Leveraging a Unique existing Cohort to elucidate the Link between sleep and cardio-metabolic disease

项目总结 尽管目前心血管和代谢性疾病(CMD)的治疗是循证的，但这些疾病 仍然非常普遍，是导致死亡的主要原因。因此，识别新的疾病机制是 最重要的是进一步减少和/或预防CMD。在潜在的CMD风险因素中， 睡眠不足正得到越来越多的认可。在这个项目中，我们将利用一个大型的、正在进行的基于家庭的 在巴西学习，招募和招收了大约2700名参与者。这样做的主要目标是 项目是检查详细的睡眠测量及其与CMD生物标记物的关联，以评估性别 睡眠和心脏代谢性疾病的差异，并确定转录和代谢途径 解释睡眠对CMD发展影响的潜在机制。越来越多的数据表明 睡眠的特定脑电特征，如慢波睡眠(SWS)或慢波活动(SWA；EEG 频谱功率在0.5-4赫兹范围内)是高度可遗传的特征，可能是亚临床心脏和心脏疾病的驱动因素 代谢性疾病通过几个危险因素的多重调节而起作用。此外，还有一些 此前的研究发现，睡眠和CMD之间存在性别差异，这引发了一些问题 关于男性或女性更容易受到睡眠不足影响的问题。目前的研究还没有 充分探讨了SWS/SWA和CMD之间的关系，也没有解决未知的潜在问题 机械装置。因此，目前的提议旨在通过在2,000个人中添加PSG来填补这一知识缺口 参与者年龄在18岁到90岁之间。我们假设：1)较少的SWS/SWA与增加的CMD相关 风险，包括更高的空腹血糖和估计的胰岛素抵抗(HOMA)，更高的血红蛋白A1c和 血脂异常(高低密度脂蛋白或低高密度脂蛋白)；2)睡眠与慢性阻塞性肺病的关联性质不同 男性和女性之间的差异；3)转录和代谢组特征将在不同的 SWA分布的低端和高端，这些差异可以影响上游驱动因素 以及不同水平的SWA的下游后果。我们提出了一项具有成本效益的研究，它将利用 现有的队列和添加睡眠PSG/EEG，重复的CMD生物标志物，以及(在子集中)代谢组学和 RNA测序，以提高我们对特定睡眠脑电特征的CMD含义的理解。这些 目标与NHLBI规定的科学优先事项一致，包括对睡眠的调查- 解释人群健康差异的相关因素和将睡眠视为一个因素 这就解释了病理生物学上的个体差异。

PROJECT SUMMARY Despite current evidence-based treatments for cardiovascular and metabolic diseases (CMD), these diseases remain highly prevalent and a leading cause of death. Therefore, identifying new disease mechanisms is paramount to further reduce and/or prevent CMD. Among potential CMD risk factors, the importance of inadequate sleep is gaining recognition. In this project, we will capitalize on a large, ongoing family-based study in Brazil that has recruited and enrolled approximately 2,700 participants. The primary objective of this project is to examine detailed measures of sleep and their associations with biomarkers of CMD, to assess sex differences in sleep and cardiometabolic disease, and to identify transcriptional and metabolic pathways as potential mechanisms to explain the effects of sleep on CMD development. Accumulating data suggest that specific EEG-based characteristics of sleep, such as slow-wave sleep (SWS) or slow-wave activity (SWA; EEG spectral power in the 0.5-4 Hz range), are highly heritable traits that may be drivers of subclinical cardiac and metabolic disease acting through the pleiotropic modulation of several risk factors. Furthermore, some previous studies have found sex differences in the association between sleep and CMD, raising questions about whether men or women are more vulnerable to the effects of inadequate sleep. Current research has not fully explored the relationship between SWS/SWA and CMD, nor does it address the unknown underlying mechanisms. Therefore, the current proposal aims to fill this gap in knowledge by adding PSG in 2,000 participants aged 18 to 90 years. We hypothesize: 1) that less SWS/SWA is associated with increased CMD risk, including higher fasting glucose and estimated insulin resistance (HOMA), higher hemoglobin A1c and dyslipidemia (high LDL or low HDL); 2) that the nature of the association between sleep and CMD will differ between men and women; 3) that transcriptional and metabolomic signatures will differ between those at the low and high ends of the distribution of SWA, and that these differences can inform on the upstream drivers and downstream consequences of differing levels of SWA. We propose a cost-effective study that will leverage an existing cohort and add sleep PSG/EEG, repeated CMD biomarkers, and (in a subset) metabolomics and RNA sequencing to improve our understanding of the CMD implications of specific sleep EEG traits. These objectives are concordant with the stated NHLBI scientific priorities, including an investigation into sleep- related factors that account for differences in health among populations and identification of sleep as a factor that accounts for individual differences in pathobiology.