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

• 批准号: 8034814
• 负责人: Susan L Slager
• 金额: $ 54.71万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8034814
• 关键词: Address; Affect; Attention; Biologic Characteristic; Biology; Case-Control Studies; Caucasians; Caucasoid Race; Chronic Lymphocytic Leukemia; Clinical; Country; Data; Development; Disease; Etiology; Genes; Genetic; Genetic Determinism; Genetic Variation; Genotype; Health; Heterogeneity; Individual; Inherited; International; Lead; Malignant Neoplasms; Maps; Molecular; Non-Hodgkin' s Lymphoma; Outcome; Patients; Persons; Phenotype; Prevention strategy; Prognostic Marker; Research; Resources; Risk; Role; Sample Size; Single Nucleotide Polymorphism; Staging; Stratification; Testing; Variant; Woman; adult leukemia; base; blood neoplasm; follow-up; genetic variant; genome wide association study; improved; men; non-genetic; novel; novel therapeutic intervention; outcome forecast; success; tumor

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.

描述（由申请人提供）：慢性淋巴细胞性白血病（CLL）是血液的肿瘤，是西方国家高加索人最常见的成人白血病形式。有证据表明，在CLL的病因学中存在遗传成分，该疾病是任何癌症的最高家族风险。尽管家族基础很强，但矛盾的是，CLL疾病的遗传学基本上是未知的。此外，早期CLL患者的临床结果存在很大的异质性。已经发现CLL的生物学特征可以预测这些早期患者的生存，但是迄今为止，遗传变异作为CLL预后的决定因素的作用受到了很少的注意。先前的遗传研究在阐明CLL风险和进展的遗传成分方面取得了有限的成功，这在很大程度上是由于统计能力低。由于CLL相对较少，每年每10万人约4.1个新病例，因此需要一项集合工作来实现必要的统计能力。我们有机会通过利用四个具有全基因组关联（GWA）数据的CLL研究来有效，迅速地满足这一需求。在此应用程序中，我们建议通过结合可用的四个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，我们将研究可获得后续数据的研究中CLL存活和进展的遗传决定因素。这项研究工作将对CLL风险和预后进行前所未有的遗传研究。我们的具体目的是：（目标1）结合四个GWA研究的数据，以确定与CLL风险相关的遗传变异。 （AIM 2）对AIM 1的确认基因座进行精细映射，以进一步完善并可能识别因果变体。 （AIM 3）使用AIM 1中的GWA数据组合数据，以识别与CLL预后相关的遗传变异。我们的建议结合了四个GWA研究的基因型和表型数据。这些研究构成了独特而协同的资源，使我们有机会有效地测试我们的假设，并有可能快速应用。该项目完成后，我们希望确定其他新型基因座影响CLL风险，而单独的GWA研究无法识别出无法识别的CLL风险，改善了从单个研究中确定的发现关联的证据，并确定了新颖的基因座影响CLL预后。总的来说，我们的发现将提供对CLL病理生物学的更好理解，并可能导致治疗CLL的新型治疗方法以及病因学假设的发展。