GENETIC EPIDEMIOLOGY OF CHRONIC LYMPHOCYTIC LEUKEMIA

描述（由申请人提供）：慢性淋巴细胞白血病（CLL）是一种主要累及骨髓、血液和淋巴结的b细胞淋巴增殖性疾病。CLL是成人中最常见的白血病类型，尽管中位生存期可以很长，在8-12年之间，但大多数人最终死于疾病。CLL的遗传成分的证据是令人信服的，但仍然未知，而且可能是复杂的。然而，通过各种独特的研究和分析设计以及合作努力，识别潜在变异的机会是显而易见的。我们提出的研究计划是多方面的，高度协作的，包括几种创新技术。我们将进行两项研究设计，每项研究设计都能识别具有不同潜在遗传模型的易感基因：基于高风险家系的共享基因组片段分析和病例对照关联分析。全基因组共享基因组片段分析是一种新的方法，它需要极其扩展的、高风险的家谱，这种家谱只有拥有家谱资源的研究人员才能获得，比如犹他州。我们的关联策略将是基因组范围和候选区域。确定将涉及两个地点（犹他州和英国谢菲尔德），并将包括不一致的基于家庭的元素（犹他州）和基于人群的样本（英国）。这种方法既利用了家庭病例增加的力量，也利用了基于人群的样本。由于我们开发的软件，我们能够共同追求这些目标。在常规分析的基础上，我们将开发高风险家系和病例对照的新方法：高风险家系和病例对照的SGS和纯合子作图。传统方法和新方法都将作为更广泛的合作努力的一部分进行。我们将建立的资源是及时的。CLL基因研究仍处于起步阶段。这些设计的同步发展定义了一种广泛的策略，用于识别含有CLL易感基因的基因组区域，并将使我们有机会在塑造CLL遗传研究方向方面发挥重要作用。特别是，犹他州的血统，通过其结构和高风险的性质，增加了一个以前没有意识到的方面。如果一个设计或合作的努力能够识别CLL的单个易感基因，我们将在CLL的病因学上取得重要而关键的发现。这一发现不仅有助于我们了解CLL的病因，还可能为其他淋巴细胞增生性疾病提供信息，并可能转化为其他癌症。

DESCRIPTION (provided by applicant): Chronic Lymphocytic Leukemia (CLL) is a B-cell lymphoproliferative disorder primarily involving the bone marrow, blood and lymph nodes. CLL is the most common type of leukemia in adults and although median survival can be quite long, between 8-12 years, most eventually succumb to their disease. The evidence for a genetic component to CLL is compelling but remains unknown, and is likely complex. However, opportunities to identify underlying variants are apparent -both by varied and unique study and analysis designs and via collaborative efforts. The research plan we propose is multifaceted, highly collaborative and includes several innovative techniques. We will pursue two study designs, each powerful to identify susceptibility genes with different underlying genetic models: high-risk pedigree-based shared genomic segment analysis and case- control association analyses. Genome-wide shared genomic segment analysis is a new method that requires extremely extended, high-risk pedigrees which are available only to researchers with genealogic resources, such as Utah. Our strategy for association will be both genome wide and candidate region. Ascertainment will involve two sites (Utah and Sheffield, UK) and will include both a discordant family-based element (Utah) and a population-based sample (UK). This approach exploits both the increased power of familial cases with the perspective of population-based samples. We are able to pursue these together due to software that we have developed. In addition to conventional analyses, we will develop new methods for the high-risk pedigree and case-control settings: homozygosity mapping in the high-risk pedigrees and case-control SGS and homozygosity mapping. Both conventional and novel methods will be performed as part of broader collaborative efforts. The resource that we will build is timely. CLL genetic research is still in its infancy. The concurrent development of these designs defines an extensive strategy for identifying regions of the genome harboring CLL susceptibility genes and will afford us the opportunity to play a significant role in shaping the direction of CLL genetic research. Particularly, Utah pedigrees, through their structure and high-risk nature, add a previously unrealized aspect to the global picture. If one design or collaborative effort can identify even a single susceptibility gene for CLL, we will have made an important and critical discovery in the etiology of CLL. Such a discovery would not only help our understanding of the etiology of CLL, but also may provide information about other lymphoproliferative disorders and may translate to other cancers.