Epidemiologic Studies

流行病学研究

• 批准号: 8330346
• 负责人: STEPHEN B GRUBER
• 金额: $ 74.47万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-08 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8330346
• 关键词: Accounting; Adenomatous Polyposis Coli; Age; Alcohols; Anti-Inflammatory Agents; Anti-inflammatory; Area; Aspirin; Calcium; Clinic; Clinical; Colorectal Cancer; Communities; Complex; Confusion; Data; Data Set; Diet; Disease; Environment; Environmental Risk Factor; Epidemiologic Studies; Etiology; Evaluation; Family; Family history of; Folate; Genes; Genetic; Genetic Variation; Genetic screening method; Genome; Hereditary Nonpolyposis Colorectal Neoplasms; Hormones; Individual; Inherited; Intervention; Lead; Malignant Neoplasms; Measurement; Meat; Modeling; Mutation; Obesity; Penetrance; Pharmaceutical Preparations; Physical activity; Population; Population Attributable Risks; Population Study; Postmenopause; Predisposition; Prospective Studies; Public Health; Research; Resources; Risk; Sample Size; Scanning; Smoking; Syndrome; Testing; Time; Translations; Validation; cancer genome; genetic risk factor; genetic variant; genome wide association study; high risk; knowledge base; population based; premature; sex; success

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.

结直肠癌（CRC）是一种多因素的复杂疾病，遗传和环境因素都有助于这种严重疾病的病因。来自全基因组关联研究（GWAS）的第一个结果已经证明在鉴定常见复杂疾病（包括CRC）中的新基因座方面取得了相当大的成功，并且预期通过对单个GWAS的组合分析来鉴定其他基因座。正如我们的提案中的第一部分所建议的那样。然而，为了充分探索常见遗传变异对CRC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。CRC与几个可改变的环境因素有关，如肥胖、体力活动、阿司匹林使用、吸烟和饮食，这为测试基因-环境（GxE）相互作用提供了机会，并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，关键是要了解新发现的基因座的突变率，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）调查与遗传变异的关联是否受到环境风险的影响 CRC的因素包括年龄、性别、CRC家族史、肥胖、体力活动、非甾体类抗肿瘤药物、绝经后激素使用、叶酸、钙、红肉、酒精和吸烟。这将需要在四个GWAS中扫描整个基因组的GxE相互作用，并在独立的研究人群中进行大规模复制。(2)确定在高危家族和人群研究中所有已确定的CRC易感基因位点的发病率和人群归因风险。(3)开发复杂的风险模型，将沿着在区域1和2中识别的遗传变异与基于人群和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。 该联盟提供了一个前所未有的机会，加速将GWAS的CRC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，为综合后GWAS发现研究提供了独特的资源。我们正面临着一个过早使用GWAS发现进行基因检测的时期，这可能会导致我们社区的混乱。GWAS研究结果与环境风险因素、传染性和风险模型的相互作用的综合评价和表征，需要为有针对性的公共卫生和临床干预措施提供严格的知识基础。