Dissecting heterogeneity of excessive daytime sleepiness and impact on cardiovascular diseases

剖析白天过度嗜睡的异质性及其对心血管疾病的影响

• 批准号: 10588200
• 负责人: Heming Wang
• 金额: $ 35.8万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-20 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588200
• 关键词: Affect; Behavioral; Biological; Cardiovascular Diseases; Cardiovascular system; Classification; Clinical; Communities; Data; Data Reporting; Electroencephalography; Excessive Daytime Sleepiness; Future; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genomics; Goals; Health; Heterogeneity; Hispanic Community Health Study/Study of Latinos; Hypersomnolence; Idiopathic Hypersomnolence; Individual; Intervention; Jackson Heart Study; Knowledge; Laboratory Research; Link; Longitudinal Studies; Measurement; Measures; Mendelian randomization; Modification; Molecular; Morbidity - disease rate; Multi-Ethnic Study of Atherosclerosis; Multiomic Data; Narcolepsy; National Heart, Lung, and Blood Institute; Outcome; Pathway interactions; Patient Self-Report; Phenotype; Physiological; Physiology; Polysomnography; Population; Population Heterogeneity; Population Study; Process; Property; Proteomics; Questionnaires; Reporting; Resources; Risk; Risk Factors; Sampling; Sleep; Sleep Architecture; Sleep Disorders; Sleep Fragmentations; Subgroup; Testing; Trans-Omics for Precision Medicine; Variant; Women' s Health; Work; actigraphy; biobank; brain tissue; cardiovascular disorder risk; clinical risk; cohort; comorbidity; design; gene environment interaction; genetic analysis; genetic variant; genome wide association study; genome-wide; genomic locus; improved; instrument; men; metabolomics; methylomics; mortality; neurophysiology; novel; osteoporosis with pathological fracture; population based; programs; public health intervention; risk stratification; screening; secondary analysis; sex; trait; transcriptomics

ABSTRACT Excessive daytime sleepiness (EDS) affects 10-20% of the population and is associated with cardiovascular diseases (CVD) and mortality. Emerging data suggest that targeting EDS may provide a novel intervention for improving CVD. However, findings are limited by self-reported data and heterogeneity. There is a need to dissect and understand the underlying drivers of EDS subtypes, and to determine whether there are subtypes causally related to CVD and potentially modifiable. Our recent work identified two subtypes of EDS – sleep propensity (SP; characterized by objectively measured long sleep duration, high efficiency, and less fragmentation) and sleep fragmentation (SF; short sleep duration and low efficiency). Each of them is common in the population, associated with adverse cardiovascular outcomes and different genetic backgrounds. We hypothesize that SP is a novel sleep phenotype that reflects a property of the need of staying asleep; dissecting EDS into SP and SF subtypes will facilitate identification of genetic and physiological mechanisms for EDS, and improve understanding of pleiotropic or causal associations with CVD risk. In order to test these hypotheses, we will leverage macro- and micro- sleep architecture measurements, genomics, and other -omics data in population-based cohorts. We will address the following specific aims: 1) To identify demographic, behavioral, clinical and neurophysiological factors (assessed by actigraphy and electroencephalography) for SP and SF, and refine classification of EDS subtypes if needed; 2) To identify genetic variants and molecular pathways associated with EDS subtypes and generate robust polygenetic risk score for risk stratification; 3) To systematically evaluate the causal or non-causal associations between EDS subtypes and CVD traits; 4) To identify the modification effect of each EDS subtype on genetic susceptibility of CVD using gene-environment interaction analyses. This work will advance our understanding of the heterogeneity of EDS, reveal biological mechanisms and pathways linking to CVD, and provide information that will guide clinical and public health interventions as well as provide directions for future laboratory research.

摘要 白天过度嗜睡（EDS）影响10-20%的人口，并与 心血管疾病（CVD）和死亡率。新出现的数据表明，针对EDS可能 为改善CVD提供了一种新的干预措施。然而，研究结果受到自我报告的限制。 数据和异质性。有必要剖析和了解EDS的基本驱动因素 亚型，并确定是否存在与CVD因果相关的亚型， 可修改.我们最近的工作确定了EDS的两种亚型-睡眠倾向（SP;特征 通过客观地测量睡眠时间长，效率高，碎片少）和睡眠 片段化（SF;睡眠时间短，效率低）。它们中的每一个都是常见的， 与不良心血管结局和不同遗传背景相关。 我们假设SP是一种新的睡眠表型，反映了停留需要的性质 将EDS分解为SP和SF亚型将有助于识别遗传和 EDS的生理机制，并提高对多效性或因果关系的理解。 与CVD风险的关联。为了验证这些假设，我们将利用宏观和微观- 睡眠结构测量、基因组学和其他基于人群的组学数据。 我们将解决以下具体目标：1）确定人口统计学，行为，临床和 SP和SF的神经生理学因素（通过活动记录仪和脑电图评估）， 并在需要时细化EDS亚型的分类; 2）识别遗传变异和分子生物学特征， 与EDS亚型相关的途径，并生成强大的多基因风险评分， 分层; 3）系统评价EDS之间的因果或非因果关系 4）鉴定各EDS亚型对遗传易感性的修饰作用， 使用基因-环境交互作用分析CVD易感性。这项工作将促进我们的 了解EDS的异质性，揭示生物学机制和途径， 心血管疾病，并提供信息，将指导临床和公共卫生干预，以及 为今后的实验室研究提供方向。