Nagarajan Pavithra, Kurniansyah Nuzulul, Lee Jiwon, Gharib Sina A, Xu Yushan, Zhang Yiyan, Spitzer Brian, Faquih Tariq, Zhou Hufeng, Boerwinkle Eric, Chen Han, Gottlieb Daniel J, Guo Xiuqing, Heard-Costa Nancy L, Hidalgo Bertha A, Levy Daniel, Liu Peter Y, Mei Hao, Montalvan Rebecca, Mukherjee Sutapa, North Kari E, O'Conner George T, Palmer Lyle J, Patel Sanjay R, Psaty Bruce M, Purcell Shaun M, Raffield Laura M, Rich Stephen S, Rotter Jerome I, Saxena Richa, Smith Albert V, Stone Katie L, Zhu Xiaofeng, Cade Brian E, Sofer Tamar, Redline Susan, Wang Heming
Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Pulmonary, Critical Care and Sleep Medicine, Medicine, University of Washington, Seattle, WA, USA.
medRxiv. 2024 Oct 28:2024.10.25.24316158. doi: 10.1101/2024.10.25.24316158.
Obstructive sleep apnea (OSA) is a multifactorial sleep disorder characterized by a strong genetic basis. Excessive daytime sleepiness (EDS) is a symptom that is reported by a subset of OSA patients, persisting even after treatment with continuous positive airway pressure (CPAP). It is recognized as a clinical subtype underlying OSA carrying alarming heightened cardiovascular risk. Thus, conceptualizing EDS as an exposure variable, we sought to investigate EDS's influence on genetic variation linked to apnea-hypopnea index (AHI), a diagnostic measure of OSA severity. This study serves as the first large-scale genome-wide gene x environment interaction analysis for AHI, investigating the interplay between its genetic markers and EDS across and within specific sex. Our work pools together whole genome sequencing data from seven cohorts, enabling a diverse dataset (four population backgrounds) of over 11,500 samples. Among the total 16 discovered genetic targets with interaction evidence with EDS, eight are previously unreported for OSA, including , , and identified in all sexes; , , and identified in males; and and identified in females. We discuss connections to insulin resistance, thiamine deficiency, and resveratrol use that may be worthy of therapeutic consideration for excessively sleepy OSA patients.
阻塞性睡眠呼吸暂停（OSA）是一种具有强大遗传基础的多因素睡眠障碍。日间过度嗜睡（EDS）是一部分OSA患者报告的症状，即使在接受持续气道正压通气（CPAP）治疗后仍会持续存在。它被认为是OSA的一种临床亚型，具有令人担忧的心血管风险升高。因此，将EDS概念化为一个暴露变量，我们试图研究EDS对与呼吸暂停低通气指数（AHI）相关的基因变异的影响，AHI是OSA严重程度的一种诊断指标。本研究是首次针对AHI进行的大规模全基因组基因与环境相互作用分析，研究其遗传标记与特定性别内外的EDS之间的相互作用。我们的工作汇集了来自七个队列的全基因组测序数据，形成了一个包含超过11,500个样本的多样化数据集（四种人群背景）。在总共16个发现的与EDS有相互作用证据的遗传靶点中，有8个是此前未报道与OSA相关的，包括在所有性别中均鉴定出的 、 和 ；在男性中鉴定出的 、 和 ；以及在女性中鉴定出的 和 。我们讨论了与胰岛素抵抗、硫胺素缺乏和白藜芦醇使用的联系，这些可能值得对过度嗜睡的OSA患者进行治疗考虑。
