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，支持特定人类白细胞抗原（HLA）基因与儿童白血病（特别是ALL）易感性或保护作用相关的证据。这项研究提供了一个独特的机会，以经济有效地检查主要组织相容性复合体（MHC），一个约3.6兆碱基对区域密集的基因参与免疫系统，包括功能性人类白细胞抗原（HLA）I类和II类基因。实施最新的分子遗传学技术和统计分析方法，将利用正在进行的北方加州儿童白血病研究（美国儿童白血病最广泛的基于人群的病例对照研究之一）的现有生物学和流行病学数据。作为确定儿童ALL中MHC潜在重要区域的第一步，将使用一组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HLA-DP基因的靶向等位基因分型，特别是HLA-DPB 1基因座，这在两项独立的基于人群的英国研究中显示与儿童ALL密切相关。这项拟议的研究将检查HLA-DP基因对美国两个主要种族群体（西班牙裔和非西班牙裔白人）儿童ALL风险的影响，并将评估这种风险是否会因感染暴露而改变。HLA-DP遗传变异与感染暴露的检查可以产生独特的信息线索，儿童ALL的免疫相关的生物学机制。

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.