Dataset Information

Aberrant DNA methylation of the toll-like receptors 2 and 6 genes in patients with obstructive sleep apnea.

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.

SUBMITTER: Huang KT

PROVIDER: S-EPMC7028278 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Aberrant DNA methylation of the toll-like receptors 2 and 6 genes in patients with obstructive sleep apnea.

Huang Kuo-Tung KT Chen Yung-Che YC Tseng Chia-Cheng CC Chang Huang-Chih HC Su Mao-Chang MC Wang Ting-Ya TY Lin Yong-Yong YY Zheng Yi-Xin YX Chang Jen-Chieh JC Chin Chien-Hung CH Hsiao Chang-Chun CC Lin Meng-Chih MC

PloS one 20200218 2

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 express ...[more]

PMID: 32069296

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Project description:Study objectivesWe hypothesized that DNA methylation patterns may contribute to disease severity or the development of hypertension and excessive daytime sleepiness (EDS) in patients with obstructive sleep apnea (OSA).MethodsIllumina's (San Diego, CA, USA) DNA methylation 27-K assay was used to identify differentially methylated loci (DML). DNA methylation levels were validated by pyrosequencing. A discovery cohort of 15 patients with OSA and 6 healthy subjects, and a validation cohort of 72 patients with sleep disordered breathing (SDB).ResultsMicroarray analysis identified 636 DMLs in patients with OSA versus healthy subjects, and 327 DMLs in patients with OSA and hypertension versus those without hypertension. In the validation cohort, no significant difference in DNA methylation levels of six selected genes was found between the primary snoring subjects and OSA patients (primary outcome). However, a secondary outcome analysis showed that interleukin-1 receptor 2 (IL1R2) promoter methylation (-114 cytosine followed by guanine dinucleotide sequence [CpG] site) was decreased and IL1R2 protein levels were increased in the patients with SDB with an oxygen desaturation index > 30. Androgen receptor (AR) promoter methylation (-531 CpG site) and AR protein levels were both increased in the patients with SDB with an oxygen desaturation index > 30. Natriuretic peptide receptor 2 (NPR2) promoter methylation (-608/-618 CpG sites) were decreased, whereas levels of both NPR2 and serum C type natriuretic peptide protein were increased in the SDB patients with EDS. Speckled protein 140 (SP140) promoter methylation (-194 CpG site) was increased, and SP140 protein levels were decreased in the patients with SDB and EDS.ConclusionsIL1R2 hypomethylation and AR hypermethylation may constitute an important determinant of disease severity, whereas NPR2 hypomethylation and SP140 hypermethylation may provide a biomarker for vulnerability to EDS in OSA.CommentaryA commentary on this article appears in this issue on page 723.

Project description:Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy of the upper extremity. It is usually associated with the compression of the median nerve in the median groove. Because the main symptoms of CTS pain and numbness worsen at night, sleep disorders in CTS patients and the impact of preferred sleeping position on CTS development have been formerly studied. However, to the best of our knowledge, this is the first study assessing the frequency of CTS in obstructive sleep apnea (OSA) patients. This study aimed to determine the frequency of CTS in OSA patients and evaluate the causative relation between the two diseases.Records of individuals who were admitted to our sleep laboratory were retrospectively scanned. Eighty patients who were diagnosed with OSA and did not have comorbidities that might cause OSA (e.g., diabetes mellitus, hypothyroiditis, rheumatic diseases, and cervical radiculopathy) were included in the study along with 80 healthy controls who matched for age, sex, and BMI of OSA patients. To maintain observer blindness, patients were not questioned regarding their symptoms or the clinical data that would be used in the study. All participants underwent nerve conduction studies. Those who were diagnosed with CTS were questioned regarding CTS symptoms and the preferred sleeping position. Subsequently, patients were given the Boston CTS questionnaire.CTS frequency in OSA patients was found to be 27.5%. There was no significant relation between preferred sleeping position or being a manual worker and having CTS.CTS frequency in OSA patients is significantly higher than that in healthy individuals. In contrast to previous studies that have been performed in the absence of polysomnographic and electrophysiological data, in our study biomechanical factors were not associated with CTS presence. Therefore, we conclude that intermittent hypoxemia is the main etiological factor for CTS in OSA patients. Inflammation may be a common factor for etiopathogenesis for both diseases, but this hypothesis needs further investigation.

Dataset Information

Aberrant DNA methylation of the toll-like receptors 2 and 6 genes in patients with obstructive sleep apnea.

Publications

Aberrant DNA methylation of the toll-like receptors 2 and 6 genes in patients with obstructive sleep apnea.

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