Genetic Susceptibility to Non-Hodgkins Lymphoma

非霍奇金淋巴瘤的遗传易感性

• 批准号: 7123953
• 负责人: MARTYN T SMITH
• 金额: $ 33.03万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7123953
• 关键词: bioenergetics; disease /disorder etiology; drug /agent; folate; gene environment interaction; gene interaction; genetic polymorphism; genetic susceptibility; high throughput technology; human data; human genetic material tag; immunogenetics; mathematical model; neoplasm /cancer epidemiology; neoplasm /cancer genetics; nonHodgkin' s lymphoma; oxidative stress; statistics /biometry; vitamin metabolism

DESCRIPTION (provided by applicant): Based on previous classical epidemiological and family studies there is a significant polygenic contribution to the etiology of lymphoma. The study design required to define the relevant genes contributing to this risk is the case-control association study. Using this study design, we plan to test the hypothesis that genetic variation within a number of pathways important in the development and function of the immune system affect the risk of developing lymphoma. By carrying out a study such as this, we will be able to define important genetic mechanisms in the etiology of lymphoma and associations described will also yield clues to important environmental factors. In particular we will evaluate the role of genetic polymorphisms in two large case-control studies that form part of the International Consortium of Investigators Working on NHL Epidemiologic Studies (InterLymph). One study based here in the U.S. comprised of at least 400 cases and 800 controls, and another study based in Leeds, England, consists of 800 cases and 800 controls. We have already extracted DNA and there is extensive epidemiological information for both study populations. One defined advantage of these current studies is the use of the REAL classification system, which allows the definition of distinct clinico-pathological subgroups of NHL, which have varying molecular characteristics. The data from each study will be analyzed separately then pooled together and eventually combined with data obtained from ongoing analyses being carried out at the NCI from a number of other studies of NHL with similar design. In this manner, we will investigate the relationship between functional polymorphisms in key candidate genes / pathways and their effect on the risk of developing NHL. Candidate genes for analysis have been selected using a hypothesis- and pathway-driven approach developed in collaboration with an international group of investigators. Functional polymorphisms in key genes involved in acquired and innate immunity, folate metabolism, energy homeostasis, xenobiotic metabolism, and oxidative stress will be analyzed primarily using high-throughput Taqman-based allelic discrimination techniques. These analyses will constitute one of the largest NHL molecular epidemiology studies to date. Using a multi-study approach will provide sufficient power to carry out multivariate analyses to detect interactions between genetic and environmental factors and NHL risk that will provide a paradigm for future international collaborative studies of rare diseases.

描述（由申请人提供）：基于先前的经典流行病学和家族研究，淋巴瘤的病因学存在显著的多基因贡献。定义导致该风险的相关基因所需的研究设计是病例对照关联研究。使用本研究设计，我们计划检验以下假设：在免疫系统发育和功能中重要的许多途径内的遗传变异会影响发生淋巴瘤的风险。通过开展这样的研究，我们将能够确定淋巴瘤病因学中的重要遗传机制，所描述的相关性也将为重要的环境因素提供线索。特别是，我们将评估遗传多态性在两个大型病例对照研究中的作用，这两个研究是NHL流行病学研究国际联盟（InterLymph）的一部分。一项在美国进行的研究包括至少400例病例和800例对照，另一项在英国利兹进行的研究包括800例病例和800例对照。我们已经提取了DNA，并且有两个研究人群的广泛流行病学信息。目前这些研究的一个明确的优势是使用真实的分类系统，它允许定义NHL的不同临床病理亚组，这些亚组具有不同的分子特征。将分别分析每项研究的数据，然后汇总在一起，最终与NCI正在进行的分析中获得的数据合并，这些分析来自其他一些设计相似的NHL研究。通过这种方式，我们将研究关键候选基因/途径的功能多态性与其对NHL发生风险的影响之间的关系。候选基因的分析已被选定使用的假设和路径驱动的方法与国际研究小组合作开发。在获得性和先天性免疫，叶酸代谢，能量稳态，异生物质代谢和氧化应激中涉及的关键基因的功能多态性将主要使用基于Taqman的高通量等位基因识别技术进行分析。这些分析将构成迄今为止最大的NHL分子流行病学研究之一。使用多研究方法将提供足够的力量来进行多变量分析，以检测遗传和环境因素与NHL风险之间的相互作用，这将为未来罕见疾病的国际合作研究提供范例。