title: DNA Methylation Profiling of Blood Monocytes in Patients With Obesity Hypoventilation Syndrome: Effect of Positive Airway Pressure Treatment.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Our work provides initial evidence of epigenetic regulation particularly involving metabolic pathways in patients with OHS who are responsive to PAP treatment.
authors.affiliation: Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, University of Chicago, Chicago, IL.
authors.forename: Rene
authors.initials: R
authors.lastname: Cortese
authors.affiliation: Center for Research Informatics, University of Chicago, Chicago, IL.
authors.forename: Chunling
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Center for Research Informatics, University of Chicago, Chicago, IL.
authors.forename: Riyue
authors.initials: R
authors.lastname: Bao
authors.affiliation: Center for Research Informatics, University of Chicago, Chicago, IL.
authors.forename: Jorge
authors.initials: J
authors.lastname: Andrade
authors.affiliation: Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, University of Chicago, Chicago, IL.
authors.forename: Abdelnaby
authors.initials: A
authors.lastname: Khalyfa
authors.affiliation: Sleep Disorders Center and Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL.
authors.forename: Babak
authors.initials: B
authors.lastname: Mokhlesi
authors.affiliation: Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, University of Chicago, Chicago, IL. Electronic address: dgozal@uchicago.edu.
authors.forename: David
authors.initials: D
authors.lastname: Gozal
mesh_terms: D000328:Adult; D045422:Continuous Positive Airway Pressure / Q000379:methods*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D010845:Obesity Hypoventilation Syndrome / Q000378:metabolism / Q000628:therapy; D047492:Peroxisome Proliferator-Activated Receptors / Q000235:genetics / Q000378:metabolism; D013223:Statistics as Topic; D016896:Treatment Outcome
chemical_list: D047492:Peroxisome Proliferator-Activated Receptors
keywords: DNA methylation; OSA; monocytes; peroxisome proliferation-activated receptor γ; positive air pressure