Phenotypic and Molecular Signatures for Sleep Apnea and Related Morbidities

睡眠呼吸暂停及相关疾病的表型和分子特征

• 批准号: 10544494
• 负责人: Susan S. Redline
• 金额: $ 92.79万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544494
• 关键词: Address; Adult; Affect; African American; Age; Anatomy; Apnea; Asian Americans; Big Data; Biological; Candidate Disease Gene; Cardiovascular system; Child; Clinical Data; Clinical Trials; Cognitive; Cohort Studies; Collaborations; Continuous Positive Airway Pressure; Data; Development; Diabetes Mellitus; Disease; Disease Outcome; Disease susceptibility; Environment; Environmental Risk Factor; Epidemiology; Ethnic Origin; Family; Functional disorder; Genetic; Genomics; Health; Healthcare; Heart failure; Hypertension; Individual; Individual Differences; Intervention; Laboratories; Leadership; Link; Measures; Medicine; Metabolic; Modernization; Molecular; Molecular Profiling; Morbidity - disease rate; Multicenter Studies; Outcome; Pathway interactions; Patients; Pattern; Phenotype; Physiological; Play; Polysomnography; Predisposition; Problem behavior; Race; Research Personnel; Resources; Risk; Risk Factors; Role; Severities; Severity of illness; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Sleep Stages; Statistical Methods; Stents; Stroke; Technology; Translating; biobank; clinical care; data streams; disorder subtype; epidemiology study; experience; functional genomics; gene function; genetic variant; genome-wide analysis; genomic data; heritability pattern; improved; indexing; insight; multidisciplinary; non rapid eye movement; novel; patient subsets; personalized medicine; precision medicine; prediction algorithm; programs; respiratory; sex; social; trait

I have over 25 years of experience in sleep medicine epidemiological research and have played a leading role in studies that address the contributions of genetic, social and environmental risk factors to sleep disorders, the influences of sleep on health outcomes in children and adults, and the role of sleep interventions in improving health outcomes. My collaborators, mentees and I have identified that sleep apnea (SA) is highly prevalent, disproportionately affects Asians and African American children, and is associated with significantly increased risks for developing hypertension, stroke, heart failure, diabetes, and behavioral problems. We also have identified variability in these outcomes by sex, race/ethnicity, age, and genetic background. We have characterized the patterns of heritability for several SDB traits and through use of family-based and cohort studies (>20,000 individuals) have identified genome-wide significant associations for genetic variants in biological candidate genes, and sex- and sleep stage-specific analyses have provided insight into mechanisms that may explain the known sex and REM/NREM differences in SA severity. Despite this progress, however, the underlying molecular and physiological mechanisms for SA are not well understood, limiting both our ability to predict which patients with SA are most vulnerable to adverse health outcomes and our ability to develop treatments that reflect individual differences in SDB pathophysiology. Our emerging data suggest that these gaps may be overcome through systematic analysis of larger sets of polysomnography data, deriving more precise SDB phenotypes that reflect specific sleep and respiratory patterns, and linking these phenotypes to genomic and clinical data. Through leadership in multiple national consortia and multi-center studies we are poised to make transformative advances in understanding the phenotypic variability and genetics of sleep apnea and related traits. We plan to harness a critical mass of data, including those in the National Sleep Research Resource and genetic, genomic and clinical data available through several consortia, including the Trans- Omics in Precision Medicine and Partners HealthCare Biobank. We will expand our genetics/epidemiology team with leaders in sophisticated respiratory phenotyping, developing a multi-disciplinary program that will systematically extract quantitative metrics of SA phenotypes and link these to genetics, genomics, specific treatment responsiveness, and cardiovascular, metabolic and cognitive outcomes. Through collaborations with functional genomics laboratories, we will help identify functional genetic variants and clarify the function of genes and pathways associated with SA. We will use sophisticated statistical methods to derive and validate personalized medicine prediction algorithms based on these data streams. This enhanced biological understanding of SA will be translated into improved clinical care through better-informed clinical trials. Finally, we will create an environment that nurtures the development of new investigators equipped to use modern technologies and “big data” to identify signatures of disease susceptibility and outcomes.

