Individual Differences in Obstructive Sleep Apnea

描述(由申请人提供)： 睡眠呼吸暂停是一种系统性疾病。由于呼吸暂停，体内的所有组织都会经历缺氧。因此，睡眠呼吸暂停会导致多种不良后果。睡眠呼吸暂停是可遗传的，尽管到目前为止还没有发现令人信服的基因变异。患者体内的风险和后果也存在重要的个体差异。这些个体差异表明，睡眠呼吸暂停是一种理想的障碍，可以发展一种个性化的风险评估、诊断和管理方法。正是这一总体概念推动了这一研究计划。该计划有3个项目和5个支持核心。第一个项目-阻塞性睡眠呼吸暂停(OSA)极端表型的机制(项目负责人：R.Schwab)-专注于了解极端表型的基础。在这个项目中，研究人员研究了患有和不患有睡眠呼吸暂停的非常肥胖的人。他们提出了一个问题--鉴于这些人存在睡眠呼吸暂停的主要风险，如何保护那些没有睡眠呼吸暂停障碍的人？这是脂肪分布的不同，不同的生理控制机制，还是两者的结合？研究人员还研究了患有和不患有睡眠呼吸暂停的瘦人，并问了同样的问题--为什么？头面部结构、脂肪的不同分布和呼吸控制系统的不稳定性在瘦人的呼吸暂停发生中起什么作用？这个项目是基于深入的表型分析。项目02-阻塞性睡眠呼吸暂停中高血压的个体差异的机制(项目负责人：S·库纳)-解决睡眠呼吸暂停患者血压反应个体差异的基础。研究人员提出，睡眠呼吸暂停对血压的最大影响将发生在那些血压没有得到降压药物控制的人身上，这些人将从PAP治疗中受益最大。他们问这个问题--为什么？研究人员提出，血压反应的个体差异与睡眠呼吸暂停的氧化应激和儿茶酚胺反应的个体差异有关。他们预测，这些被提出的介体是由导致氧化应激的关键酶-NADPH氧化酶-的遗传差异驱动的，并建议对调节这种酶活性的基因进行测序。最后一个项目--睡眠呼吸暂停及其后果的遗传学(项目负责人：A.Pack)--继续了遗传主题，但提出了一种新的策略，以确定与睡眠呼吸暂停及其后果相关的风险基因。这一战略涉及到小鼠，特别是遗传异质多样性远交种小鼠，这是一种最近开发的、最先进的通过动物模型发现基因的方法，已经表明它有能力发现新的遗传关联。这些小鼠的高通量表型鉴定，加上全基因组SNP芯片的基因鉴定，可以识别与正在研究的表型相关的小基因组区域。项目03中正在评估的表型包括：舌头脂肪(与项目01中的解剖学相关)、对低氧/高碳酸血症的呼吸反应(与项目01中的生理机制相关)，以及对周期性间歇性低氧的血压反应，类似于睡眠呼吸暂停(与项目02相关)。因此，所有三个项目都协同工作。所有项目都得到5个核心的支持：a)行政，b)睡眠研究和招募，c)磁共振成像，d)分子评估，e)生物统计和数据管理。

DESCRIPTION (Provided by applicant): Sleep apnea is a systematic disorder. All tissues in the body experience hypoxia that occurs as a consequence of apneas. Thus, sleep apnea leads to multiple adverse consequences. Sleep apnea is heritable, although to date no convincing gene variants have been identified. There are also important individual differences in risks and consequences within patients. These individual differences suggest that sleep apnea is an ideal disorder to develop a PERSONALIZED approach to risk assessment, diagnosis and management. It is this overall concept that motivates this program of research. The program has 3 projects and 5 supporting cores. The first project-Mechanisms of Extreme Phenotypes in Obstructive Sleep Apnea (OSA) (Project Leader: R. Schwab)-is focused on understanding the basis of extreme phenotypes. In this project the investigators study very obese individuals with and without sleep apnea. They ask the question-given that these individuals have the major risk for sleep apnea, what protects those without the disorder? Is it a difference in fat distribution, different physiological control mechanisms or a combination? The investigators also study lean individuals with and without sleep apnea and ask the same question-why? What role does craniofacial structure, different distributions of fat and ventilatory control system instablity play in the development of apnea in thin individuals? This project is based on in-depth phenotyping. Project 02-Mechanisms for Individual Differences in Hypertension in Obstructive Sleep Apnea (Project Leader: S. Kuna)-addresses the basis of individual differences in blood pressure response to sleep apnea. The investigators propose that the largest effect of sleep apnea on blood pressure will occur in individuals whose BP is not controlled on anti-hypertensive medications, and that these individuals will benefit most from PAP treatment. They ask the question-why? The investigators propose that the individual differences in blood pressure response are related to individual differences in oxidative stress and catecholamine responses to sleep apnea. They predict that these proposed mediators are driven by genetic differences in the key enzyme that leads to oxidative stress-NADPH oxidase-and propose sequencing of genes that regulate activity of this enzyme. The final project-Genetics of Sleep Apnea and Its Consequences (Project Leader: A. Pack)-continues the genetic theme, but proposes a new strategy to identify genes conferring risk for sleep apnea and its consequences. This strategy involves mice, in particular the genetically heterogeneous Diversity Outbred mice, a recently developed, state-of-the-art approach to genetic discovery through animal models that has already shown its ability to discover new genetic associations. High throughput phenotyping of these mice, together with genotyping with a genome-wide SNP chip, allows identification of small genomic regions that relate to the phenotype being studied. The phenotypes being assessed in Project 03 are: tongue fat (relevant to anatomy in Project 01), ventilatory responses to hypoxia/hypercapnia (related to physiological mechanisms in Project 01), and blood pressure response to cyclical intermittent hypoxia, akin to that which occurs in sleep apnea (relevant to Project 02). Thus all 3 projects work synergistically. All projects are supported by 5 cores: a) Administrative, b) Sleep Study and Recruitment, c) Magnetic Resonance Imaging, d) Molecular Assessment, and e) Biostatistics and Data Management.