TY - JOUR
T1 - Proteomic biomarkers of sleep apnea
AU - Ambati, Aditya
AU - Ju, Yo El
AU - Lin, Ling
AU - Olesen, Alexander N.
AU - Koch, Henriette
AU - Hedou, Julien Jacques
AU - Leary, Eileen B.
AU - Sempere, Vicente Peris
AU - Mignot, Emmanuel
AU - Taheri, Shahrad
N1 - Funding Information:
We are thankful to the individuals who consented to be studied as part of the Stanford sleep cohort, further we thank Jing Zhang at the Stanford Center for sleep science and medicine for sample biobanking. We thank the anonymous reviewers whose inputs have improved the manuscript. The Stanford Sleep cohort was supported by unrestricted funds of Stanford Center for Sleep Sciences and Medicine and NIH 5R01HL071515. Longitudinal CPAP cohort study was supported by National Institutes of Health awards K23-NS089922, UL1RR024992 Sub-Award KL2-TR000450, and the Washington University Institute of Clinical and Translational Sciences grant UL1TR000448 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health. SomaScan assays for the entire cohort were supported by Biomedical Research Program at Weill Cornell Medicine Qatar funded by Qatar Foundation.
Publisher Copyright:
© Sleep Research Society 2020. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
KW - Apnea
KW - Biomarkers
KW - Oxygen saturation
KW - Polysomnography
KW - Proteomics
KW - Serum
KW - Sleep-disordered breathing
UR - http://www.scopus.com/inward/record.url?scp=85096886915&partnerID=8YFLogxK
U2 - 10.1093/sleep/zsaa086
DO - 10.1093/sleep/zsaa086
M3 - Article
C2 - 32369590
AN - SCOPUS:85096886915
SN - 0161-8105
VL - 43
JO - Sleep
JF - Sleep
IS - 11
M1 - zsaa086
ER -