Pooling and expansion of Chronic Lymphocytic Leukemia GWA data

项目总结（见说明）： 慢性淋巴细胞白血病（CLL）是一种血液肿瘤， 在西方国家的白种人中的成人白血病。证据很充分 CLL的病因学中存在遗传成分，该疾病具有 所有癌症的最高家族风险。奇怪的是，尽管有如此强大的家庭基础， CLL疾病的遗传学在很大程度上是未知的。此外，还有深刻的 早期CLL患者临床结果的异质性。生物 已发现CLL的特征可预测这些早期患者的存活率， 但到目前为止，遗传变异作为CLL预后决定因素的作用， 很少受到关注。以前的遗传学研究在以下方面取得了有限的成功： 阐明CLL风险和进展的遗传成分，在很大程度上是由于低 统计力量由于CLL相对罕见，每例患者约有4.1例新发病例， 每年10万人，需要集中努力，以实现必要的统计数字， 动力.我们有机会通过利用 四项CLL研究与全基因组关联（GWA）数据。在本申请中，我们 建议通过合并四项CLL GWA研究的数据来最大化样本量 提供了大约3000例CLL病例和13000例 对照此外，我们将研究CLL生存的遗传决定因素， 有随访数据的研究进展。这项研究工作将产生 一项关于慢性淋巴细胞白血病风险和预后的前所未有的遗传学研究。我们的目标是：（目标 1)联合收割机从四个GWA研究中获得的数据，以识别遗传变异 与CLL风险有关。(Aim 2）对来自以下的已确认的基因座进行精细定位： 目的1进一步完善和潜在地识别因果变异。(Aim（3）使用 结合目标1的GWA数据，以确定 与CLL预后相关。我们的建议结合了基因型和表型 来自四项GWA研究的数据。这些研究构成了独特和协同的资源 这使我们有机会有效地测试我们的假设， 应用程序.在这个项目完成后，我们希望确定更多的新基因座 影响单个GWA研究无法识别的CLL风险， 改进从个别研究中确定的发现之间的关联的证据， 鉴定影响CLL预后新基因座。总的来说，我们的研究结果将提供一个 更好地了解CLL病理生物学，并可能导致新的治疗方法 治疗慢性淋巴细胞白血病，以及病因假说的发展。

PROJECT SUMMARY (See instructions): Chronic lymphocytic leukemia (CLL) is a neoplasm of the blood and is the most common form of adult leukemia in Caucasians in the Western countries. The evidence is great that a genetic component exists in the etiology of CLL, with the disease having amongst the highest familial risk of any cancer. Paradoxically despite this strong familial basis, the genetics of CLL disease is largely unknown. Further, there is profound heterogeneity in the clinical outcome among early-stage CLL patients. Biological characteristics of CLL have been found to predict survival in these early-stage patients, but to date, the role of inherited genetic variation as a determinant of CLL prognosis has received scant attention. Previous genetic studies have had limited success in elucidating the genetic components of CLL risk and progression, in large part due to low statistical power. Because CLL is relatively rare with approximately 4.1 new cases per 100,000 persons per year, a pooling effort is needed to achieve requisite statistical power. We have the opportunity to address this need efficiently and rapidly by exploiting four CLL studies with genome-wide association (GWA) data. In this application, we propose to maximize the sample size by combining data from four CLL GWA studies that are available, thereby providing data on approximately 3000 CLL cases and 13,000 controls. In addition, we will investigate the genetic determinants of CLL survival and progression in studies for which follow-up data is available. This research effort will yield an unprecedented genetic study of CLL risk and prognosis. Our Specific Aims are: (Aim 1) To combine data from four GWA studies in order to identify genetic variants associated with CLL risk. (Aim 2) To perform fine mapping of confirmed loci from Aim 1 to further refine and potentially identify causal variants. (Aim 3) To use the combined GWA data from Aim 1 in order to identify genetic variants that are associated with CLL prognosis. Our proposal combines genotype and phenotype data from four GWA studies. These studies constitute unique and synergistic resources that afford us the opportunity to efficiently test our hypotheses with the potential for rapid application. At the completion of this project, we expect to identify additional novel loci influencing CLL risk that could not have been identified by the individual GWA studies, improve the evidence of associations of findings identified from individual studies, and identify novel loci influencing CLL prognosis. Collectively, our findings will provide for a better understanding of CLL pathobiology and may lead to novel therapeutic approaches to treating CLL, as well as the development of etiological hypotheses.