Epidemiologic Studies

结直肠癌（CRC）是一种多因素复杂疾病，遗传和环境因素共同导致了这种严重疾病的病因。全基因组关联研究 (GWAS) 的初步结果表明，在识别常见复杂疾病（包括结直肠癌）的新基因座方面取得了相当大的成功，预计将通过单个 GWAS 的综合分析来识别其他基因座。正如我们提案的第 1 领域中所提议的。然而，为了充分探索常见遗传变异对结直肠癌风险的影响，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非常重要。 CRC 与多种可改变的环境因素相关，例如肥胖、体力活动、阿司匹林使用、吸烟和饮食，这为测试基因与环境 (GxE) 相互作用提供了机会，并有可能提供有针对性的干预。为了加快将这些发现转化为临床和公共卫生，了解新发现的基因座的外显率并开发和验证风险模型（包括环境和遗传风险因素）至关重要。为了全面探讨这些问题，我们提出以下具体目标； (1) 研究与遗传变异的关联是否会受到环境风险的影响 结直肠癌的因素，包括年龄、性别、结直肠癌家族史、肥胖、体力活动、非甾体抗炎药、绝经后激素的使用、叶酸、钙、红肉、酒精和吸烟。这将需要在四个 GWAS 中扫描基因组中的 GxE 相互作用，并在独立研究群体中进行大量复制。 (2) 确定高风险家庭和基于人群的研究中所有已识别的 CRC 易感基因座的外显率和人群归因风险。 (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基于人群的前瞻性研究中的环境风险因素结合起来。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。 该联盟提供了前所未有的机会，加速将 CRC 的 GWAS 研究结果转化为临床和公共卫生。我们的跨学科团队的专业知识、大样本量以及基于人群和前瞻性研究的详细暴露确定为 GWAS 后综合发现研究提供了独特的资源。我们正面临着过早使用 GWAS 结果进行基因检测的时期，这可能会导致我们社区的混乱。需要对 GWAS 研究结果与环境风险因素、外显率和风险模型的相互作用进行全面评估和表征，以便为有针对性的公共卫生和临床干预措施提供严格的知识库。

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.