MHC Genetic Variation, Exposure to Infections and Risk of Childhood Leukemia

描述(由申请人提供)： 儿童白血病是儿童癌症死亡的主要原因，其原因在很大程度上是未知的。急性淋巴细胞白血病(ALL)约占所有儿童白血病的80%。越来越多的证据支持免疫机制在儿童白血病病因学中的作用，更具体地说，证据支持特定的人类白细胞抗原(HLA)基因与儿童白血病(尤其是ALL)的易感性或保护性有关。这项拟议的研究提供了一个以经济高效的方式检查主要组织相容性复合体(MHC)的独特机会，MHC是一个约3.6兆碱基对的区域，其中包含与免疫系统有关的基因，包括功能性人类白细胞抗原(HL A)I类和II类基因。采用最新的分子遗传技术和统计分析方法，现有的生物学和流行病学数据将来自正在进行的北加州儿童白血病研究，这是美国最广泛的儿童白血病病例对照研究之一。作为确定儿童ALL期间MHC潜在重要区域的第一步，将使用一套专门的微卫星标记对MHC区域进行全面筛查。这项工作将伴随着对人类白细胞抗原-DP基因，特别是人类白细胞抗原-DPB1基因座的定向等位基因分型，在英国两项独立的基于人群的研究中显示，这与儿童ALL有很强的相关性。这项拟议的研究将检查美国两个主要种族--拉美裔和非拉美裔白人--的儿童ALL风险的人类白细胞抗原-DP基因，并将评估这种风险是否会因接触传染病而改变。结合感染暴露对人类白细胞抗原-DP基因变异进行检测，可以为儿童急性淋巴细胞白血病的潜在免疫相关生物学机制提供独特的信息线索。

DESCRIPTION (provided by applicant): Childhood leukemia is the leading cause of cancer death among children and its causes are largely unknown. Acute lymphoblastic leukemia (ALL) accounts for approximately 80% of all pediatric leukemias. There is growing evidence supporting a role for immunologic mechanisms in the etiology of childhood leukemia and, more specifically, evidence to support an association of specific human leukocyte antigen (HLA) genes with the susceptibility to, or protection from, childhood leukemia, particularly ALL. The proposed study presents a unique opportunity to cost-effectively examine the major histocompatibility complex (MHC), a ~3.6 megabase pair region dense in genes involved in the immune system, including the functional human leukocyte antigen (HLA) class I and class II genes. Implementing the most recent molecular genetic techniques and statistical analytic methods, existing biologic and epidemiologic data will be utilized from the ongoing Northern California Childhood Leukemia Study, one of the most extensive population-based case-control studies of childhood leukemia in the United States. As an initial step towards identifying potentially important regions of the MHC in childhood ALL, a comprehensive screen of the MHC region using a specialized set of microsatellite markers will be conducted. This effort will be accompanied by targeted allelic typing of HLA-DP genes, particularly the HLA-DPB1 locus, which was shown to be strongly associated with childhood ALL in two independent population-based United Kingdom studies. The proposed study will examine the HLA-DP genes on risk of childhood ALL in two major ethnic groups in the United States, Hispanics and non-Hispanic Whites, and will evaluate whether this risk is modified by infectious exposures. An examination of HLA-DP genetic variation in concert with infectious exposures could yield uniquely informative clues as to the underlying immune-related biological mechanism of childhood ALL.