Changes in Expression of the CLOCK Gene in Obstructive Sleep Apnea Syndrome Patients Are Not Reverted by Continuous Positive Airway Pressure Treatment

Abstract

PurposeMetabolic syndrome and cardiovascular disease are strongly associated with obstructive sleep apnea syndrome (OSAS), which causes substantial changes to normal circadian physiological functions, including metabolic pathways. Because core clock genes are known to be modulated by sleep/vigilance cycles, we asked whether the expression level of mRNA coding for clock genes is altered in non-treated OSAS patients and if it can be corrected by standard continuous positive airway pressure (CPAP) treatment.MethodsPeripheral blood was collected from male patients diagnosed with severe OSAS (apnea-hypopnea index ≥ 30/h) before and after treatment initiation. qPCR was used to measure mRNA levels of genes associated with the central circadian pacemaker including CLOCK, BMAL1, Cry1, Cry2, and three Period genes (Per 1, 2, 3) in peripheral blood mononuclear cells (PBMCs).ResultsWe found statistically significant differences for CLOCK (p-value = 0.022) expression in PBMCs of OSAS patients which were not reverted by treatment with CPAP. We have also found a substantial decrease in the slow wave sleep (SWS) content in OSAS patients (p-value < 0.001) that, contrary to REM sleep, was not corrected by CPAP (p-value = 0.875).ConclusionCPAP treatment does not correct substantial changes in expression of core clock genes in OSAS patients. Because CPAP treatment is also unable to normalize the SWS in these patients, it is likely that additional therapeutic interventions that increase SWS content and complement the benefits of CPAP are required to more effectively reduce the known increased cardiovascular risk associated with OSAS patients.

Alternations of Circadian Clock Genes Expression and Oscillation in Obstructive Sleep Apnea

“…Consistent with our current study, the expression of clock genes has been shown to be altered in patients with OSA [19,25]. Moreira et al further revealed that the altered expression of CLOCK gene in seven patients with OSA was not reverted by continuous positive airway pressure (CPAP) treatment [25]. In contrast, Burioka et al demonstrated that the PER1 expression elevated at 02:00 in patients with OSA was significantly decreased by CPAP treatment [19].…”

Effect of Type 2 Diabetes Mellitus on the Hypoxia-Inducible Factor 1-Alpha Expression. Is There a Relationship with the Clock Genes?

“…Similarly, and following this bidirectional pattern, it is plausible to think that the treatment of nocturnal hypoxemia with CPAP can partially restore the impaired hypoxic pathways and improve the clock genes transcription. However, Moreira et al failed to find improvement in CLOCK expression with CPAP treatment in 17 men with severe SAHOS without type 2 diabetes [34]. This result could suggest that other mechanisms beyond hypoxia and hyperglycemia are involved in the complex regulation of the clock gene system.…”

“…However, Moreira et al . failed to find improvement in CLOCK expression with CPAP treatment in 17 men with severe SAHOS without type 2 diabetes [ 34 ]. This result could suggest that other mechanisms beyond hypoxia and hyperglycemia are involved in the complex regulation of the clock gene system.…”

Short-term exposure to intermittent hypoxia leads to changes in gene expression seen in chronic pulmonary disease

“…Alterations in expression of clock genes are reported in peripheral blood cells from patients with OSA ( Yang et al, 2019 ). These changes in expression in blood cells are not affected by CPAP treatment ( Moreira et al, 2017 ), suggesting that they persist despite treatment. It is known that the circadian clock in alveolar epithelial cells impacts pulmonary physiology, and its disruption can contribute to disease in animal models ( Zhang et al, 2019 ).…”