Genetic Susceptibility to Non-Hodgkins Lymphoma

非霍奇金淋巴瘤的遗传易感性

• 批准号: 6806520
• 负责人: MARTYN T SMITH
• 金额: $ 33.82万
• 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 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6806520
• 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学研究，淋巴瘤的病因学有显著的多基因贡献。确定导致这种风险的相关基因所需的研究设计是病例对照关联研究。利用这项研究设计，我们计划检验这一假设，即在免疫系统的发育和功能中至关重要的一些途径中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，我们将评估基因多态在两项大型病例对照研究中的作用，这两项研究是国际非霍奇金淋巴瘤流行病学研究(InterLymph)研究人员联盟的一部分。美国的一项研究包括至少400个病例和800个对照，英国利兹的另一项研究包括800个病例和800个对照。我们已经提取了DNA，而且这两个研究人群都有广泛的流行病学信息。目前这些研究的一个明确的优势是使用真实的分类系统，它允许定义具有不同分子特征的不同的NHL临床病理亚组。每项研究的数据将被分开分析，然后汇集在一起，最终与国家癌症研究所正在进行的分析所获得的数据结合在一起，这些数据来自具有类似设计的许多其他非霍奇金淋巴瘤研究。通过这种方式，我们将研究关键候选基因/通路的功能多态与其发生NHL风险之间的关系。通过与一个国际研究小组合作开发的假设和途径驱动的方法，已经选择了用于分析的候选基因。涉及获得性免疫和先天免疫、叶酸代谢、能量稳态、异体代谢和氧化应激的关键基因的功能多态性将主要使用基于高通量Taqman的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非霍奇金淋巴瘤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进行多变量分析，以检测遗传和环境因素与非霍奇金淋巴瘤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一个范例。