Whole Genome DNA Methylation Analysis of Obstructive Sleep Apnea:IL1R2,NPR2,AR,SP140Methylation and Clinical Phenotype

Chen, Yung Che; Chen, Ting-Wen; Su, Mao Chang; Chen, Chung‐Jen; Chen, Kuang Den; Liou, Chia Wei; Tang, Petrus; Wang, Ting Ya; Chang, Jen-Chieh; Wang, Chin Chou; Lin, Huang‐Chi; Chin, Chien Hung; Huang, Kuo Tung; Lin, Meng C.; Hsiao, Chang‐Chun

doi:10.5665/sleep.5620

Cited by 47 publications

(36 citation statements)

References 49 publications

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“…In personality disorders, increased levels of sIL‐1R2 correlated with aggression . In respiratory diseases, hypomethylation of the IL1R2 gene was associated with disease severity in obstructive sleep apnea, whereas alveolar macrophages and circulating leukocytes of patient with acute respiratory distress syndrome showed increased expression of the IL1R2 gene and higher levels of circulating sIL‐1R2, correlating with survival . In cancer, IL1R2 expression was found increased in squamous cell carcinoma, and IL‐1R2 expression inhibition by shRNA could inhibit the proliferation of osteosarcoma cells in culture …”

Section: Focus On the Il‐1r Familymentioning

confidence: 99%

The family of the interleukin‐1 receptors

Boraschi

Italiani

Weil

et al. 2017

Immunological Reviews

275

225

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The extracellular forms of the IL-1 cytokines are active through binding to specific receptors on the surface of target cells. IL-1 ligands bind to the extracellular portion of their ligand-binding receptor chain. For signaling to take place, a non-binding accessory chain is recruited into a heterotrimeric complex. The intracellular approximation of the Toll-IL-1-receptor (TIR) domains of the 2 receptor chains is the event that initiates signaling. The family of IL-1 receptors (IL-1R) includes 10 structurally related members, and the distantly related soluble protein IL-18BP that acts as inhibitor of the cytokine IL-18. Over the years the receptors of the IL-1 family have been known with many different names, with significant confusion. Thus, we will use here a recently proposed unifying nomenclature. The family includes several ligand-binding chains (IL-1R1, IL-1R2, IL-1R4, IL-1R5, and IL-1R6), 2 types of accessory chains (IL-1R3, IL-1R7), molecules that act as inhibitors of signaling (IL-1R2, IL-1R8, IL-18BP), and 2 orphan receptors (IL-1R9, IL-1R10). In this review, we will examine how the receptors of the IL-1 family regulate the inflammatory and anti-inflammatory functions of the IL-1 cytokines and are, more at large, involved in modulating defensive and pathological innate immunity and inflammation. Regulation of the IL-1/IL-1R system in the brain will be also described, as an example of the peculiarities of organ-specific modulation of inflammation.

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Section: Focus On the Il‐1r Familymentioning

confidence: 99%

The family of the interleukin‐1 receptors

Boraschi

Italiani

Weil

et al. 2017

Immunological Reviews

275

225

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“…KSR1 has been found to be up-regulated after sleep-restriction 80 in 26 participants studied in a laboratory-based assessment. DNAm at this gene has been associated with sleep apnea as well, though in a small study at a high significance level (FDR<0.5) 81 . This KSR1 probe (cg17585031) did not replicate in CHS AA and had opposite sign of association compared to the probe reported in this gene from the sleep apnea study 81 .…”

Section: Discussionmentioning

confidence: 89%

“…DNAm at this gene has been associated with sleep apnea as well, though in a small study at a high significance level (FDR<0.5) 81 . This KSR1 probe (cg17585031) did not replicate in CHS AA and had opposite sign of association compared to the probe reported in this gene from the sleep apnea study 81 . A significant association was observed for the CpG site near a master cytokine TGFB1 .…”

Section: Discussionmentioning

confidence: 89%

Epigenome-wide association analysis of daytime sleepiness in the Multi-Ethnic Study of Atherosclerosis reveals African-American specific associations

