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， 包括代谢和心血管功能，关于昼夜节律的破坏是如何发生的， 节律可能在更广泛的人群中促进心脏代谢疾病的发展。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 比如夜班工人的轮换。在这个应用程序中，我们将考虑不规律的睡眠时间表， 慢性昼夜节律紊乱的普遍存在的标志物，并评估其在心脏代谢疾病中的作用 发展首先，我们将利用英国生物银行（UKB）的大量数据， 在92,644名参与者中使用加速度计进行习惯性睡眠。我们将描述剂量反应 睡眠不规律与高血压、糖尿病和心血管疾病风险的关系， 识别潜在阈值以定义什么水平的睡眠可变性可能是心脏代谢不健康的。我们 还将评估观察到的关联是否因社会人口因素而不同（例如，年龄性别 种族/民族）或其它睡眠特征（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变的风险因素，我们将评估是否有规律的睡眠时间表 可能会抵消心脏代谢疾病的遗传易感性。第二，在护士健康研究3中， （NHS 3），我们建议使用Fitbit和血浆代谢组学在1,000名护士中测量习惯性睡眠， 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，不规律的睡眠时间表与代谢物的改变有关， 节奏，如ω-3脂肪酸，亚油酸，精氨酸和酪氨酸。我们进一步假设， 代谢谱介导不规则睡眠和心脏代谢特征之间的关联， 肥胖、血压和心率变异性。此外，我们还将收集有关几种新兴风险的新数据， 在以前的工作中没有检查过的不规则睡眠的因素，包括移动终端的使用， 进食、不吃早餐、养宠物和生育/抚养女性。为了增加严谨性，可重复性 和普遍性，我们将证实我们的主要发现，从UKB和NHS 3在多样化的多民族研究 的研究（n= 2，156），这些研究有客观测量的习惯性睡眠，基因组学， 代谢组学和传统流行病学危险因素。总的来说，该项目将提供更大规模，更多 在美国，不规律的睡眠时间表对心脏代谢的影响有多种多样的更深入的证据， 欧洲人群，阐明潜在的生物学机制，并最终促进发展， 潜在的公共卫生建议和干预措施，以减少不规律的睡眠， 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.