GENE-ENVIRONMENT INTERACTIONS: THE ODYSSEY COHORT

控制外源化合物代谢和DNA修复过程的许多基因的多态与癌症和其他慢性疾病的易感性有关。我们需要在设计上更加全面的研究，并提供对拥有特定基因类型对健康的净影响的见解。我们提出了一项基于人群的队列研究，以考察候选基因的遗传变异及其与环境暴露的交互作用对癌症发病率和存活率的广泛影响，以及更广泛的健康和老龄化。来自两个血液和数据标本库(线索I(1974)和线索II(1989))的参与者(N=8395)组成了研究队列(奥德赛队列)。这一队列已经前瞻性地跟踪了24年，早在1963年就可以获得有关吸烟、教育和住房等环境因素的信息。我们将从参赛者的黄褐色皮毛标本中提取DNA，并将其保存在-70℃下。我们将研究以下酶编码基因的多态性：1)代谢营养和激素(MTHFR、VDR、细胞色素P17、细胞色素P1B1、COMT、细胞色素P3A4)；2)代谢致癌物(ADH、GSTM1、GSTT1、GSTP1、NAT1和NAT2、NOS、CYP1A1、CYP1B1、EH)；以及3)控制DNA修复过程(XRCC1、XRCC3、XPD)。在这个队列中，对于主要癌症部位(如乳腺癌、前列腺癌和结直肠癌)，检测基因-环境和基因-基因交互作用的相对危险度大于90%，对于主要癌症部位(如乳腺癌、前列腺癌和结直肠癌)，检测基因-环境和基因-基因交互作用的相对危险度大于90%，对于不常见的癌症，如子宫内膜癌和膀胱癌，检测相对危险度为3-5倍。随着候选基因中与主要健康结局潜在相关的其他多态被识别出来，我们将能够调查它们对健康和生存的影响，提供宝贵的资源。

Polymorphisms of many genes controlling metabolism of xenobiotic compounds and DNA repair processes are associated with susceptibility to cancer as well as other chronic diseases. We need studies that are more holistic in design and provide insights into the net effect on health of having specific genotypes. We propose a population-based cohort study to examine the broad impact of genetic variation in candidate genes and their interaction with environmental exposures on cancer incidence and survival specifically, and health and aging more generally. Participants (N=8395) of two blood and data specimen banks (CLUE I (1974) and CLUE II (1989)) comprise the study cohort (Odyssey Cohort). The cohort has been followed prospectively for 24 years and information on environmental factors such as smoking, education and housing are available as far back as 1963. DNA will be extracted from buffy coat specimens obtained from participants in 1989 and stored at - 70 C. We will investigate polymorphisms in genes coding for enzymes that:1) metabolize nutrients and hormones (MTHFR, VDR, CYP17, CYP1B1, COMT, CYP3A4 ); 2) metabolize carcinogens (ADH, GSTM1, GSTT1, GSTP1, NAT1 and NAT2, NOS, CYP1A1, CYP1B1, EH); and 3) control DNA repair processes (XRCC1, XRCC3, XPD). In this cohort, power is greater than 90 percent to detect a relative risk of 2 for main effects of genotypes on mortality and cancer incidence and at least 80 percent to detect gene-environment and gene-gene interactions of two-fold for the major cancer sites (such as breast, prostate and colorectal) and 3- to 5-fold for less common cancers such as endometrial and bladder cancer. As additional polymorphisms in candidate genes with potential relevance to the major health outcomes are identified we will be able to investigate their impact on health and survival, providing a valuable resource.