Metabolomics of obstructive sleep apnea

摘要 阻塞性睡眠呼吸暂停(OSA)是一种常见的疾病，患病率正在上升。众所周知，OSA拥有 不同的病理生理，具有不同的亚型、临床后果和治疗 个别患者的反应。睡眠研究会和国家睡眠研究会最近发表的一篇文章 心、肺和血液研究所强调已确定的定量OSA生物标记物的潜在临床用途 使用无偏见的“组学”方法。目前还没有已建立的定量生物标记物可以 用于了解异质性或为临床实践提供信息。因此，本研究建议利用 代谢组学方法，反映对低氧的动态反应，以确定OSA中的代谢物特征。这个 激励这一提议的首要假设是血液中的代谢物签名导致 从周期性间歇性低氧引起的新陈代谢损害，反复唤醒和深度缺乏 阻塞性睡眠呼吸暂停综合征的睡眠特征将为更好地了解疾病提供定量的生物标志物 异质性，并告知临床护理。在目标1中，我们将区分OSA和非OSA，充分利用- 从现有研究项目的大量患者中精心挑选的表型样本(目标1A)。 我们的初步研究表明，阻塞性睡眠呼吸暂停综合征患者和对照组之间存在明显的代谢物差异。此外，我们 将利用这些现有样本来确定已建立的睡眠障碍的OSA症状亚型(例如， 失眠)、过度嗜睡和轻微症状都有不同的代谢特征(目标1B)， 将提供对已识别的心血管风险差异的见解，并支持精确医学方法。 这些利用银行样本的分析得到了一项精心设计的OSA前瞻性研究的支持 AIM 2正压治疗前后的患者。这项研究旨在对照 在使用最先进的因果模型进行采样和数据收集时，与现场特定方差相关的偏差 技巧。作为前瞻性研究的一部分，我们将进行支持代谢组学的补充分析。 特征(目标2A)，确定与PAP使用的小时和天数相关的代谢特征(目标 2B)并评估PAP治疗的代谢变化是否因肥胖(目标2C)或症状而不同 子类型(目标2D)。为了支持这一目标，初步数据表明，PAP治疗后代谢发生了变化。 最后，在目标3中，我们将利用肥胖OSA受试者的现有样本，这些样本以前被随机分配到 三种治疗方法中的一种--单独减肥，单独PAP，或联合减肥和PAP。差异在于 这三个随机组之间的代谢变化将为深入了解 肥胖和周期性间歇性低氧对代谢反应和代谢途径的影响。最终，由此产生的结果是 提案将提供有关代谢组特征的全面信息，可用作 定量生物标志物加深我们对OSA异质性的理解并指导临床实践 以及阻塞性睡眠呼吸暂停患者的个性化用药。 OSA的R01代谢组学-第1页

ABSTRACT Obstructive sleep apnea (OSA) is a common disorder that is increasing in prevalence. OSA is known to have heterogeneous pathophysiology, with different subtypes, clinical consequence, and treatment responses among individual patients. A recent publication from the Sleep Research Society and National Heart, Lung and Blood Institute highlighted the potential clinical utility of quantitative OSA biomarkers identified using unbiased “omics” approaches.There are currently no established quantitative biomarkers that can be used to understand heterogeneity or inform clinical practice. Thus, the present study proposes to utilize metabolomic methods which reflect dynamic responses to hypoxia to identify metabolite signatures in OSA. The overarching hypothesis motivating this proposal is that blood-borne metabolite signatures that result from metabolic insults caused by the cyclical intermittent hypoxia, recurrent arousals and lack of deep sleep characteristic of OSA will provide a quantitative biomarker to better understand disease heterogeneity and inform clinical care. In Aim 1, we will differentiate OSA from non-OSA leveraging well- phenotyped samples carefully chosen from a large pool of patients from existing research projects (Aim 1A). Our preliminary suggest clear metabolite differences between patients with OSA and controls. Furthermore, we will leverage these existing samples to determine if established OSA symptom subtypes of disturbed sleep (e.g., insomnia), excessive sleepiness, and minimally symptomatic have distinct metabolomic profiles (Aim 1B) which will provide insights into identified differences in cardiovascular risk and support a precision medicine approach. These analyses utilizing banked samples are supported by a carefully designed prospective study of OSA patients before and after positive airway pressure (PAP) treatment in Aim 2. The study is designed to control for bias related to site-specific variance in sampling and data collection using state-of-the-art causal modeling techniques. As part of the prospective study, we will perform complementary analyses supporting metabolomic signatures (Aim 2A), determine a metabolomic signature that correlates with hours and days of PAP usage (Aim 2B) and evaluate whether the metabolomic changes with PAP treatment differ by obesity (Aim 2C) or symptom subtype (Aim 2D). In support of this Aim, preliminary data suggest metabolomic changes with PAP treatment.. Finally, in Aim 3 we will leverage existing samples of obese OSA subjects that were previously randomized to one of three treatments – weight-loss alone, PAP alone, or combined weight-loss and PAP. Differences in metabolomic changes among these three randomized groups will provide insights into the relative roles of obesity and cyclical intermittent hypoxia on metabolic responses and pathways. Ultimately, results from this proposal will provide comprehensive information on metabolomic signatures that can be utilized as quantitative biomarkers to further our understanding of OSA heterogeneity and inform clinical practice and personalized medicine among OSA patients. R01 Metabolomics of OSA - Page 1