A Genome-Wide Association Study of Non-Hodgkin Lymphoma

描述（由申请人提供）：在过去的40年里，非霍奇金淋巴瘤（NHL）的发病率在美国和其他工业化国家急剧上升，尽管这种发病率上升的原因在很大程度上尚不清楚。2005年，据估计，NHL将造成56,390例新诊断病例和19,200例相关死亡。基于家庭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，共同基因等位基因的作用和基因与环境的相互作用还有待进一步研究。使用Perlegen高密度寡核苷酸阵列，对混合DNA进行全基因组基因分型，以筛选NHL易感标记。在旧金山湾区的一项基于人群的病例对照研究中，将对来自1000例NHL病例和1000例对照的基因组DNA库中的26.7万个单倍型标记单核苷酸多态性（SNPs）进行评估（招募2000例病例和2000例对照将于2006年春季完成）。已经确定了1400多个病例和1400个对照，并从所有研究参与者收集了广泛的流行病学信息。一旦通过合并基因分型确定了靶基因，这些基因座与NHL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7000个snp将在人类白细胞抗原（HLA）区域单独进行基因分型，以研究HLA位点在NHL发病机制中的作用。阳性结果将在第二组1000例非霍奇金淋巴瘤病例和1000例对照中得到重复。将对确定的感兴趣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，将扩大我们目前对淋巴瘤发生的重要机制途径的理解。此外，这些结果可能转化为NHL筛查，预防或治疗方案。这项研究产生的数据将为NHL联盟InterLymph的进一步研究提供一个框架。结果将在稍后与其他InterLymph病例对照研究合并分析。

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.