The role of irregular sleep schedules as a ubiquitous marker of chronic circadian disruption in cardiometabolic disease development

摘要 尽管昼夜节律被确立为各种生物过程中的基本机制， 包括新陈代谢和心血管功能在内，关于昼夜节律如何扰乱的知之甚少 节律可能有助于在更广泛的人群中发展心脏代谢性疾病。之前 流行病学研究主要集中在经历极端昼夜节律的特定人群。 中断，例如轮流上夜班的工人。在本应用程序中，我们将不规律的睡眠时间视为 慢性昼夜节律紊乱的普遍标志及其在心脏代谢性疾病中的作用 发展。首先，我们将利用来自英国生物库(UKB)的丰富数据，该银行已经衡量了 对92,644名参与者使用加速度计进行了习惯性睡眠调查。我们将描述剂量反应的特征 睡眠时间不规律与高血压、糖尿病和心血管疾病风险的关系 确定潜在的阈值，以确定何种程度的睡眠变化可能对心脏代谢不健康。我们 还将评估观察到的关联是否因社会人口因素(例如，年龄、性别、 种族/民族)或其他睡眠特征(例如，平均睡眠时间和失眠症状)。此外，鉴于 睡眠规律是一个高度可改变的风险因素，我们将评估是否有规律的睡眠时间表 可以抵消心脏代谢性疾病的遗传易感性。第二，在护士健康研究中3 (NHS3)，我们建议使用Fitbit和血浆代谢组学来测量1000名护士的习惯性睡眠， 包括睡眠时间表的广泛变化(包括夜班工作的随机子集)。 我们假设睡眠时间不规律与表现出昼夜节律的代谢物改变有关。 节律，如欧米茄-3脂肪酸、亚油酸、精氨酸和酪氨酸。我们进一步假设这一点 代谢特征介导了睡眠不规律和心脏代谢特征之间的关联，包括 肥胖、血压和心率变异性。此外，我们还将收集有关几个新风险新数据 睡眠不规律的因素在以前的工作中没有被研究过，包括使用移动设备，很晚 女性的饮食、不吃早餐、养宠物和生育/养育。以增加严密性、重复性 和概括性，我们将在多样化的多种族研究中确认我们来自UKB和NHS3的主要发现 动脉粥样硬化(n=2,156)，其现有数据关于客观测量的习惯性睡眠，基因组学， 代谢组学和常规流行病学危险因素。总体而言，该项目将提供更大规模、更多 美国和美国睡眠时间不规律对心脏代谢影响的不同和更深入的证据 欧洲人口，阐明潜在的生物机制，并最终促进 潜在的公共健康建议和干预措施，以减少睡眠不规律和改善 心脏代谢健康。

Abstract Although circadian rhythms are established as a fundamental mechanism in various biologic processes, including metabolic and cardiovascular functioning, less is known regarding how disruption of circadian rhythms may contribute to development of cardiometabolic disease in broader human populations. Prior epidemiologic studies have predominantly focused on specific populations who experience extreme circadian disruption, such as rotating night shift workers. In this application, we will consider irregular sleep schedules as a ubiquitous marker of chronic circadian disruption and evaluate its role in cardiometabolic disease development. First, we will leverage the wealth of data from the UK Biobank (UKB), which has measured habitual sleep using accelerometer among 92,644 participants. We will characterize the dose-response relationships of irregular sleep schedules with risk of hypertension, diabetes and cardiovascular disease and identify potential threshold to define what level of sleep variability may be cardiometabolically unhealthy. We will also evaluate whether the observed associations differed by sociodemographic factors (e.g., age, sex, race/ethnicity) or other sleep traits (e.g., average sleep duration and insomnia symptoms). Further, given that sleep regularity represents a highly modifiable risk factor, we will evaluate whether regular sleep schedules may counteract genetic predisposition to cardiometabolic disease. Second, in the Nurses’ Health Study 3 (NHS3), we propose to measure habitual sleep using Fitbit and plasma metabolomics among 1,000 nurses, encompassing a wide range of variations in sleep schedules (including a random subset with night shift work). We hypothesize that irregular sleep schedules are associated with altered metabolites exhibiting circadian rhythms, such as omega-3 fatty acids, linoleate, arginine and tyrosine. We further hypothesize that this metabolic profile mediates the associations between irregular sleep and cardiometabolic traits including obesity, blood pressure and heart rate variability. In addition, we will collect new data on several emerging risk factors for irregular sleep that have not been examined in previous work, including mobile device use, late eating, breakfast skipping, pet ownership and childbearing/rearing in women. To increase rigor, reproducibility and generalizability, we will confirm our primary findings from UKB and NHS3 in the diverse Multi-Ethnic Study of Atherosclerosis (n=2,156), which have existing data on objectively measured habitual sleep, genomics, metabolomics and conventional epidemiologic risk factors. Overall, this project will provide larger-scale, more diverse and more in-depth evidence for the cardiometabolic impact of irregular sleep schedules in US and European populations, elucidate underlying biologic mechanisms, and ultimately foster development of potential public health recommendations and interventions to reduce irregular sleep and improve cardiometabolic health.