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Genetic Markers in Sleep Disorders
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Genetic Markers in Sleep Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (29 February 2020) | Viewed by 16135

Special Issue Editor

Prof. Dr. Abdelnaby Khalyfa

E-Mail Website
Guest Editor
Department of Child Health, Medical School, University of Missouri, Columbia, MO, USA
Interests: sleep-disordered; metabolic dysfunction; sleep-disordered breathing; cell biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Sleep is a fundamental physiological process with important restorative functions that are essential for optimal day-time functioning. Insufficient or poor-quality sleep has been associated with neurocognitive impairments, end-organ dysfunction, and chronic health conditions. Obstructive sleep apnea (OSA) is characterized by episodic partial or complete upper airway obstruction during sleep in association with loud snoring, altered gas exchange, and sleep fragmentation. OSA is associated with increased risk for morbidity and mortality affecting cardiovascular, metabolic, and neurocognitive systems, and more recently with non-alcoholic fatty liver disease (NAFLD) and cancer-related deaths, in which both genetic and environmental factors may be involved. Obesity is the strongest risk factor for OSA and is rooted in both environmental and genetic factors, varying significantly according to race. The definitive diagnosis of OSA currently requires an overnight polysomnographic evaluation in a sleep laboratory, and is, therefore, an onerous and labor-intensive procedure, such that delays in the timely diagnosis and treatment are frequent occurrences. Although much has been learned about the pathophysiology and consequences of adult and pediatric OSA in the last 40 years, the mechanisms and specific genes associated with such processes remain poorly defined. A challenge in the development of non-invasive diagnostic assays in body fluids is the ability to identify clinically relevant biomarkers. The proposal of this Special Issue is to understand and to identify a genetic marker that may contribute to sleep disorders in both adults and children and is gained either from singular or multiple markers. The information obtained by such a non a priori approach offers an extraordinary opportunity to fully characterize biological processes in terms of pathophysiology and health outcomes.

You may choose our Joint Special Issue in Clocks & Sleep.

Prof. Dr. Abdelnaby Khalyfa
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

  • Sleep disorders
  • Genetic markers
  • Obstructive sleep apnea (OSA)
  • Obesity
  • Cardiovascular disease
  • Metabolic dysfunction
  • Neurocognitive deficits

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Published Papers (3 papers)

