Low oxygen saturation during sleep reduces CD1D and RAB20 expressions that are reversed by CPAP therapy
Tamar Sofer,
Ruitong Li,
Roby Joehanes,
Honghuang Lin,
Adam C. Gower,
Heming Wang,
Nuzulul Kurniansyah,
Brian E. Cade,
Jiwon Lee,
Stephanie Williams,
Reena Mehra,
Sanjay R. Patel,
Stuart F. Quan,
Yongmei Liu,
Jerome I. Rotter,
Stephen S. Rich,
Avrum Spira,
Daniel Levy,
Sina A. Gharib,
Susan Redline,
Daniel J. Gottlieb
Affiliations
Tamar Sofer
Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA; Corresponding author at: Brigham and Women's Hospital, Department of Medicine, 221 Longwood Ave, Suite 225C, Boston, MA 02115, USA.
Ruitong Li
Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
Roby Joehanes
The Population Sciences Branch of the National Heart, Lung and Blood Institute, Bethesda, MD, USA and the Framingham Heart Study, Framingham, MA, USA; Hebrew SeniorLife, Harvard Medical School, Boston, MA, USA
Honghuang Lin
The Population Sciences Branch of the National Heart, Lung and Blood Institute, Bethesda, MD, USA and the Framingham Heart Study, Framingham, MA, USA; Department of Medicine, Boston University School of Medicine, Boston, MA, USA
Adam C. Gower
Clinical and Translational Science Institute, Boston University School of Medicine, Boston, USA
Heming Wang
Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
Nuzulul Kurniansyah
Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
Brian E. Cade
Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
Jiwon Lee
Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
Stephanie Williams
Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
Reena Mehra
Neurologic Institute, Cleveland Clinic, Cleveland, OH, USA
Sanjay R. Patel
Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA
Stuart F. Quan
Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
Yongmei Liu
Department of Medicine, Duke University School of Medicine, Durham, NC, USA
Jerome I. Rotter
The Institute for Translational Genomics and Population Sciences, Departments of Pediatrics and Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
Stephen S. Rich
Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
Avrum Spira
Boston University School of Medicine and Boston Medical Center, Boston, MA, USA
Daniel Levy
The Population Sciences Branch of the National Heart, Lung and Blood Institute, Bethesda, MD, USA and the Framingham Heart Study, Framingham, MA, USA
Sina A. Gharib
Computational Medicine Core, Center for Lung Biology, University of Washington Medicine Sleep Center, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Washington, Seattle, WA, USA
Susan Redline
Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Computational Medicine Core, Center for Lung Biology, University of Washington Medicine Sleep Center, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Washington, Seattle, WA, USA
Daniel J. Gottlieb
Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, USA; Division of Sleep and Circadian Disorders, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; VA Boston Healthcare System, Boston, MA, USA
Background: Sleep 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. Methods: In 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. Findings: Twenty-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). Interpretation: Low oxygen saturation during sleep is associated with alterations in gene expression and transcriptional programs that are partially reversed by CPAP treatment.
