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Original Research: Sleep Disorders |

DNA Methylation Profiling of Blood Monocytes in Patients With Obesity Hypoventilation Syndrome: Effect of Positive Airway Pressure Treatment

Rene Cortese, PhD; Chunling Zhang, MSc; Riyue Bao, PhD; Jorge Andrade, PhD; Abdelnaby Khalyfa, PhD; Babak Mokhlesi, MD; David Gozal, MD, FCCP
Author and Funding Information

FUNDING/SUPPORT: This work was supported by the Herbert T. Abelson Chair in Pediatrics and by National Institutes of Health [Grant R01HL119161 to B. M.].

aSection of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, University of Chicago, Chicago, IL

bCenter for Research Informatics, University of Chicago, Chicago, IL

cSleep Disorders Center and Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL

CORRESPONDENCE TO: David Gozal, MD, FCCP, Department of Pediatrics, University of Chicago, KCBD, Room 4100, 900 E 57th St, Mailbox 4, Chicago, IL 60637


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(1):91-101. doi:10.1016/j.chest.2016.02.648
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Background  OSA is a highly prevalent condition that is associated with a wide range of long-term morbidities including metabolic, cardiovascular, and cognitive alterations, possibly via activation of systemic inflammatory and oxidative stress pathways. Implementation of positive airway pressure (PAP) is the first-line treatment for OSA, as well as for obesity hypoventilation syndrome (OHS), its most severe phenotype. However, the molecular and cellular mechanisms underlying OHS-induced morbidities and their response to PAP treatment remain unclear, and could be mediated, in part, by OSA-induced epigenetic changes.

Methods  Blood was collected before starting PAP treatment (PRE group), as well as 6 weeks after PAP treatment (POST group) in 15 adult patients with OHS. DNA methylation profiles were studied by methylated DNA immunoprecipitation coupled to microarrays (MeDIP-chip) in six representative patients and further verified in a cohort of 15 patients by MeDIP-quantitative PCR.

Results  We identified 1,847 regions showing significant differential DNA methylation (P < .001; model-based analysis of tiling arrays score, > 4) between the groups. Analysis of biochemical pathways and gene networks demonstrated that differentially methylated regions were associated with immune responses, and particularly with mechanisms governing gene regulation by peroxisome proliferation-activated receptors (PPARs). Single-locus quantitative PCR analysis revealed that DNA methylation was increased at the PPAR-responsive elements (PPAREs) of eight genes in the post-treatment samples (PRE/POST fold changes: ABCA1, 3.11; ABCG1, 1.72; CD36, 5.04; FABP4, 2.49; HMOX, 2.74; NOS2, 7.78; PEPCK, 9.27; and ADIPOQ, 1.73), suggesting that PAP treatment leads to an increase in DNA methylation at PPAREs, possibly affecting the binding of the PPAR-γ complex and downstream gene expression.

Conclusions  Our work provides initial evidence of epigenetic regulation particularly involving metabolic pathways in patients with OHS who are responsive to PAP treatment.

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