Urine 5-Eicosatetraenoic Acids as Urinary Screening Markers for Obstructive Sleep Apnea

Abstract

Discovery of reliable biomarkers for obstructive sleep apnea (OSA) is needed to reduce cardiovascular sequelae and mortality. Full-night polysomnography has been used for diagnosing OSA, but it is too expensive and inconvenient to address the increasing number of patients. To develop an easily applicable screening tool for OSA, we searched for OSA biomarkers reflecting hypoxic stress during sleep. We collected the first morning urines from newly diagnosed patients with OSA in three different cohorts. Metabolome-wide analyses were performed to find and validate surrogate markers for OSA. We further investigated the mechanism underlying hypoxic induction of the markers in human cells and mice. Arachidonic acid derivatives 5-HETE and 5-oxoETE were detected in urine samples. The levels (mean±SD, ng per mg creatinine) of 5-HETE and 5-oxoETE were 56.4±26.2 and 46.9±18.4 in OSA patients, respectively, which were significantly higher than those in controls (22.5±4.6 and 18.7±3.6). Both levels correlated with the apnea-hypopnea index and the lowest oxygen saturation on polysomnography. After OSA patients were treated with the continuous positive airway pressure, the metabolite levels were significantly reduced compared with those before the treatment. In human mononuclear cells subjected to intermittent hypoxia, 5-HETE and 5-oxoETE productions were induced by hypoxia-inducible factor 1 and glutathione peroxidase. When mice were exposed to intermittent hypoxia, 5-HETE and 5-oxoETE were excreted more in urine. 5-HETE and 5-oxoETE were identified and verified as new OSA markers reflecting hypoxic stress. These urinary metabolites could be used for screening OSA and evaluating the treatment outcomes. Funding Statement: Supported by the National Research Foundation of Korea (2019R1A2B5B03069677 and 2020R1A4A2002903) and funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI17C1669). Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: The institutional review board of Seoul National University Hospital (C-1003-063-313 for the discovery and verification phase; H-1412-048-632 for multicenter validation phase) approved this research. The Institutional Animal Use and Care Committee of Seoul National University approved this animal study (SNU140103-1).