Aberrant DNA methylation levels of the formyl peptide receptor 1/2/3 genes are associated with obstructive sleep apnea and its clinical phenotypes

Yung-Che Chen; Kuo-Tung Huang; Mao-Chang Su; Po-Yuan Hsu; Chien-Hung Chin; I-Chun Lin; Chia-Wei Liou; Ting-Ya Wang; Yong-Yong Lin; Chang-Chun Hsiao; Meng-Chih Lin

Aberrant DNA methylation levels of the formyl peptide receptor 1/2/3 genes are associated with obstructive sleep apnea and its clinical phenotypes

Am J Transl Res. 2020 Jun 15;12(6):2521-2537. eCollection 2020.

Authors

Yung-Che Chen^{1

2}, Kuo-Tung Huang^{1

2}, Mao-Chang Su^{1

2

3}, Po-Yuan Hsu¹, Chien-Hung Chin^{1

2

4}, I-Chun Lin⁵, Chia-Wei Liou⁶, Ting-Ya Wang¹, Yong-Yong Lin¹, Chang-Chun Hsiao⁷, Meng-Chih Lin^{1

2}

Affiliations

¹ Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
² Sleep Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
³ Chang Gung University of Science and Technology Chia-yi, Taiwan.
⁴ Chung Shan Medical University School of Medicine Taichung, Taiwan.
⁵ Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
⁶ Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine Kaohsiung 83301, Taiwan.
⁷ Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University Taoyuan 33302, Taiwan.

PMID: 32655788
PMCID: PMC7344102

Abstract

Background: FPR1 over-expression and insufficiency of FPR2 and FPR3 are associated with disease severity of obstructive sleep apnea (OSA). We hypothesized that epigenetic modification of the FPR1/2/3 genes may underlie intermittent hypoxia with re-oxygenation (IHR) injury in OSA.

Methods: DNA methylation levels over 17 CpG sites of the FPR1/2/3 genes and their gene expression levels in the peripheral blood mononuclear cells were determined in 40 treatment-naïve OSA patients, 12 severe OSA patients under long-term continuous positive airway pressure treatment, 16 primary snoring (PS) subjects, and 10 healthy non-snorers (HS).

Results: Both -524 and -264 CpG sites of the FPR1 gene were hypomethylated in treatment-naïve OSA versus HS, while -264 CpG site methylation level was negatively correlated with FPR1/FPR3 gene expression ratio and associated with prevalent diabetes mellitus. Both +8802 and +8845 CpG sites of the FPR2 gene were hypermethylated in treatment-naive OSA versus HS, while hypermethylated +9132 and +9150 CpG sites were both associated with prevalent hypertension. FPR3 gene expression and DNA methylation levels over -842/-516 CpG sites of the FPR3 gene were both decreased in treatment-naive OSA versus HS, while hypermethylated -429 CpG site was associated with elevated serum C-reactive protein level. In vitro IHR stimuli in human monocytic THP-1 cells resulted in gene promoter hypomethylation-mediated FPR1 over-expression, increased production of reactive oxygen species, and increased cell apoptosis, which could be reversed with re-methylation agent, folic acid, treatment.

Conclusions: Aberrant DNA methylation patterns of the FPR1/2/3 gene promoters contribute to disease severity and diabetes mellitus or cardiovascular disease in OSA patients, probably through regulating FPR1/2/3 gene expressions.

Keywords: DNA methylation; Obstructive sleep apnea; formyl peptide receptor; intermittent hypoxia with re-oxygenation.