Genome-Wide Association Study of Childhood Leukemia by Hispanic Status

描述(申请人提供)：尽管急性淋巴细胞性白血病(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，拉美裔儿童的ALL发病率高于任何其他族裔/种族；他们患ALL的风险是非拉美裔白人儿童的1.3倍。两项小型全基因组关联研究(GWAS)最近确定了2-3个儿童ALL的遗传风险因素，但仅在非基于人群的确定的欧洲白人群体中。在大多数研究中，出生体重高和其他胎儿生长标志一直与童年风险的增加有关，而且拉美裔人似乎在怀孕早期就加速了胎儿的生长。在目前的应用中，我们试图通过使用专门为这两个种族设计的高维阵列，在加利福尼亚州以大样本为基础的拉美裔和非拉美裔白人中阐明遗传易感性和胎儿生长在儿童病因学中的作用，从而显著推进白血病研究。我们将(1)将加州出生记录与加州癌症登记处(1988-2008)的数据联系起来，以汇编一项基于人群的病例对照研究，规模空前(4,000例病例和4,000名对照，其中约一半将是西班牙裔和一半非西班牙裔白人)；(2)从加州公共卫生部获得所有病例和对照的新生儿干血点档案；(3)用为加州人口设计的定制Affymetrix全基因组阵列对研究人群进行基因分型，分别为西班牙裔和非西班牙裔白人设计优化设计；(4)使用来自这些病例和对照的数据来确定西班牙裔和非西班牙裔白人的不同和共同的遗传风险等位基因；以及(5)在加州儿童白血病研究(正在进行的一项由NIH资助的病例对照研究中，有一个单独和不同的主题确定，1000例病例和1000例对照，其中大约一半将是西班牙裔，一半是非西班牙裔白人)和巴西儿童白血病研究中，验证GWA值最高的命中率。此外，我们将利用1988-2008年间加州所有出生人口的特征数据来开发一种算法，根据胎龄、性别、出生顺序、父母种族、父母西班牙裔状况和父母年龄等因素预测出生体重，并通过将所有病例和对照组(n=8000)的实际观察出生体重除以该算法得出的预期出生体重来计算预期出生体重(PEBW)的比例。随后，我们将确定在西班牙裔和非西班牙裔白人中，PEBW或出生体重是否分别与(I)儿童ALL，(Ii)GWA值最高，以及(Iii)潜在与胎儿生长相关的基因中的SNPs有关。考虑到前所未有的样本量，特别是包括大量拉美裔美国人，以及具有巨大基因组覆盖范围的种族特定基因分型小组，这项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，并在此过程中找出疾病发病率存在令人困惑的种族差异的潜在原因。

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.