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

MHC 遗传变异、感染暴露和儿童白血病风险

• 批准号: 7321548
• 负责人: Patricia A Buffler
• 金额: $ 6.02万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7321548
• 关键词: Accounting; Acute; Acute Lymphocytic Leukemia; Alleles; Amino Acid Sequence; Binding; Biological; California; Cancer Etiology; Case-Control Studies; Cessation of life; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Childhood Leukemia; Class; Complex; Data; Disease Association; Ethnic group; Etiology; Exposure to; Frequencies; Future; Genes; Genetic Techniques; Genetic Variation; Genome; Genotype; HLA Antigens; Haplotypes; Hispanics; Immune; Immune system; Immunologics; Infection; Infectious Agent; Lead; Lymphoblastic Leukemia; MHC Class II Genes; Major Histocompatibility Complex; Major Histocompatibility Complex Gene; Maps; Methods; Microsatellite Repeats; Molecular Genetics; Not Hispanic or Latino; Peptides; Polymorphic Microsatellite Marker; Population; Predisposition; Regulation; Reporting; Research; Risk; Role; Specimen; Time; United Kingdom; United States; Variant; base; cost; human leukocyte antigen gene; leukemia

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.

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尚不清楚。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，有证据支持特定人类白细胞抗原 (HLA) 基因与儿童白血病（尤其是 ALL）的易感性或预防性之间的关联。拟议的研究提供了一个独特的机会，可以经济有效地检查主要组织相容性复合体（MHC），这是一个约 3.6 兆碱基对的区域，富含与免疫系统相关的基因，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加州儿童白血病研究的现有生物学和流行病学数据，该研究是美国最广泛的基于人群的儿童白血病病例对照研究之一。作为识别儿童 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 区域进行全面筛选。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-DPB1 基因座，两项独立的基于人群的英国研究表明，该基因座与儿童 ALL 密切相关。拟议的研究将检查 HLA-DP 基因与美国两个主要种族（西班牙裔和非西班牙裔白人）儿童 ALL 风险的关系，并将评估这种风险是否会因接触感染而改变。对 HLA-DP 遗传变异与感染暴露的结合进行检查，可以为儿童 ALL 潜在的免疫相关生物学机制提供独特的信息线索。