A Genome-Wide Association Study of Non-Hodgkin Lymphoma

描述（由申请人提供）：在过去的40年里，美国和其他工业化国家的非霍奇金淋巴瘤（NHL）发病率急剧增加，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，NHL将占56，390例新诊断病例和19，200例相关死亡。基于家族和人群的研究提供了遗传易感性在淋巴瘤发生中起作用的证据。然而，共同的遗传等位基因和基因-环境互作的贡献需要进一步研究。使用Perlegen高密度寡核苷酸阵列，对合并DNA进行全基因组基因分型，以筛选NHL易感性标志物。在旧金山弗朗西斯科海湾地区的一项大型基于人群的病例-对照研究中，将评估267，000个单倍型标记单核苷酸多态性（SNP），这些SNP跨越来自1，000例NHL病例和1，000例对照的DNA库的基因组（招募2，000例病例和2，000例对照将于2006年春季完成）。通过从所有研究参与者收集的广泛流行病学信息，已经确定了1，400多例病例和1，400例对照。一旦通过合并基因分型确定了靶基因，将通过个体基因分型验证并进一步研究这些基因座与NHL风险的相关性。另外7，000个SNP将在人类白细胞抗原（HLA）区域中单独进行基因分型，以研究HLA基因座在NHL发病机制中的参与。阳性结果将在第二组1,000例NHL病例和1,000例对照中重复。将对确认的目标基因进行精细定位基因分型。为了增加额外的复制步骤，将对来自先前NHL研究（基于旧金山弗朗西斯科湾区）的另外约400例NHL病例和800例对照进行基因分型。这项研究，这是迄今为止进行的最大的病例对照NHL遗传流行病学研究之一，将拓宽我们目前对淋巴瘤发生中重要机制途径的理解。此外，这些结果可以转化为NHL筛查，预防或治疗方案。本研究产生的数据将为NHL联盟InterLymph的进一步研究提供框架。随后将结果与其他InterLymph病例对照研究的结果合并进行汇总分析。

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.