A Genome-Wide Association Study of Non-Hodgkin Lymphoma

描述(申请人提供)：在过去的40年里，非霍奇金淋巴瘤(NHL)在美国和其他工业化国家的发病率急剧上升，尽管发病率上升的原因在很大程度上无法解释。据估计，2005年非霍奇金淋巴瘤将导致56,390例新确诊病例和19,200例相关死亡。基于家庭和人群的研究提供了证据，证明遗传易感性在淋巴肿大中发挥作用。然而，常见的遗传等位基因和基因-环境交互作用的贡献还有待进一步研究。使用PerLegen高密度寡核苷酸阵列，将对汇集的DNA进行全基因组基因分型，以筛选NHL易感标记。将在旧金山湾区进行一项基于人群的大型病例对照研究(招募2,000名病例和2,000名对照，将于2006年春季完成)，评估267,000个单倍型标记单核苷酸多态(SNPs)，这些SNPs跨越来自1,000例NHL病例和1,000名对照的DNA池。通过从所有研究参与者那里收集广泛的流行病学信息，已经确定了1400多例病例和1400多名对照。一旦通过混合基因分型确定了目标基因，这些基因座与非霍奇金淋巴瘤风险的关联将通过个体基因分型得到验证和进一步研究。另外7,000个SNPs将在人类白细胞抗原(人类白细胞抗原)区域单独进行基因分型，以研究人类白细胞抗原基因座在NHL发病机制中的作用。阳性发现将在第二组1000例NHL病例和1000例对照中重复。将对已确认的感兴趣基因进行精细定位基因分型。为了增加一个额外的复制步骤，来自之前的一项NHL研究(以旧金山湾区为基础)的另外大约400例NHL病例和800名对照将进行基因分型。这项研究是迄今为止进行的最大的病例对照非霍奇金淋巴瘤遗传流行病学研究之一，它将扩大我们目前对淋巴肿大涉及的重要机制途径的理解。此外，这些结果可能被转化为NHL的筛查、预防或治疗方案。这项研究产生的数据将为NHL财团InterLymph内的进一步调查提供一个框架。结果稍后将与其他InterLymph病例对照研究的结果结合在一起进行分析。

DESCRIPTION (provided by applicant): Incidence rates of non-Hodgkin lymphoma (NHL) have increased dramatically in the U.S. and other industrialized countries over the past 40 years, though reasons for this rise in rates are largely unexplained. In 2005, it has been estimated that NHL will account for 56,390 newly diagnosed cases and 19,200 associated deaths. Family and population-based studies provide evidence that genetic susceptibility plays a role in lymphomagenesis. However, the contribution of common genetic alleles and gene-environment interactions needs further investigation. Using Perlegen high-density oligonucleotide arrays, genome-wide genotyping on pooled DNA will be conducted to screen for NHL susceptibility markers. 267,000 haplotype tagging single nucleotide polymorphisms (SNPs) will be evaluated that span the genome on DNA pools from 1,000 NHL cases and 1,000 controls in a large population-based case-control study in the San Francisco Bay Area (recruitment of 2,000 cases and 2,000 controls to be completed in Spring 2006). Over 1,400 cases and 1,400 controls already have been ascertained with extensive epidemiological information collected from all study participants. Once target genes are identified by pooled genotyping, the association of these loci with NHL risk will be verified and further investigated by individual genotyping. An additional 7,000 SNPs will be individually genotyped in the human leukocyte antigen (HLA) region to investigate the involvement of HLA loci in the pathogenesis of NHL. Positive findings will be replicated in a second set of 1,000 NHL cases and 1,000 controls. Fine mapping genotyping will be performed on confirmed genes of interest. To add an additional replication step, another approximately 400 NHL cases and 800 controls from a previous NHL study (based in the San Francisco Bay Area) will be genotyped. This study, which constitutes one of the largest case-control NHL genetic epidemiology studies conducted to date, will broaden our current understanding of important mechanistic pathways involved in lymphomagenesis. Furthermore, these results may be translated to NHL screening, prevention or treatment regimens. The data generated from this study will provide a framework for further investigation within the NHL consortium, InterLymph. Results will later be combined with that from other InterLymph case-control studies in pooled analyses.