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      Partial Sleep Restriction Activates Immune Response-Related Gene Expression Pathways: Experimental and Epidemiological Studies in Humans

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          Abstract

          Epidemiological studies have shown that short or insufficient sleep is associated with increased risk for metabolic diseases and mortality. To elucidate mechanisms behind this connection, we aimed to identify genes and pathways affected by experimentally induced, partial sleep restriction and to verify their connection to insufficient sleep at population level. The experimental design simulated sleep restriction during a working week: sleep of healthy men (N = 9) was restricted to 4 h/night for five nights. The control subjects (N = 4) spent 8 h/night in bed. Leukocyte RNA expression was analyzed at baseline, after sleep restriction, and after recovery using whole genome microarrays complemented with pathway and transcription factor analysis. Expression levels of the ten most up-regulated and ten most down-regulated transcripts were correlated with subjective assessment of insufficient sleep in a population cohort (N = 472). Experimental sleep restriction altered the expression of 117 genes. Eight of the 25 most up-regulated transcripts were related to immune function. Accordingly, fifteen of the 25 most up-regulated Gene Ontology pathways were also related to immune function, including those for B cell activation, interleukin 8 production, and NF-κB signaling ( P<0.005). Of the ten most up-regulated genes, expression of STX16 correlated negatively with self-reported insufficient sleep in a population sample, while three other genes showed tendency for positive correlation. Of the ten most down-regulated genes, TBX21 and LGR6 correlated negatively and TGFBR3 positively with insufficient sleep. Partial sleep restriction affects the regulation of signaling pathways related to the immune system. Some of these changes appear to be long-lasting and may at least partly explain how prolonged sleep restriction can contribute to inflammation-associated pathological states, such as cardiometabolic diseases.

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          Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk.

          We sought to investigate the effects of sleep loss on high-sensitivity C-reactive protein (CRP) levels. Concentrations of high-sensitivity CRP are predictive of future cardiovascular morbidity. In epidemiologic studies, short sleep duration and sleep complaints have also been associated with increased cardiovascular morbidity. Two studies were undertaken to examine the effect of acute total and short-term partial sleep deprivation on concentrations of high-sensitivity CRP in healthy human subjects. In Experiment 1, 10 healthy adult subjects stayed awake for 88 continuous hours. Samples of high-sensitivity CRP were collected every 90 min for 5 consecutive days, encompassing the vigil. In Experiment 2, 10 subjects were randomly assigned to either 8.2 h (control) or 4.2 h (partial sleep deprivation) of nighttime sleep for 10 consecutive days. Hourly samples of high-sensitivity CRP were taken during a baseline night and on day 10 of the study protocol. The CRP concentrations increased during both total and partial sleep deprivation conditions, but remained stable in the control condition. Systolic blood pressure increased across deprivation in Experiment 1, and heart rate increased in Experiment 2. Both acute total and short-term partial sleep deprivation resulted in elevated high-sensitivity CRP concentrations, a stable marker of inflammation that has been shown to be predictive of cardiovascular morbidity. We propose that sleep loss may be one of the ways that inflammatory processes are activated and contribute to the association of sleep complaints, short sleep duration, and cardiovascular morbidity observed in epidemiologic surveys.
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            A prospective study of sleep duration and coronary heart disease in women.

            Long-term sleep deprivation is common in today's society. Recent experiments have demonstrated that short-term sleep deprivation in healthy subjects results in adverse physiologic changes, including a decreased glucose tolerance and an increased blood pressure. However, the long-term health consequences of long-term sleep deprivation are unclear. The objective of this study was to determine whether decreased sleep duration (from self-reports) is associated with an increased risk of coronary events. We studied a cohort of 71 617 US female health professionals (aged 45-65 years), without reported coronary heart disease (CHD) at baseline, who were enrolled in the Nurses' Health Study. Subjects were mailed a questionnaire in 1986 asking about daily sleep duration. Subjects were followed up until June 30, 1996, for the occurrence of CHD-related events. We assessed the relationship between self-reported sleep duration and incident CHD. A total of 934 coronary events were documented (271 fatal and 663 nonfatal) during the 10 years of follow up. Age-adjusted relative risks (95% confidence intervals) of CHD (with 8 hours of daily sleep being considered the reference group) for individuals reporting 5 or fewer, 6, and 7 hours of sleep were 1.82 (1.34-2.41), 1.30 (1.08-1.57), and 1.06 (0.89-1.26), respectively. The relative risk (95% confidence interval) for 9 or more hours of sleep was 1.57 (1.18-2.11). After adjusting for various potential confounders, including snoring, body mass index, and smoking, the relative risks of CHD (95% confidence intervals) for individuals reporting 5 or fewer, 6, and 7 hours of sleep were 1.45 (1.10-1.92), 1.18 (0.98-1.42), and 1.09 (0.91-1.30), respectively. The relative risk (95% confidence interval) for 9 or more hours of sleep was 1.38 (1.03-1.86). Short and long self-reported sleep durations are independently associated with a modestly increased risk of coronary events.
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              Adverse effects of modest sleep restriction on sleepiness, performance, and inflammatory cytokines.

