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

项目摘要 尽管目前对心血管和代谢疾病（CMD）的循证治疗，这些疾病 仍然非常普遍，是死亡的主要原因。因此，识别新的疾病机制是 进一步减少和/或预防CMD是至关重要的。在潜在的CMD风险因素中， 睡眠不足正在得到重视。在这个项目中，我们将利用一个大的，正在进行的家庭为基础的 在巴西进行的一项研究招募并登记了约2，700名参与者。这项工作的主要目的是 一个项目是检查睡眠的详细测量及其与CMD生物标志物的关联，以评估性别 睡眠和心脏代谢疾病的差异，并确定转录和代谢途径， 解释睡眠对CMD发展的影响的潜在机制。不断积累的数据表明， 睡眠的特定的基于EEG的特征，例如慢波睡眠（SWS）或慢波活动（SWA; EEG 频谱功率在0.5-4 Hz范围内），是高度遗传的性状，可能是亚临床心脏和 代谢性疾病通过多种危险因素的多效性调节发挥作用。此外，一些 先前的研究发现睡眠和CMD之间的关系存在性别差异， 关于男性和女性是否更容易受到睡眠不足的影响。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。 机制等因此，目前的建议旨在通过在2000年增加PSG来填补这一知识空白 参与者年龄在18至90岁之间。我们假设：1）较小的SWS/SWA与CMD增加相关 风险，包括较高的空腹血糖和估计的胰岛素抵抗（HOMA），较高的血红蛋白A1 c和 血脂异常（高LDL或低HDL）; 2）睡眠和CMD之间的关联性质不同 男性和女性之间; 3）转录和代谢组学签名将在那些在不同的年龄段之间不同。 SWA分布的低端和高端，这些差异可以反映上游驱动因素 以及不同SWA水平的下游后果。我们提出了一项具有成本效益的研究， 现有队列，并添加睡眠PSG/EEG、重复CMD生物标志物和（在子集中）代谢组学， RNA测序，以提高我们对特定睡眠EEG特征的CMD含义的理解。这些 目标与NHLBI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，并将睡眠确定为一个因素 解释了病理学上的个体差异。

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.