我在睡眠医学流行病学研究方面拥有超过25年的经验并发挥了主导作用 在研究遗传、社会和环境风险因素对睡眠障碍的影响时， 睡眠对儿童和成人健康结果的影响，以及睡眠干预在改善健康方面的作用 健康结果。我和我的合作者、学员发现睡眠呼吸暂停 (SA) 非常普遍， 不成比例地影响亚洲人和非裔美国儿童，并且与显着增加有关 患高血压、中风、心力衰竭、糖尿病和行为问题的风险。我们还有 确定了这些结果因性别、种族/民族、年龄和遗传背景而存在的差异。我们有 通过使用基于家庭和队列的方法，描述了几种 SDB 性状的遗传力模式 研究（超过 20,000 名个体）已经确定了基因组范围内遗传变异的显着关联 生物学候选基因以及性别和睡眠阶段特异性分析提供了对机制的深入了解 这可以解释 SA 严重程度中已知的性别和 REM/NREM 差异。然而，尽管取得了这些进展， SA 的潜在分子和生理机制尚不清楚，限制了我们的能力 预测哪些 SA 患者最容易受到不良健康结果的影响以及我们发展的能力 反映 SDB 病理生理学个体差异的治疗方法。我们的新数据表明，这些 通过对更大的多导睡眠图数据集进行系统分析，可以克服差距，得出更多 反映特定睡眠和呼吸模式的精确 SDB 表型，并将这些表型与 基因组和临床数据。通过在多个国家联盟和多中心研究中的领导作用，我们 准备在了解睡眠呼吸暂停的表型变异性和遗传学方面取得变革性进展 以及相关的特征。我们计划利用大量数据，包括国家睡眠研究中的数据 资源和遗传、基因组和临床数据可通过多个联盟获得，包括 Trans- 精准医学组学和合作伙伴医疗保健生物银行。我们将扩展我们的遗传学/流行病学 与复杂呼吸表型分析领域的领导者组成的团队，开发了一个多学科计划，该计划将 系统地提取 SA 表型的定量指标，并将其与遗传学、基因组学、特定 治疗反应性以及心血管、代谢和认知结果。通过与以下机构的合作 功能基因组实验室，我们将帮助识别功能遗传变异并阐明其功能 与 SA 相关的基因和途径。我们将使用复杂的统计方法来推导和验证 基于这些数据流的个性化药物预测算法。这种增强的生物 对 SA 的了解将通过更明智的临床试验转化为改善的临床护理。最后， 我们将创造一个环境，培养能够使用现代技术的新调查人员的发展 技术和“大数据”来识别疾病易感性和结果的特征。

项目成果

Normalized electroencephalogram power: a trait with increased risk of dementia.

标准化脑电图功率：痴呆风险增加的特征。

• DOI: 10.1093/sleep/zsad195
• 发表时间: 2023
• 期刊: Sleep
• 影响因子: 5.6
• 作者: Younes,Magdy;Redline,Susan;Peters,Katherine;Yaffe,Kristine;Purcell,Shaun;Djonlagic,Ina;Stone,KatieL
• 通讯作者: Stone,KatieL

Rest-activity rhythms across the lifespan: cross-sectional findings from the US representative National Health and Nutrition Examination Survey.

整个生命周期的休息活动节律：美国代表性国家健康和营养检查调查的横断面调查结果。

• DOI: 10.1093/sleep/zsad220
• 发表时间: 2023
• 期刊: Sleep
• 影响因子: 5.6
• 作者: Wallace,DanielleA;Johnson,DaynaA;Redline,Susan;Sofer,Tamar;Kossowsky,Joe
• 通讯作者: Kossowsky,Joe

Characterization of sleep apnea among a sample of adults from Samoa.

萨摩亚成年人样本中睡眠呼吸暂停的特征。

• DOI: 10.1101/2023.11.16.23298644
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Heinsberg,LaceyW;Pomer,Alysa;Cade,BrianE;Carlson,JennaC;Naseri,Take;Reupena,MuagututiaSefuiva;Viali,Satupa'itea;Weeks,DanielE;McGarvey,StephenT;Redline,Susan;Hawley,NicolaL
• 通讯作者: Hawley,NicolaL

Individual periodic limb movements with arousal are temporally associated with nonsustained ventricular tachycardia: a case-crossover analysis.

伴有唤醒的个体周期性肢体运动在时间上与非持续性室性心动过速相关：病例交叉分析。

• DOI: 10.1093/sleep/zsz165
• 发表时间: 2019
• 期刊: Sleep
• 影响因子: 5.6
• 作者: May,AnnaM;May,RyanD;Bena,James;Wang,Lu;Monahan,Ken;Stone,KatieL;Barrett-Connor,Elizabeth;Koo,BrianB;Winkelman,JohnW;Redline,Susan;Mittleman,MurrayA;Mehra,Reena;OsteoporoticFracturesinMen(MrOS)StudyGroup
• 通讯作者: OsteoporoticFracturesinMen(MrOS)StudyGroup

Emergence of racial/ethnic and socioeconomic differences in objectively measured sleep-wake patterns in early infancy: results of the Rise & SHINE study.

婴儿早期客观测量的睡眠觉醒模式中出现种族/民族和社会经济差异：崛起的结果

• DOI: 10.1093/sleep/zsaa193
• 发表时间: 2021
• 期刊: Sleep
• 影响因子: 5.6
• 作者: Yu,Xinting;Quante,Mirja;Rueschman,Michael;Ash,Tayla;Kaplan,EmilyR;Guo,Na;Horan,ChristineM;Haneuse,Sebastien;Davison,Kirsten;Taveras,ElsieM;Redline,Susan
• 通讯作者: Redline,Susan