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Pooling and expansion of Chronic Lymphocytic Leukemia GWA data

慢性淋巴细胞白血病 GWA 数据的汇集和扩展

基本信息

批准号：
8240110
负责人：
Susan L Slager
金额：
$ 53.69万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2013-09-30
项目状态：
已结题

项目摘要

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.

项目总结(见说明)：慢性淋巴细胞白血病(CLL)是一种血液肿瘤，是最常见的西方国家高加索人的成人白血病。证据确凿慢性淋巴细胞性白血病的病因中存在遗传成分，这种疾病在是所有癌症中风险最高的家族。矛盾的是，尽管有很强的家庭基础， CLL病的遗传学在很大程度上是未知的。此外，还存在着深刻的早期慢性淋巴细胞性白血病患者临床结局的异质性。生物学已发现CLL的特征可以预测这些早期患者的存活率，但到目前为止，遗传遗传变异作为CLL预后的决定因素的作用已经却鲜有人关注。以前的基因研究在以下方面的成功有限阐明慢性淋巴细胞性白血病风险和进展的遗传成分，在很大程度上是由于低统计学上的力量。因为慢性淋巴细胞性白血病相对罕见，每年大约有4.1例新病例每年100,000人，需要共同努力才能实现必要的统计权力。我们有机会通过利用用全基因组关联(GWA)数据进行的四项CLL研究。在此应用程序中，我们建议通过合并来自四项CLL GWA研究的数据来最大化样本量，从而提供了大约3000个CLL病例和13,000个CLL病例的数据控制。此外，我们将研究慢性淋巴细胞性白血病存活率的遗传决定因素和可获得随访数据的研究进展。这项研究工作将产生一项史无前例的关于慢性淋巴细胞白血病风险和预后的遗传学研究。我们的具体目标是：(目标 1)结合来自GWA的四项研究的数据，以确定遗传变异与CLL风险相关。(目标2)对已确认的基因座进行精细定位目标1进一步提炼和潜在地识别因果变异。(目标3)使用结合来自AIM 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GWA的四项研究的数据。这些研究构成了独特和协同的资源。这为我们提供了有效地测试我们的假设的机会，并具有快速申请。在这个项目完成后，我们希望确定更多的新基因座影响GWA个别研究无法确定的CLL风险，改进从个别研究中确定的研究结果的相关性的证据，以及寻找影响慢性淋巴细胞性白血病预后的新基因。总体而言，我们的发现将提供一个更好地了解CLL的病理生物学，并可能导致新的治疗方法治疗慢性淋巴细胞性白血病，以及病因假说的发展。