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Research

24 pages, 2056 KiB  
Article
Transcriptomic Changes of Murine Visceral Fat Exposed to Intermittent Hypoxia at Single Cell Resolution
by Abdelnaby Khalyfa, Wesley Warren, Jorge Andrade, Christopher A. Bottoms, Edward S. Rice, Rene Cortese, Leila Kheirandish-Gozal and David Gozal
Int. J. Mol. Sci. 2021, 22(1), 261; https://doi.org/10.3390/ijms22010261 - 29 Dec 2020
Cited by 8 | Viewed by 4569
Abstract
Intermittent hypoxia (IH) is a hallmark of obstructive sleep apnea (OSA) and induces metabolic dysfunction manifesting as inflammation, increased lipolysis and insulin resistance in visceral white adipose tissues (vWAT). However, the cell types and their corresponding transcriptional pathways underlying these functional perturbations are [...] Read more.
Intermittent hypoxia (IH) is a hallmark of obstructive sleep apnea (OSA) and induces metabolic dysfunction manifesting as inflammation, increased lipolysis and insulin resistance in visceral white adipose tissues (vWAT). However, the cell types and their corresponding transcriptional pathways underlying these functional perturbations are unknown. Here, we applied single nucleus RNA sequencing (snRNA-seq) coupled with aggregate RNA-seq methods to evaluate the cellular heterogeneity in vWAT following IH exposures mimicking OSA. C57BL/6 male mice were exposed to IH and room air (RA) for 6 weeks, and nuclei from vWAT were isolated and processed for snRNA-seq followed by differential expressed gene (DEGs) analyses by cell type, along with gene ontology and canonical pathways enrichment tests of significance. IH induced significant transcriptional changes compared to RA across 14 different cell types identified in vWAT. We identified cell-specific signature markers, transcriptional networks, metabolic signaling pathways, and cellular subpopulation enrichment in vWAT. Globally, we also identify 298 common regulated genes across multiple cellular types that are associated with metabolic pathways. Deconvolution of cell types in vWAT using global RNA-seq revealed that distinct adipocytes appear to be differentially implicated in key aspects of metabolic dysfunction. Thus, the heterogeneity of vWAT and its response to IH at the cellular level provides important insights into the metabolic morbidity of OSA and may possibly translate into therapeutic targets. Full article
(This article belongs to the Special Issue Genetic Markers in Sleep Disorders)
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25 pages, 2791 KiB  
Article
Circulating Exosomal miRNAs Signal Circadian Misalignment to Peripheral Metabolic Tissues
by Abdelnaby Khalyfa, Shobhan Gaddameedhi, Elena Crooks, Chunling Zhang, Yan Li, Zhuanhong Qiao, Wojciech Trzepizur, Steve A. Kay, Jorge Andrade, Brieann C. Satterfield, Devon A. Hansen, Leila Kheirandish-Gozal, Hans P. A. Van Dongen and David Gozal
Int. J. Mol. Sci. 2020, 21(17), 6396; https://doi.org/10.3390/ijms21176396 - 3 Sep 2020
Cited by 27 | Viewed by 7690
Abstract
Night shift work increases risk of metabolic disorders, particularly obesity and insulin resistance. While the underlying mechanisms are unknown, evidence points to misalignment of peripheral oscillators causing metabolic disturbances. A pathway conveying such misalignment may involve exosome-based intercellular communication. Fourteen volunteers were assigned [...] Read more.
Night shift work increases risk of metabolic disorders, particularly obesity and insulin resistance. While the underlying mechanisms are unknown, evidence points to misalignment of peripheral oscillators causing metabolic disturbances. A pathway conveying such misalignment may involve exosome-based intercellular communication. Fourteen volunteers were assigned to a simulated day shift (DS) or night shift (NS) condition. After 3 days on the simulated shift schedule, blood samples were collected during a 24-h constant routine protocol. Exosomes were isolated from the plasma samples from each of the blood draws. Exosomes were added to naïve differentiated adipocytes, and insulin-induced pAkt/Akt expression changes were assessed. ChIP-Seq analyses for BMAL1 protein, mRNA microarrays and exosomal miRNA arrays combined with bioinformatics and functional effects of agomirs and antagomirs targeting miRNAs in NS and DS exosomal cargo were examined. Human adipocytes treated with exosomes from the NS condition showed altered Akt phosphorylation responses to insulin in comparison to those treated with exosomes from the DS condition. BMAL1 ChIP-Seq of exosome-treated adipocytes showed 42,037 binding sites in the DS condition and 5538 sites in the NS condition, with a large proportion of BMAL1 targets including genes encoding for metabolic regulators. A significant and restricted miRNA exosomal signature emerged after exposure to the NS condition. Among the exosomal miRNAs regulated differentially after 3 days of simulated NS versus DS, proof-of-concept validation of circadian misalignment signaling was demonstrated with hsa-mir-3614-5p. Exosomes from the NS condition markedly altered expression of key genes related to circadian rhythm in several cultured cell types, including adipocytes, myocytes, and hepatocytes, along with significant changes in 29 genes and downstream gene network interactions. Our results indicate that a simulated NS schedule leads to changes in exosomal cargo in the circulation. These changes promote reduction of insulin sensitivity of adipocytes in vitro and alter the expression of core clock genes in peripheral tissues. Circulating exosomal miRNAs may play an important role in metabolic dysfunction in NS workers by serving as messengers of circadian misalignment to peripheral tissues. Full article
(This article belongs to the Special Issue Genetic Markers in Sleep Disorders)
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12 pages, 2490 KiB  
Article
Forkhead Box P3 Methylation and Expression in Men with Obstructive Sleep Apnea
by David Sanz-Rubio, Arianne Sanz, Luis Varona, Rosa Bolea, Marta Forner, Ana V. Gil, Pablo Cubero, Marta Marin-Oto, Inmaculada Martin-Burriel and Jose M. Marin
Int. J. Mol. Sci. 2020, 21(6), 2233; https://doi.org/10.3390/ijms21062233 - 23 Mar 2020
Cited by 7 | Viewed by 3128
Abstract
Background: Epigenetic changes in obstructive sleep apnea (OSA) have been proposed as a mechanism for end-organ vulnerability. In children with OSA, Forkhead Box P3 (FOXP3) DNA methylation were associated with inflammatory biomarkers; however, the methylation pattern and its effect in the expression of [...] Read more.
Background: Epigenetic changes in obstructive sleep apnea (OSA) have been proposed as a mechanism for end-organ vulnerability. In children with OSA, Forkhead Box P3 (FOXP3) DNA methylation were associated with inflammatory biomarkers; however, the methylation pattern and its effect in the expression of this gene have not been tested in adults with OSA. Methods: Plasma samples from subjects without comorbid conditions other than OSA were analyzed (the Epigenetics Status and Subclinical Atherosclerosis in Obstructive Sleep Apnea (EPIOSA) Study: NCT02131610). In 16 patients with severe OSA (Apnea-Hypopnea Index—AHI- > 30 events/h) and seven matched controls (AHI < 5), methylation of FOXP3 gen was evaluated by PCR of the promoter and by pyrosequencing of the intron 1 Treg-specific demethylated region (TSDR). In another 74 patients with OSA (AHI > 10) and 31 controls, we quantified FOXP3 protein expression by ELISA and gene expression by quantitative real-time PCR. C-reactive protein (CRP) and plasma Treg cells were also evaluated. Results: Neither the levels of the promoter nor the TSDR demethylated region were different between controls and patients with OSA, whether they were grouped by normal or high CRP. FOXP3 protein and mRNA expression did not differ between groups. Conclusions: FOXP3 methylation or its expression is not altered in adults with OSA, whatever their inflammatory status. Full article
(This article belongs to the Special Issue Genetic Markers in Sleep Disorders)
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