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）：慢性淋巴细胞白血病（CLL）是一种血液肿瘤，是西方国家高加索人中最常见的成人白血病。有大量证据表明，CLL的病因学中存在遗传成分，该疾病是任何癌症中家族风险最高的疾病之一。奇怪的是，尽管有这种强大的家族基础，CLL疾病的遗传学在很大程度上是未知的。此外，早期慢性淋巴细胞白血病患者的临床结局存在严重异质性。已发现CLL的生物学特征可预测这些早期患者的生存率，但迄今为止，遗传性遗传变异作为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相对罕见，每年每10万人中约有4.1例新发病例，因此需要汇集努力以实现必要的统计功效。我们有机会通过利用四项CLL研究与全基因组关联（GWA）数据来有效和快速地解决这一需求。在本申请中，我们建议通过结合四项CLL GWA研究的数据来最大化样本量，从而提供约3000例CLL病例和13，000例对照的数据。此外，我们将在随访数据可用的研究中调查CLL生存和进展的遗传决定因素。这项研究工作将产生一个前所未有的CLL风险和预后的遗传学研究。我们的具体目标是：（目标1）结合联合收割机的数据，从四个GWA研究，以确定与CLL风险相关的遗传变异。(Aim 2）对来自目标1的确认基因座进行精细定位，以进一步细化和潜在地鉴定致病变体。(Aim 3）使用来自Aim 1的组合GWA数据以鉴定与CLL预后相关的遗传变异。我们的建议结合了来自四项GWA研究的基因型和表型数据。这些研究构成了独特和协同的资源，使我们有机会有效地测试我们的假设与快速应用的潜力。在这个项目完成后，我们希望确定额外的新的基因座影响CLL的风险，不能已经确定的个别GWA研究，提高证据的关联发现从个别研究，并确定新的基因座影响CLL的预后。总的来说，我们的研究结果将提供一个更好地了解慢性淋巴细胞白血病的病理生物学，并可能导致新的治疗方法来治疗慢性淋巴细胞白血病，以及病因学假说的发展。