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

Kuo-Tung Huang; Yung-Che Chen; Chia-Cheng Tseng; Huang-Chih Chang; Mao-Chang Su; Ting-Ya Wang; Yong-Yong Lin; Yi-Xin Zheng; Jen-Chieh Chang; Chien-Hung Chin; Chang-Chun Hsiao; Meng-Chih Lin

doi:10.1371/journal.pone.0228958

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

PLoS One. 2020 Feb 18;15(2):e0228958. doi: 10.1371/journal.pone.0228958. eCollection 2020.

Authors

Kuo-Tung Huang^{1

2

3

4}, Yung-Che Chen^{1

2

3}, Chia-Cheng Tseng^{1

2

3}, Huang-Chih Chang^{1

2

3}, Mao-Chang Su^{1

2

5}, Ting-Ya Wang¹, Yong-Yong Lin¹, Yi-Xin Zheng¹, Jen-Chieh Chang¹, Chien-Hung Chin^{1

2}, Chang-Chun Hsiao³, Meng-Chih Lin^{1

2

5}

Affiliations

¹ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
² Sleep Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
³ Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
⁴ Department of Nursing, Meiho University, Pingtung, Taiwan.
⁵ Chang Gung University of Science and Technology, Chia-yi, Taiwan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Case-Control Studies
Continuous Positive Airway Pressure / methods
CpG Islands / genetics
DNA Methylation / genetics
Epigenesis, Genetic / genetics
Female
Humans
Male
Middle Aged
Phenotype
Polysomnography / methods
Promoter Regions, Genetic / genetics
Sleep Apnea, Obstructive / genetics*
Sleep Apnea, Obstructive / metabolism
Sleep Apnea, Obstructive / physiopathology
Taiwan
Toll-Like Receptor 2 / genetics*
Toll-Like Receptor 2 / metabolism
Toll-Like Receptor 6 / genetics*
Toll-Like Receptor 6 / metabolism
Toll-Like Receptors / genetics

Substances

TLR2 protein, human
TLR6 protein, human
Toll-Like Receptor 2
Toll-Like Receptor 6
Toll-Like Receptors

Grants and funding

This research was funded by grants from the Chang Gung Memorial Hospital (CMRPG 8C1181/1182/1183 to M.C. Lin), Taiwan, and by grants (NMRPG8F6071-6073/105-2314-B-182A-092-MY3 to M.C. Lin) from the Ministry of Science and Technology, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.