Dataset Information

Proteomic biomarkers of sleep apnea.

ABSTRACT:

Study objectives

Obstructive sleep apnea (OSA) is characterized by recurrent partial to complete upper airway obstructions during sleep, leading to repetitive arousals and oxygen desaturations. Although many OSA biomarkers have been reported individually, only a small subset have been validated through both cross-sectional and intervention studies. We sought to profile serum protein biomarkers in OSA in unbiased high throughput assay.

Methods

A highly multiplexed aptamer array (SomaScan) was used to profile 1300 proteins in serum samples from 713 individuals in the Stanford Sleep Cohort, a patient-based registry. Outcome measures derived from overnight polysomnography included Obstructive Apnea Hypopnea Index (OAHI), Central Apnea Index (CAI), 2% Oxygen Desaturation index, mean and minimum oxygen saturation indices during sleep. Additionally, a separate intervention-based cohort of 16 individuals was used to assess proteomic profiles pre- and post-intervention with positive airway pressure.

Results

OAHI was associated with 65 proteins, predominantly pathways of complement, coagulation, cytokine signaling, and hemostasis which were upregulated. CAI was associated with two proteins including Roundabout homolog 3 (ROBO3), a protein involved in bilateral synchronization of the pre-Bötzinger complex and cystatin F. Analysis of pre- and post intervention samples revealed IGFBP-3 protein to be increased while LEAP1 (Hepicidin) to be decreased with intervention. An OAHI machine learning classifier (OAHI >=15 vs OAHI<15) trained on SomaScan protein measures alone performed robustly, achieving 76% accuracy in a validation dataset.

Conclusions

Multiplex protein assays offer diagnostic potential and provide new insights into the biological basis of sleep disordered breathing.

SUBMITTER: Ambati A

PROVIDER: S-EPMC7686561 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Untreated and long-lasting obstructive sleep apnea (OSA) may lead to important vascular abnormalities, including endothelial cell (EC) dysfunction, hypertension, and atherosclerosis. We observed a correlation between microcirculatory reactivity and endothelium-dependent release of nitric oxide in OSA patients. Therefore, we hypothesized that OSA affects (micro)vasculature and we aimed to identify vascular gene targets of OSA that could possibly serve as reliable biomarkers of severity of the disease and possibly of vascular risk. Using quantitative RT-PCR, we evaluated gene expression in skin biopsies of OSA patients, mouse aortas from animals exposed to 4-week intermittent hypoxia (IH; rapid oscillations in oxygen desaturation and reoxygenation), and human dermal microvascular (HMVEC) and coronary artery endothelial cells (HCAEC) cultured under IH. We demonstrate a significant upregulation of endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha-induced protein 3 (TNFAIP3; A20), hypoxia-inducible factor 1 alpha (HIF-1??? and vascular endothelial growth factor (VEGF) expression in skin biopsies obtained from OSA patients with severe nocturnal hypoxemia (nadir saturated oxygen levels [SaO2]<75%) compared to mildly hypoxemic OSA patients (SaO2 75%-90%) and a significant upregulation of vascular cell adhesion molecule 1 (VCAM-1) expression compared to control subjects. Gene expression profile in aortas of mice exposed to IH demonstrated a significant upregulation of eNOS and VEGF. In an in vitro model of OSA, IH increased expression of A20 and decreased eNOS and HIF-1? expression in HMVEC, while increased A20, VCAM-1 and HIF-1?expression in HCAEC, indicating that EC in culture originating from distinct vascular beds respond differently to IH stress. We conclude that gene expression profiles in skin of OSA patients may correlate with disease severity and, if validated by further studies, could possibly predict vascular risk in OSA patients.