SNP可能与胎儿生长，西班牙裔和非西班牙裔白人分别与胎儿生长有关。鉴于前所未有的样本量，尤其是包括大量西班牙裔的样本，以及具有巨大基因组覆盖率的民族特异性基因分型面板，这项研究将阐明遗传易感性在儿童期中的作用，涉及胎儿生长的机制，以及在此过程中识别出令人困惑的种族差异的疾病差异的原因。