Low oxygen saturation during sleep reduces CD1D and RAB20 expressions that are reversed by CPAP therapy

Tamar Sofer,Reena Mehra,Ruitong Li,Sina A Gharib,Susan Redline,Roby Joehanes,Honghuang Lin,Sanjay R Patel,Yongmei Liu,Avrum Spira,Daniel Levy,Heming Wang,Brian E Cade,Nuzulul Kurniansyah,Stephen S Rich,Daniel J Gottlieb,Jerome I Rotter,Stuart F Quan,Jiwon Lee,Adam C Gower,Stephanie Williams

doi:10.1016/j.ebiom.2020.102803

Abstract

BackgroundSleep Disordered Breathing (SDB) is associated with a wide range of pathophysiological changes due, in part, to hypoxemia during sleep. We sought to identify gene transcription associations with measures of SDB and hypoxemia during sleep, and study their response to treatment.MethodsIn two discovery cohorts, Framingham Offspring Study (FOS; N = 571) and the Multi-Ethnic Study of Atherosclerosis (MESA; N = 580), we studied gene expression in peripheral blood mononuclear cells in association with three measures of SDB: Apnea Hypopnea Index (AHI); average oxyhemoglobin saturation (avgO2) during sleep; and minimum oxyhemoglobin saturation (minO2) during sleep. Associated genes were used for analysis of gene expression in the blood of 15 participants with moderate or severe obstructive sleep apnea (OSA) from the Heart Biomarkers In Apnea Treatment (HeartBEAT) trial. These genes were studied pre- and post-treatment (three months) with continuous positive airway pressure (CPAP). We also performed Gene Set Enrichment Analysis (GSEA) on all traits and cohort analyses.FindingsTwenty-two genes were associated with SDB traits in both MESA and FOS. Of these, lower expression of CD1D and RAB20 was associated with lower avgO2 in MESA and FOS. CPAP treatment increased the expression of these genes in HeartBEAT participants. Immunity and inflammation pathways were up-regulated in subjects with lower avgO2; i.e., in those with a more severe SDB phenotype (MESA), whereas immuno-inflammatory processes were down-regulated following CPAP treatment (HeartBEAT).InterpretationLow oxygen saturation during sleep is associated with alterations in gene expression and transcriptional programs that are partially reversed by CPAP treatment.

Highlights

Sleep Disordered Breathing (SDB) is characterized by abnormal respiratory patterns during sleep and is usually associated with impaired gas exchange
We started with a single-gene association discovery step, in which we studied the association of gene-expression with SDB traits in two discovery cohorts: the Framingham Offspring Study (FOS) and the Multi-Ethnic Study of Atherosclerosis (MESA)
We performed a comprehensive study of the association of SDB traits with genome-wide gene expression in peripheral blood

Summary

Introduction

Sleep Disordered Breathing (SDB) is characterized by abnormal respiratory patterns during sleep and is usually associated with impaired gas exchange. Six studies ranging in size from 18 to 48 individuals have evaluated the impact of OSA on gene expression in peripheral blood monocytes or total leukocytes, either cross-sectionally in comparison to those without OSA [10À12], or pre- and post-treatment with continuous positive airway pressure (CPAP; [13,14]), the most common therapy for OSA, or following two weeks of CPAP withdrawal into either sham or oxygen supplement treatment [15]. Associated genes were used for analysis of gene expression in the blood of 15 participants with moderate or severe obstructive sleep apnea (OSA) from the Heart Biomarkers In Apnea Treatment (HeartBEAT) trial These genes were studied pre- and post-treatment (three months) with continuous positive airway pressure (CPAP).

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