Genome-wide gene expression array identifies novel genes related to disease severity and excessive daytime sleepiness in patients with obstructive sleep apnea

Yung-Che Chen; Kuang-Den Chen; Mao-Chang Su; Chien-Hung Chin; Chung-Jen Chen; Chia-Wei Liou; Ting-Wen Chen; Ya-Chun Chang; Kuo-Tung Huang; Chin-Chou Wang; Ting-Ya Wang; Jen-Chieh Chang; Yong-Yong Lin; Yi-Xin Zheng; Meng-Chih Lin; Chang-Chun Hsiao

doi:10.1371/journal.pone.0176575

Genome-wide gene expression array identifies novel genes related to disease severity and excessive daytime sleepiness in patients with obstructive sleep apnea

PLoS One. 2017 May 17;12(5):e0176575. doi: 10.1371/journal.pone.0176575. eCollection 2017.

Authors

Yung-Che Chen^{1

2

3}, Kuang-Den Chen⁴, Mao-Chang Su^{1

2

5}, Chien-Hung Chin^{1

2}, Chung-Jen Chen⁶, Chia-Wei Liou⁷, Ting-Wen Chen⁸, Ya-Chun Chang^{1

2}, Kuo-Tung Huang^{1

2}, Chin-Chou Wang^{1

2

5}, Ting-Ya Wang¹, Jen-Chieh Chang⁴, Yong-Yong Lin¹, Yi-Xin Zheng¹, Meng-Chih Lin^{1

2

3}, Chang-Chun Hsiao^{9

10}

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 Department of Medicine, Chang Gung University, Taoyuan, Taiwan.
⁴ Center of Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
⁵ Chang Gung University of Science and Technology, Chia-yi, Taiwan.
⁶ Division of Rheumatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
⁷ Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
⁸ Molecular Medicine Research Center, and Bioinformatics Center, Chang Gung University, Taoyuan, Taiwan.
⁹ Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
¹⁰ Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.

Abstract

We aimed to identify novel molecular associations between chronic intermittent hypoxia with re-oxygenation and adverse consequences in obstructive sleep apnea (OSA). We analyzed gene expression profiles of peripheral blood mononuclear cells from 48 patients with sleep-disordered breathing stratified into four groups: primary snoring (PS), moderate to severe OSA (MSO), very severe OSA (VSO), and very severe OSA patients on long-term continuous positive airway pressure treatment (VSOC). Comparisons of the microarray gene expression data identified eight genes up-regulated with OSA and down-regulated with CPAP treatment, and five genes down-regulated with OSA and up-regulated with CPAP treatment. Protein expression levels of two genes related to endothelial tight junction (AMOT P130, and PLEKHH3), and three genes related to anti-or pro-apoptosis (BIRC3, ADAR1 P150, and LGALS3) were all increased in the VSO group, while AMOT P130 was further increased, and PLEKHH3, BIRC3, and ADAR1 P150 were all decreased in the VSOC group. Subgroup analyses revealed that AMOT P130 protein expression was increased in OSA patients with excessive daytime sleepiness, BIRC3 protein expression was decreased in OSA patients with hypertension, and LGALS3 protein expression was increased in OSA patients with chronic kidney disease. In vitro short-term intermittent hypoxia with re-oxygenation experiment showed immediate over-expression of ADAR1 P150. In conclusion, we identified a novel association between AMOT/PLEKHH3/BIRC3/ADAR1/LGALS3 over-expressions and high severity index in OSA patients. AMOT and GALIG may constitute an important determinant for the development of hypersomnia and kidney injury, respectively, while BIRC3 may play a protective role in the development of hypertension.

MeSH terms

Adult
Biomarkers
Comorbidity
Disorders of Excessive Somnolence / diagnosis*
Disorders of Excessive Somnolence / etiology*
Female
Gene Expression Profiling*
Gene Expression Regulation
Gene Regulatory Networks
Genetic Predisposition to Disease*
Genome-Wide Association Study*
Humans
Leukocytes, Mononuclear / metabolism
Male
Middle Aged
Proteomics / methods
Severity of Illness Index
Signal Transduction
Sleep Apnea, Obstructive / complications*
Sleep Apnea, Obstructive / diagnosis
Sleep Apnea, Obstructive / genetics*

Substances

Biomarkers

Grants and funding

This work was supported by grants from the Ministry of Science and Technology, Taiwan (NMRPG8D6131/103-2314-B-182A-094-MY2 & NMRPG8B6192/101-2314-B-182A-130-MY2 to M.C. Lin) and grants from Chang Gung Memorial Hospital (CMRPG8C1181-1182 to M.C. Lin), Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.