Barfield

Wang

Liu

et al. 2018

Preprint

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3 Study Objectives: Excessive daytime sleepiness (EDS) is a consequence of inadequate sleep, or of a primary disorder of sleep-wake control. Population variability in prevalence of EDS and susceptibility to EDS are likely due to genetic and biological factors as well as social and environmental influences. Epigenetic modifications (such as DNA methylation-DNAm) are potential influences on a range of health outcomes. Here, we explored the association between DNAm and daytime sleepiness quantified by the Epworth Sleepiness Scale (ESS). Methods:We performed multi-ethnic and ethnic-specific epigenome-wide association studies for DNAm and ESS in 619 individuals from the Multi-Ethnic Study of Atherosclerosis. Replication was assessed in the Cardiovascular Health Study (CHS). Genetic variants in genes proximal to ESS-associated DNAm were analyzed to identify methylation quantitative trait loci and followed with replication of genotype-sleepiness associations in the UK Biobank.Results: 61 methylation sites were associated with ESS (FDR ≤ 0.1) in African Americans only, including an association in KCTD5, a gene strongly implicated in sleep. One association (cg26130090) replicated in CHS African Americans (p-value 0.0004). We identified a sleepinessassociated methylation site in the gene RAI1, a gene associated with sleep and circadian phenotypes. In a follow-up analysis, a genetic variant within RAI1 associated with both DNAm and sleepiness score. The variant's association with sleepiness was replicated in the UK Biobank. Conclusions:Our analysis identified methylation sites in multiple genes that may be implicated in EDS. These sleepiness-methylation associations were specific to African Americans. Future work is needed to identify mechanisms driving ancestry-specific methylation effects. 4Excessive daytime sleepiness is associated with negative health outcomes such as reduction in quality of life, increased workplace accidents, and cardiovascular mortality. There are race/ethnic disparities in excessive daytime sleepiness, however, the environmental and biological mechanisms for these differences are not yet understood. We performed an association analysis of DNA methylation, measured in monocytes, and daytime sleepiness within a racially diverse study population. We detected numerous DNA methylation markers associated with daytime sleepiness in African Americans, but not in European and Hispanic Americans. Future work is required to elucidate the pathways between DNA methylation, sleepiness, and related behavioral/environmental exposures. analysis using the lumi Bioconductor package 37 . These included color bias adjustments via smooth quantile normalization, median background adjustment, standard quantile adjustment, checks for potential sex or race mismatches, and outlier detection via multidimensional plots.Additional details on pre-processing of the DNAm data can be found in Liu et al 34 . Following DNAm preprocessing, each of 484,882 methylation probes for each person has a Beta-value, representing the proportion ...

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“…Persistent hypoxia can induce hypermethylation or demethylation of specific genes [24][25][26], while the impact of chronic intermittent hypoxia on DNA methylation remains uncertain. Previous studies [15,27] have found aberrant DNA methylations in several genes and might constitute an important determinant of disease severity and vulnerability to EDS in OSA. In addition, both TLR2/6 co-expressions on neutrophil and monocyte were increased either in OSA patients or with intermittent hypoxia with re-oxygenation treatment in vitro [16].…”

Section: Multivariate Linear Regressionmentioning

confidence: 94%

“…Although aberrant DNA methylation in the promoter regions of several inflammationrelated genes such as IL1R2 (interleukin 1 receptor 2), AR (androgen receptor), NPR2 (natriuretic peptide receptor 2), and SP140 (speckled protein 140) genes have been reported in patients with OSA [15], little is known about the role of DNA methylation over the TLR genes in the development of OSA and its clinical phenotypes. In our previous study, we found coupregulation of TLR 2 and 6 on peripheral blood neutrophils and mononuclear cells in patients with OSA, and these changes could be reversed after continuous positive airway pressure (CPAP) treatment [16,17].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Whole Genome DNA Methylation Analysis of Obstructive Sleep Apnea:IL1R2,NPR2,AR,SP140Methylation and Clinical Phenotype

Abstract: A commentary on this article appears in this issue on page 723.

Cited by 47 publications

References 49 publications

The family of the interleukin‐1 receptors

The family of the interleukin‐1 receptors

Epigenome-wide association analysis of daytime sleepiness in the Multi-Ethnic Study of Atherosclerosis reveals African-American specific associations

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

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