Genetic Susceptibility to Non-Hodgkins Lymphoma

描述（由申请人提供）：根据以往的经典流行病学和家庭研究，淋巴瘤的病因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，我们计划验证在免疫系统发育和功能的一些重要途径中的遗传变异影响淋巴瘤发生风险的假设。通过开展这样的研究，我们将能够确定淋巴瘤病因的重要遗传机制，所描述的关联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项大型病例对照研究中的作用，这两项研究是NHL流行病学研究国际研究联盟（InterLymph）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，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REAL分类系统，该系统允许定义具有不同分子特征的NHL不同临床病理亚群。每项研究的数据将分别进行分析，然后汇总在一起，最终与NCI正在进行的分析中获得的数据相结合，这些分析来自许多其他具有类似设计的NHL研究。通过这种方式，我们将研究关键候选基因/途径的功能多态性及其对NHL发病风险的影响之间的关系。候选基因的分析已经选择使用假设和途径驱动的方法开发与一个国际研究小组合作。参与获得性和先天免疫、叶酸代谢、能量稳态、外源代谢和氧化应激的关键基因的功能多态性将主要使用高通量taqman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能力进行多变量分析，以检测遗传和环境因素与NHL风险之间的相互作用，这将为未来罕见病的国际合作研究提供范例。

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.