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.