Nightshift Work and DNA Methylation of Circadian Genes

描述(由申请人提供)：北美和欧洲估计有15%至20%的工人从事夜班工作，夜间工作可能导致患癌症风险增加，这是一个重要的公共卫生问题。鉴于夜班工作致癌性的实验证据和流行病学证据之间的差异，对夜班工作人员影响的生物标记物的研究可以提供关于可能的病因联系的重要新信息。核心昼夜节律基因对于调节昼夜节律是必不可少的，这些基因参与了许多重要的致癌机制。因此，通过调节DNA甲基化，这些基因的差异表达可能是夜班工人患癌症风险增加的一个机制。这项可行性研究的总体目标是确定是否可以使用来自仔细评估的轮班工人组的现有样本，在夜班和白班工人之间检测到昼夜节律基因中的差异甲基化位点。这将是第一项能够评估机器人男性和女性之间差异的研究。中心假设是，与夜班工作相关的昼夜节律中断导致了昼夜节律基因的差异表达，这通过这些基因中不同的基因位点甲基化来体现。此外，还将评估夜班工作的适应性指标，如时型和睡眠质量，以确定对夜班工作人员DNA甲基化的潜在影响。利用现有的血液样本和问卷数据，这项研究建议评估在抽血时积极上夜班的第一年的受试者(n=230)和积极上白班工作的第一年的受试者(n=114)。这些假设将通过追求以下具体目标来检验：1)评估夜班和白班工人之间12个核心昼夜节律基因中334个基因座的甲基化差异；2)在探索性分析中，评估性别、种族、时型和睡眠质量是否影响夜班工作对334个基因座DNA甲基化的影响。这项研究将为在倒班工人中进行表观遗传和其他生物标记物的大规模调查提供必要的初步数据。此外，这项研究的结果将有助于未来流行病学研究的设计，通过提供关于收集最相关的工作历史和睡眠相关数据、纳入潜在有用的生物标记物和产生新的假设的数据来检查癌症风险。预计这一系列研究最终将为干预措施提供目标，以减轻夜班工人的负面健康影响。

DESCRIPTION (provided by applicant): With an estimated 15 to 20% of workers in North America and Europe engaged in nightshift work, the possibility that working at night can result in an increased risk of developing cancer is an important public health concern. Given the discrepancy between the strength of experimental and epidemiologic evidence for the carcinogenicity of nightshift work, studies of biomarkers of effect among nightshift workers can provide important new information regarding the possible etiologic link. The core circadian genes are essential for regulation of circadian rhythms and these genes are involved in a number of mechanisms important to carcinogenesis. Thus, differential expression of these genes, through modulation of DNA methylation, may be a mechanism by which nightshift workers are at an increased risk of developing cancer. The overall objective of this feasibility study is to determine whether differentially methylated sites can be detected in circadian genes between night and dayshift workers using existing samples from a carefully evaluated group of shift workers. This will be the first study with the capability to evaluate such differences in bot men and women. The central hypothesis is that circadian disruption associated with working the nightshift results in differential expression of circadian genes that is manifest through differental methylation of loci in these genes. In addition, measures of adaptability to nightshift work, such as chronotype and sleep quality, will be evaluated for a potential impact on DNA methylation among nightshift workers. Using existing blood samples and questionnaire data, the study proposes to evaluate subjects who, at the time of blood draw, were actively working the nightshift for e1 year (n=230) and subjects who were actively working the dayshift for e1 year (n=114). The hypotheses will be tested by pursuing the following specific aims: 1) Evaluate differences in methylation at 334 loci in the 12 core circadian genes between established night and dayshift workers; 2) In exploratory analyses, evaluate if gender, race, chronotype and sleep quality affect the impact of nightshift work on DNA methylation at the 334 loci. This study will provide essential preliminary data for the pursuit of large scale investigations of epigenetic and other biomarkers among shift workers. Furthermore, the results of this study will be useful to the design of future epidemiologic studies examining cancer risk by providing data regarding the collection of the most relevant work history and sleep-related data, the incorporation of potentially useful biomarkers and the generation of new hypotheses. It is anticipated that this line of research will ultimately provide targets for interventions to mitigate negative health effets among nightshift workers.