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. Statement of Significance Sleep apnea is a prevalent sleep disorder caused by recurrent collapse of upper airway leading to oxygen desaturation and arousals, with consequences for increased daytime sleepiness, impaired performance, and cardiovascular morbidity. Although, overnight polysomnography (PSG) is the gold standard in diagnosis of sleep apnea, it is costly, cumbersome, and limited in availability. Here we implemented blood serum-based proteomic assays in 713 individuals to find protein biomarkers of apnea correlating these measures with gold-standard PSG. Obstructive sleep apnea was associated with 65 proteins, predominantly modulating complement and coagulation pathways, while central apnea was associated with ROBO3 and cystatin F proteins. Our study identifies proteomic signatures and associated biological pathways in sleep apnea.