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Treatment of obstructive sleep apnea alters cancer-associated transcriptional signatures in circulating leukocytes.

ABSTRACT: Obstructive sleep apnea (OSA) has been associated with a number of chronic disorders that may improve with effective therapy. However, the molecular pathways affected by continuous positive airway pressure (CPAP) treatment are largely unknown. We sought to assess the system-wide consequences of CPAP therapy by transcriptionally profiling peripheral blood leukocytes (PBLs).Subjects in whom severe OSA was diagnosed were treated with CPAP, and whole-genome expression measurement of PBLs was performed at baseline and following therapy. We used gene set enrichment analysis (GSEA) to identify pathways that were differentially enriched. Network analysis was then applied to highlight key drivers of processes influenced by CPAP.Eighteen subjects with significant OSA underwent CPAP therapy and microarray analysis of their PBLs. Treatment with CPAP improved apnea-hypopnea index (AHI), daytime sleepiness, and blood pressure, but did not affect anthropometric measures. GSEA revealed a number of enriched gene sets, many of which were involved in neoplastic processes and displayed downregulated expression patterns in response to CPAP. Network analysis identified several densely connected genes that are important modulators of cancer and tumor growth.Effective therapy of OSA with CPAP is associated with alterations in circulating leukocyte gene expression. Functional enrichment and network analyses highlighted transcriptional suppression in cancer-related pathways, suggesting potentially novel mechanisms linking OSA with neoplastic signatures.

SUBMITTER: Gharib SA

PROVIDER: S-EPMC3954174 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Treatment of obstructive sleep apnea alters cancer-associated transcriptional signatures in circulating leukocytes.

Gharib Sina A SA Seiger Ashley N AN Hayes Amanda L AL Mehra Reena R Patel Sanjay R SR

Sleep 20140401 4

<h4>Rationale</h4>Obstructive sleep apnea (OSA) has been associated with a number of chronic disorders that may improve with effective therapy. However, the molecular pathways affected by continuous positive airway pressure (CPAP) treatment are largely unknown. We sought to assess the system-wide consequences of CPAP therapy by transcriptionally profiling peripheral blood leukocytes (PBLs).<h4>Methods</h4>Subjects in whom severe OSA was diagnosed were treated with CPAP, and whole-genome expressi ...[more]

PMID: 24688164

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Project description:A growing number of studies provide epidemiological evidence linking obstructive sleep apnea (OSA) with a number of chronic disorders. Transcriptional analyses have been conducted to analyze the gene expression data. However, the weighted gene coexpression network analysis (WGCNA) method has not been applied to determine the transcriptional consequence of continuous positive airway pressure (CPAP) therapy in patients with severe OSA. The aim of this study was to identify key pathways and genes in patients with OSA that are influenced by CPAP treatment and uncover/unveil potential molecular mechanisms using WGCNA. We analyzed the microarray data of OSA (GSE 49800) listed in the Gene Expression Omnibus database. Coexpression modules were constructed using WGCNA. In addition, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were also conducted. After the initial data processing, 5101 expressed gene profiles were identified. Next, a weighted gene coexpression network was established and 16 modules of coexpressed genes were identified. The interaction analysis demonstrated a relative independence of gene expression in these modules. The black module, tan module, midnightblue module, pink module, and greenyellow module were significantly associated with the alterations in circulating leukocyte gene expression at baseline and after exposure to CPAP. The five hub genes were considered to be candidate OSA-related genes after CPAP treatment. Functional enrichment analysis revealed that steroid biosynthesis, amino sugar and nucleotide sugar metabolism, protein processing in the endoplasmic reticulum, and the insulin signaling pathway play critical roles in the development of OSA in circulating leukocyte gene expression at baseline and after exposure to CPAP. Using this new systems biology approach, we identified several genes and pathways that appear to be critical to OSA after CPAP treatment, and these findings provide a better understanding of OSA pathogenesis.

Project description:BackgroundObstructive sleep apnea (OSA) patients are at increased risk for pulmonary and cardiovascular complications; perioperative mortality risk is unclear. This report analyzes cases submitted to the OSA Death and Near Miss Registry, focusing on factors associated with poor outcomes after an OSA-related event. We hypothesized that more severe outcomes would be associated with OSA severity, less intense monitoring, and higher cumulative opioid doses.MethodsInclusion criteria were age ≥18 years, OSA diagnosed or suspected, event related to OSA, and event occurrence 1992 or later and <30 days postoperatively. Factors associated with death or brain damage versus other critical events were analyzed by tests of association and odds ratios (OR; 95% confidence intervals [CIs]).ResultsSixty-six cases met inclusion criteria with known OSA diagnosed in 55 (83%). Patients were middle aged (mean = 53, standard deviation [SD] = 15 years), American Society of Anesthesiologists (ASA) III (59%, n = 38), and obese (mean body mass index [BMI] = 38, SD = 9 kg/m); most had inpatient (80%, n = 51) and elective (90%, n = 56) procedures with general anesthesia (88%, n = 58). Most events occurred on the ward (56%, n = 37), and 14 (21%) occurred at home. Most events (76%, n = 50) occurred within 24 hours of anesthesia end. Ninety-seven percent (n = 64) received opioids within the 24 hours before the event, and two-thirds (41 of 62) also received sedatives. Positive airway pressure devices and/or supplemental oxygen were in use at the time of critical events in 7.5% and 52% of cases, respectively. Sixty-five percent (n = 43) of patients died or had brain damage; 35% (n = 23) experienced other critical events. Continuous central respiratory monitoring was in use for 3 of 43 (7%) of cases where death or brain damage resulted. Death or brain damage was (1) less common when the event was witnessed than unwitnessed (OR = 0.036; 95% CI, 0.007-0.181; P < .001); (2) less common with supplemental oxygen in place (OR = 0.227; 95% CI, 0.070-0.740; P = .011); (3) less common with respiratory monitoring versus no monitoring (OR = 0.109; 95% CI, 0.031-0.384; P < .001); and (4) more common in patients who received both opioids and sedatives than opioids alone (OR = 4.133; 95% CI, 1.348-12.672; P = .011). No evidence for an association was observed between outcomes and OSA severity or cumulative opioid dose.ConclusionsDeath and brain damage were more likely to occur with unwitnessed events, no supplemental oxygen, lack of respiratory monitoring, and coadministration of opioids and sedatives. It is important that efforts be directed at providing more effective monitoring for OSA patients following surgery, and clinicians consider the potentially dangerous effects of opioids and sedatives-especially when combined-when managing OSA patients postoperatively.

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Treatment of obstructive sleep apnea alters cancer-associated transcriptional signatures in circulating leukocytes.

Publications

Treatment of obstructive sleep apnea alters cancer-associated transcriptional signatures in circulating leukocytes.

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