              Total sleep restriction in humans is associated with increased daytime sleepiness, decreased performance, and hormonal/metabolic disturbances. The effects of mild chronic sleep restriction that mimic real life are not known. To assess the effects of modest sleep restriction from 8 to 6 h/night for 1 wk, 25 young, healthy, normal sleepers (12 men and 13 women) were studied for 12 consecutive nights in the sleep laboratory. After 1 wk of sleep restriction, although subjects' nighttime sleep was deeper, subjects were significantly sleepier (multiple sleep latency test) and performed worse in four primary variables of psychomotor vigilance test (both P < 0.01). Furthermore, 24-h secretion of IL-6 was increased by 0.8 +/- 0.3 pg/ml (P < 0.05) in both sexes, whereas TNFalpha was increased only in men. Also, the peak cortisol secretion was lower after sleep restriction than at baseline, and this difference was stronger in men (55.18 +/- 24.83 nmol/liter; P < 0.05) than in women (35.87 +/- 24.83 nmol/liter; P < 0.16). We conclude that in young men and women, modest sleep loss is associated with significant sleepiness, impairment of psychomotor performance, and increased secretion of proinflammatory cytokines. Given the potential association of these behavioral and physical alterations with health, well-being, and public safety, the idea that sleep or parts of it are optional should be regarded with caution.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                23 October 2013
                : 8
                : 10
                : e77184
                Affiliations
                [1 ]Department of Physiology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland
                [2 ]Department of Molecular Medicine, National Institute for Health and Welfare, Helsinki, Finland
                [3 ]FIMM, Finnish Institute of Molecular Medicine, Helsinki, Finland
                [4 ]Department of Psychiatry, HUCH, Helsinki, Finland
                [5 ]Research Programs Unit, Genome-Scale Biology & Institute of Biomedicine, University of Helsinki, Helsinki, Finland
                [6 ]Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland
                [7 ]Centre of Expertise for Human Factors at Work, Finnish Institute of Occupational Health, Helsinki, Finland
                [8 ]Stress Research Institute, Stockholm University, Stockholm, Sweden
                [9 ]Unit of Systems Toxicology, Centre of Expertise for Health and Work Ability, Finnish Institute of Occupational Health, Helsinki, Finland
                [10 ]Department of Medical Epidemiology & Biostatistics, Karolinska Institute, Stockholm, Sweden
                [11 ]Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom
                [12 ]Agora Center, University of Jyväskylä, Jyväskylä, Finland
                Université de Montréal, Canada
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: TPH MH MS. Performed the experiments: VA HMO WMAvL ML. Analyzed the data: VA HMO VR EK WMAvL ML IS. Contributed reagents/materials/analysis tools: VS. Wrote the paper: VA HMO TPH. Provided expertise for data analysis and interpretation: SR EK SM VS MJ HA TP.

                Article
                PONE-D-13-15147
                10.1371/journal.pone.0077184
                3806729
                24194869
                adf86708-9002-447a-8dc5-8cdcefcf7205
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 11 April 2013
                : 30 August 2013
                Page count
                Pages: 12
                Funding
                The authors gratefully acknowledge support for this work from the EU (LSHM-CT-2005-518189 and QLK6-CT-2000-00499), Finska Läkaresällskapet, and the Finnish Work Environment Fund (to VA), the Instrumentarium Foundation, the Jalmari and Rauha Ahokas Foundation, the Biomedicum Helsinki Foundation, the Emil Aaltonen Foundation, Finnish foundation for Cardiovascular research, the Paavo Nurmi Foundation, the Finnish Brain Foundation, and the GPBM graduate school (to HMO), the Marie Curie ESRS project (046036) (to WvL), the Academy of Finland Center of Excellence in Complex Disease Genetics (213506 and 129680) (to SR), the Sigrid Juselius Foundation (to SR and TP), and the Academy of Finland (251217 to SR, 129494 and 139635 to VS, and 137575 to TPH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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