title: Whole Genome DNA Methylation Analysis of Obstructive Sleep Apnea: IL1R2, NPR2, AR, SP140 Methylation and Clinical Phenotype.
abstract: OBJECTIVE
  We 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).
  
  
  METHODS
  Illumina'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).
  
  
  RESULTS
  Microarray 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.
  
  
  CONCLUSIONS
  IL1R2 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.
  
  
  CONCLUSIONS
  A commentary on this article appears in this issue on page 723.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Sleep Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taiwan.
authors.forename: Yung-Che
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Molecular Medicine Research Center, Chang Gung University, Taiwan.|Bioinformatics Center, Chang Gung University, Taiwan.
authors.forename: Ting-Wen
authors.initials: TW
authors.lastname: Chen
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Sleep Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Chang Gung University of Science and Technology, Chia-yi, Taiwan.
authors.forename: Mao-Chang
authors.initials: MC
authors.lastname: Su
authors.affiliation: Division of Rheumatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Chung-Jen
authors.initials: CJ
authors.lastname: Chen
authors.affiliation: Center of Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Kuang-Den
authors.initials: KD
authors.lastname: Chen
authors.affiliation: Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Liou
authors.affiliation: Molecular Medicine Research Center, Chang Gung University, Taiwan.|Bioinformatics Center, Chang Gung University, Taiwan.
authors.forename: Petrus
authors.initials: P
authors.lastname: Tang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Ting-Ya
authors.initials: TY
authors.lastname: Wang
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taiwan.
authors.forename: Jen-Chieh
authors.initials: JC
authors.lastname: Chang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Sleep Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Chang Gung University of Science and Technology, Chia-yi, Taiwan.
authors.forename: Chin-Chou
authors.initials: CC
authors.lastname: Wang
authors.affiliation: Sleep Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Hsin-Ching
authors.initials: HC
authors.lastname: Lin
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Sleep Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Chien-Hung
authors.initials: CH
authors.lastname: Chin
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Sleep Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Kuo-Tung
authors.initials: KT
authors.lastname: Huang
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Sleep Center, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taiwan.
authors.forename: Meng-Chih
authors.initials: MC
authors.lastname: Lin
authors.affiliation: Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taiwan.
authors.forename: Chang-Chun
authors.initials: CC
authors.lastname: Hsiao
mesh_terms: D000328:Adult; D000368:Aged; D034961:Antigens, Nuclear / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D015894:Genome, Human / Q000235:genetics; D023281:Genomics; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D017286:Polysomnography; D011401:Promoter Regions, Genetic / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics*; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics*; D053574:Receptors, Interleukin-1 Type II / Q000235:genetics*; D015203:Reproducibility of Results; D012891:Sleep Apnea Syndromes / Q000235:genetics; D020181:Sleep Apnea, Obstructive / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D012894:Sleep Stages / Q000235:genetics*; D012913:Snoring / Q000150:complications / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult; D000099242:Atrial Natriuretic Factor Receptor B
chemical_list: D034961:Antigens, Nuclear; D010100:Oxygen; D011944:Receptors, Androgen; D017461:Receptors, Atrial Natriuretic Factor; D053574:Receptors, Interleukin-1 Type II; D014157:Transcription Factors; D000099242:Atrial Natriuretic Factor Receptor B; C410798:AR protein, human; C508592:IL1R2 protein, human; C102470:SP140 protein, human
keywords: AR; DNA methylation; IL1R2; NPR2; SP140; excessive daytime sleepiness; obstructive sleep apnea; oxygen desaturation index