Genetic Susceptibility to Non-Hodgkins Lymphoma

描述（由申请人提供）：根据先前的经典流行病学和家庭研究，淋巴瘤的病因学具有显着的多基因作用。定义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，我们计划检验以下假设：在免疫系统的发育和功能中重要的许多途径中的遗传变异会影响患淋巴瘤的风险。通过开展此类研究，我们将能够定义淋巴瘤病因学中的重要遗传机制，所描述的关联也将提供重要环境因素的线索。我们将特别评估遗传多态性在两项大型病例对照研究中的作用，这两项研究是国际NHL流行病学研究研究者联盟（InterLymph）的一部分。一项在美国进行的研究包含至少 400 个病例和 800 个对照，另一项在英国利兹进行的研究包含 800 个病例和 800 个对照。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 的不同临床病理亚组。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，该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/通路的功能多态性之间的关系及其对发生 NHL 风险的影响。使用与国际研究小组合作开发的假设和途径驱动的方法来选择用于分析的候选基因。将主要使用基于高通量 Taqman 的等位基因辨别技术来分析涉及获得性和先天免疫、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。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。使用多研究方法将为进行多变量分析提供足够的能力，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。

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.