Pooling and expansion of Chronic Lymphocytic Leukemia GWA data

描述(申请人提供)：慢性淋巴细胞白血病(CLL)是一种血液肿瘤，是西方国家高加索人最常见的成人白血病形式。有很好的证据表明，慢性淋巴细胞性白血病的病因中存在遗传成分，这种疾病在任何癌症的家族风险中都是最高的。矛盾的是，尽管有很强的家族性基础，但CLL病的遗传学在很大程度上是未知的。此外，早期慢性淋巴细胞性白血病患者的临床结果存在严重的异质性。CLL的生物学特性被发现可以预测这些早期患者的生存，但到目前为止，遗传基因变异作为CLL预后决定因素的作用还没有引起足够的重视。以前的遗传学研究在阐明慢性淋巴细胞性白血病风险和进展的遗传成分方面取得的成功有限，这在很大程度上是由于统计能力较低。由于慢性淋巴细胞性白血病相对罕见，每年每10万人中约有4.1例新病例，因此需要共同努力才能获得必要的统计能力。我们有机会通过利用四项具有全基因组关联(GWA)数据的CLL研究来有效和快速地满足这一需求。在这项应用中，我们建议通过组合来自四项可用CLL GWA研究的数据来最大化样本量，从而提供大约3000个CLL病例和13,000个对照的数据。此外，我们将在有后续数据的研究中调查慢性淋巴细胞性白血病存活和进展的遗传决定因素。这项研究工作将产生一项史无前例的CLL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，以确定与CLL风险相关的遗传变异。(目标2)从目标1开始对已确认的基因座进行精细定位，以进一步提炼和潜在地识别因果变异。(AIM 3)使用来自AIM 1的综合GWA数据，以确定与慢性淋巴细胞性白血病预后相关的遗传变异。我们的建议结合了来自四项GWA研究的基因和表型数据。这些研究构成了独特和协同的资源，使我们有机会有效地检验我们的假设，并具有快速应用的潜力。在该项目完成后，我们期望确定其他影响慢性淋巴细胞性白血病风险的新基因座，这些新基因座不能由GWA个别研究确定，改善从个别研究确定的结果与相关性的证据，并确定影响慢性淋巴细胞性白血病预后的新基因座。总而言之，我们的发现将有助于更好地了解CLL的病理生物学，并可能导致治疗CLL的新的治疗方法，以及病因学假说的发展。

DESCRIPTION (provided by applicant): 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.