Elucidating Inflammatory and Metabolic Pathways in Obstructive Sleep Apnea Development

摘要 阻塞性睡眠呼吸暂停(OSA)是成人常见的慢性睡眠障碍，严重影响健康。 除了年龄和性别，肥胖已被确定为阻塞性睡眠呼吸暂停综合征的最大风险因素。然而， 肥胖与阻塞性睡眠呼吸暂停综合征发病相关的潜在机制尚不完全清楚。虽然 越来越多的证据(主要基于横断面研究)表明，炎症和 代谢功能障碍可能代表了阻塞性睡眠呼吸暂停综合征的两种潜在的可改变的病因途径，很少有人- 已经进行了基于前瞻性的研究，以评估它们在阻塞性睡眠呼吸暂停低通气综合征发展中的作用。在这个高度 翻译项目，我将利用来自4个大型预期美国队列的丰富数据：护士健康 NHS研究(NHS)、NHSII、卫生专业人员后续研究(HPFS)和 动脉粥样硬化(MESA)。我将使用基于遗传学和生物标志物的方法来阐明 阻塞性睡眠呼吸暂停病因学中的炎症和代谢途径。在目标1中，我将使用孟德尔随机化来 检查肥胖、炎症和代谢功能障碍的遗传易感性是否与 发生阻塞性睡眠呼吸暂停综合征的风险较高。孟德尔随机化的结果将有助于区分因果关系和非因果关系 由非遗传、横断面、观察性研究产生的因果关系，原因是混淆或 反向因果关系。我将进一步研究基因-生活方式的相互作用和这些基因中的性别差异 联想。在目标2中，我将评估炎症性(例如，C反应蛋白、IL-6、肿瘤坏死因子-α)和代谢(例如， 代谢组学、胰岛素、瘦素、胆固醇)生物标记物已从存档的血液样本中测量 预测睡眠呼吸紊乱。这些生物标记物将为进一步深入了解 可作为干预的潜在治疗和药物靶点的途径。最后，我会 使用FDA批准的设备测量200名NHS/NHSII/HPFS参与者的睡眠障碍呼吸 专为家庭OSA诊断而设计，并复制目标2中的生物标志物关联 措施。我将获得睡眠流行病学、睡眠呼吸暂停生理学、基因分析和 主要睡眠数据收集/管理。我的训练和研究将由一位世界级的 指导/咨询团队，每个人都在核心领域拥有丰富的专业知识：Susan Redline博士(OSA)，Frank Hu(生活方式)、Shelley Tworoger(生物标志物)、Richa Saxena(遗传学)、Clary Clish(代谢组学)和Eric Tchetgen Tchetgen(生物统计学)。总而言之，这个创新的项目将增进我们对 从多个维度研究阻塞性睡眠呼吸暂停综合征发展中的炎症和代谢途径，并帮助我成为 在睡眠/阻塞性睡眠呼吸暂停综合征流行病学研究方面具有独特的跨学科技能的独立调查员。

ABSTRACT Obstructive sleep apnea (OSA) is a common chronic sleep disorder in adults with a serious impact on health. In addition to age and sex, obesity has been identified as the strongest risk factor for OSA. However, the underlying mechanisms linking obesity with OSA pathogenesis are not fully understood. Although accumulating evidence (based predominantly on cross-sectional studies) suggests that inflammation and metabolic dysfunction may represent two potential modifiable etiologic pathways for OSA, few population- based, prospective studies have been conducted to evaluate their roles in OSA development. In this highly translational project, I will leverage the wealth of data from 4 large prospective US cohorts: the Nurses' Health Study (NHS), NHSII, the Health Professional Follow-up Study (HPFS) and the Multi-Ethnic Study of Atherosclerosis (MESA). I will use genetic and biomarker-based approaches to elucidate the importance of inflammatory and metabolic pathways in OSA etiology. In Aim 1, I will use Mendelian randomization to examine whether genetic susceptibility to obesity, inflammation and metabolic dysfunction is associated with higher risk of developing OSA. Results from Mendelian randomization will help distinguish causal from non- causal associations that arise from non-genetic, cross-sectional, observational studies due to confounding or reverse causation. I will further examine gene-lifestyle interactions and sex differences in these genetic associations. In Aim 2, I will evaluate whether inflammatory (e.g., CRP, IL-6, TNF-α) and metabolic (e.g., metabolomics, insulin, leptin, cholesterol) biomarkers that have been measured from archived blood samples predict sleep-disordered breathing. These biomarkers will provide further insights into the mechanistic pathways that may serve as potential therapeutic and pharmaceutical targets for intervention. Lastly, I will measure sleep-disordered breathing in 200 NHS/NHSII/HPFS participants using an FDA-approved device designed for at-home OSA diagnosis, and replicate the biomarker associations in Aim 2 with the objective measures. I will acquire additional expertise in sleep epidemiology, OSA physiology, genetic analysis, and primary sleep data collection/management. My training and research will be guided by a world-class mentoring/consulting team, each with substantial expertise in the core areas: Drs. Susan Redline (OSA), Frank Hu (lifestyles), Shelley Tworoger (biomarkers), Richa Saxena (genetics), Clary Clish (metabolomics) and Eric Tchetgen Tchetgen (biostatistics). In sum, this innovative project will advance our understanding of the inflammatory and metabolic pathways in OSA development from multiple dimensions, and help me emerge as an independent investigator with unique interdisciplinary skills in sleep/OSA epidemiology research.