Nightshift Work and DNA Methylation of Circadian Genes

夜班工作与昼夜节律基因的 DNA 甲基化

• 批准号: 8771439
• 负责人: Parveen Bhatti
• 金额: $ 26.4万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8771439
• 关键词: Affect; Air Pollution; Biological; Biological Markers; Blood; Blood specimen; Carbon; Carcinogens; Cell Cycle Regulation; Cell physiology; Circadian Rhythms; Collection; CpG dinucleotide; Cytosine; DNA; DNA Damage; DNA Methylation; Data; Environmental Exposure; Epidemiologic Studies; Epidemiology; Epigenetic Process; Europe; Exposure to; Feasibility Studies; Fostering; Future; Gender; Generations; Genes; Genome; Health; Hour; Human; International Agency for Research on Cancer; Intervention; Investigation; Link; Malignant Neoplasms; Measures; Methylation; Mission; North America; Patient Self-Report; Population Study; Predisposition; Public Health; Questionnaires; Race; Recording of previous events; Regulation; Regulator Genes; Research; Risk; Sampling; Schedule; Site; Sleep; Smoking; Source; Testing; Time; Tissue-Specific Gene Expression; Western World; Woman; Work; actigraphy; base; cancer risk; carcinogenesis; carcinogenicity; circadian pacemaker; cost; cost effective; design; differential expression; epigenetic marker; experience; improved; men; population based; preference; shift work

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.

据估计，北美和欧洲有15%至20%的工人从事夜班工作，夜间工作可能导致患癌症的风险增加，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，夜班工作者中效应生物标志物的研究可以提供有关可能的病因学联系的重要新信息。核心昼夜节律基因是调节昼夜节律所必需的，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种机制。这项可行性研究的总体目标是确定是否差异甲基化位点可以检测到昼夜节律基因之间的夜班和白班工人使用现有的样本，从一个仔细评估组的轮班工人。这将是第一项有能力评估机器人男性和女性之间这种差异的研究。核心假设是与夜班工作相关的昼夜节律破坏导致昼夜节律基因的差异表达，这通过这些基因中基因座的差异甲基化来表现。此外，将评估夜班工作适应性的措施，如时钟类型和睡眠质量，以评估夜班工人对DNA甲基化的潜在影响。使用现有的血液样本和问卷调查数据，该研究建议评估在抽血时积极上夜班的受试者（n=230）和积极上白班的受试者（n=114）。这些假设将通过追求以下具体目标进行检验：1）评估夜班和白班工人之间12个核心昼夜节律基因中334个位点的甲基化差异; 2）在探索性分析中，评估性别，种族，时间型和睡眠质量是否影响夜班工作对334个位点DNA甲基化的影响。这项研究将提供必要的初步数据，追求大规模调查的表观遗传和其他生物标志物的倒班工人。此外，本研究的结果将有助于设计未来的流行病学研究，检查癌症的风险，提供有关收集最相关的工作史和睡眠相关的数据，纳入潜在有用的生物标志物和新的假设的产生。预计这一系列研究将最终为减轻夜班工人负面健康影响的干预措施提供目标。