Epidemiologic Studies

结直肠癌(CRC)是一种多因素的复杂疾病，遗传和环境因素共同参与了这一严重疾病的病因。全基因组关联研究的第一批结果表明，在包括结直肠癌在内的常见复杂疾病中识别新的基因座取得了相当大的成功，预计将通过对单个基因组关联研究的联合分析来识别更多的基因座。正如我们提案的第1区所建议的那样。然而，为了充分探索常见遗传变异对结直肠癌风险的影响，重要的是探索遗传变异之间以及遗传变异与环境风险因素之间的相互作用。结直肠癌与几个可改变的环境因素有关，如肥胖、体力活动、阿司匹林的使用、吸烟和饮食，这为测试基因-环境(GxE)的相互作用提供了机会，并可能提供有针对性的干预。为了加速将这些发现转化为临床和公共卫生，关键是要了解新确定的基因座的外显性，并开发和验证风险模型，包括环境和遗传风险因素。为了全面探讨这些问题，我们提出了以下具体目标：(1)调查环境风险是否改变了与遗传变异的关联 结直肠癌的发病因素包括年龄、性别、结直肠癌家族史、肥胖、体力活动、非类固醇抗炎药、绝经后激素使用、叶酸、钙、红肉、酒精和吸烟。这将需要在四个GWA中扫描基因组中的GxE相互作用，并在独立研究人群中进行大规模复制。(2)在高危家系研究和人群研究中确定所有已识别的结直肠癌易感基因座的外显性和人群归因风险。(3)开发复杂的风险模型，将区域1和区域2中确定的遗传变异与环境风险因素结合在一起，进行基于人群的和前瞻性研究。作为这一目标的一部分，我们将评估这些风险模型的临床和公共卫生有效性。 该联盟提供了一个前所未有的机会，以加速将全球儿童基金会的研究结果转化为临床和公共卫生。我们跨学科团队的专业知识、庞大的样本量以及在基于人群和前瞻性研究中的详细暴露确定，为后GWAS发现综合研究提供了独特的资源。我们正面临着一个过早地将GWAS的结果用于基因测试的时代，这可能会在我们的社区导致混乱。在与环境风险因素、外显性和风险模型的相互作用方面，需要对全球气候变化研究结果进行全面的评估和表征，以便为有针对性的公共卫生和临床干预提供严格的知识基础。

Colorectal cancer (CRC) is a multifactorial complex disease with both genetic and environmental factors contributing to the etiology of this severe disease. First results from genome-wide association studies (GWAS) have demonstrated considerable success in identifying new loci in common complex diseases, including CRC and additional loci are expected to be identified through combined analyses of individual GWAS. as proposed in Area 1 of our proposal. However, to fully explore the impact of common genetic variants on the risk of CRC it will be important to explore interactions between genetic variants as well as between genetic variants and environmental risk factors. CRC is associated with several modifiable environmental factors, such as obesity, physical activity, aspirin use, smoking and diet providing the opportunity to test gene-environment (GxE) interactions and potentially provide targeted intervention. To expedite the translation of these findings into the clinic and public health it is critical to understand the penetrance of the newly identified loci and develop and validate risk models, including both environmental and genetic risk factors. To comprehensively explore these questions we propose the following specific aims; (1) To investigate whether associations with genetic variants are modified by environmental risk factors for CRC, including age, sex, family history of CRC, obesity, physical activity, non-steroidal antiinflammatory drugs, postmenopausal hormone use, folate, calcium, red meat, alcohol, and smoking. This will entail both scanning across the genome for GxE interactions in four GWAS and a large replication in independent study populations. (2) To determine the penetrance and population attributable risk of all identified CRC susceptibility loci within both high risk family and population-based studies. (3) To develop complex risk models that incorporate genetic variants identified in Area 1 and 2 along with environmental risk factors in population-based and prospective studies. As part of this aim we will evaluate the clinical and public health validity of these risk models. This Consortium provides an unprecedented opportunity to accelerate the translation of GWAS findings for CRC into the clinic and public health. The expertise of our transdisciplinary team, the large sample size, and the detailed exposure ascertainment in population-based and prospective studies provide a unique resource for integrative post-GWAS discovery research. We are facing a time of premature use of GWAS findings for genetic testing that will likely lead to confusion in our community. Comprehensive evaluation and characterization of GWAS findings with respect to interactions with environmental risk factors, penetrance, and risk models is needed to provide a rigorous knowledge base for targeted public health and clinical interventions.