Abstract
Obstructive sleep apnea (OSA) is a syndrome leading to chronic intermittent hypoxia, and the up-regulation of toll-like receptors (TLR) 2 and 6 on peripheral blood cells has been reported. We hypothesized that DNA methylation in TLR2 and TLR6 genes may play a role in the development of OSA and its excessive daytime sleepiness (EDS) phenotype. DNA methylation over 28 cytosine-phosphate-guanine (CpG) sites of the TLR2 promoter region and 3 CpG sites of the TLR6 gene body, and their protein expressions were measured by using pyrosequencing and ELISA methods in 18 heathy subjects (HS) and 58 patients with severe OSA (divided into 18 non-EDS and 40 EDS group). Patients with severe OSA had higher DNA methylation levels over five CpG sites (#1, #2, #3, #25 and #28) and lower DNA methylation levels over CpG site #18 of the TLR2 promoter region, higher DNA methylation levels over two CpG sites (#1 and #3) of the TLR6 gene body, and higher protein expressions of TLR6 than HS. The CpG site #2 of the TLR6 gene body was hypermethylated in severe OSA patients with EDS. Both DNA methylation levels over CpG site #1 of the TLR6 gene body and protein expressions of TLR6 were reduced after more than 6 months of nasal CPAP treatment in seven selected patients. Aberrant DNA methylation of the TLR2 promoter region and TLR6 gene body are associated with the consequence of severe OSA and its EDS phenotype.
Highlights
Obstructive sleep apnea (OSA) is a syndrome characterized by repetitive upper airway collapse during sleep, leading to chronic intermittent hypoxia, sleep fragmentation, oxidative stress and the damage similar to that caused by ischemia-reperfusion injury [1, 2]
Multivariate linear regression with hierarchical comparison was performed in two steps with all potential co-variables to determine independent factors contributing to the DNA methylation of the TLR2 promoter region and the TLR6 gene body, and their protein expressions in patients
DNA methylation levels over CpG sites #1, #2, #3, #8, #9, #13, #19, #22, #25 and #28 of the TLR2 promoter region and TLR2 protein expression were all increased in patients with severe OSA as compared with heathy subjects (HS), while DNA methylation levels over CpG site #18 of the TLR2 promoter region was decreased (Fig 2 and S2 Table)
Summary
Obstructive sleep apnea (OSA) is a syndrome characterized by repetitive upper airway collapse during sleep, leading to chronic intermittent hypoxia, sleep fragmentation, oxidative stress and the damage similar to that caused by ischemia-reperfusion injury [1, 2]. The down-regulation of TLR2 expressions through aberrant DNA methylation of certain CpG sites over TLR2 promoter region has been demonstrated in patients with active pulmonary tuberculosis (TB) disease and cystic fibrosis [20]. We hypothesized that DNA methylation in the promoter region of TLR2 and in the TLR6 gene body might play a role in the development of severe OSA and the EDS phenotype
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