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性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全面的研究，并提供对特定基因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，以研究候选基因的遗传变异及其与环境暴露的相互作用对癌症发病率和生存的广泛影响，以及更广泛的健康和衰老。两个血液和数据标本库（CLUE I（1974）和CLUE II(1989)）的参与者（N=8395）组成了研究队列（奥德赛队列）。研究人员对这群人进行了24年的前瞻性随访，有关吸烟、教育和住房等环境因素的信息可以追溯到1963年。DNA将从1989年从参与者身上获得的灰白色被毛标本中提取，并在- 70℃下保存。我们将研究编码酶的基因多态性：1)代谢营养物质和激素（MTHFR， VDR, CYP17, CYP1B1， COMT, CYP3A4）；2)代谢致癌物（ADH、GSTM1、GSTT1、GSTP1、NAT1和NAT2、NOS、CYP1A1、CYP1B1、EH）；3)控制DNA修复过程（XRCC1, XRCC3， XPD）。在这个队列中，检测基因型对死亡率和癌症发病率的主要影响的相对风险大于90%，检测基因-环境和基因-基因相互作用的相对风险至少为80%，对于主要癌症部位（如乳腺癌、前列腺癌和结肠直肠癌）为2倍，对于不太常见的癌症（如子宫内膜癌和膀胱癌）为3至5倍。随着候选基因中与主要健康结果潜在相关的其他多态性的确定，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.