Objective: Adolescence is a developmental stage of critical changes in sleep and its circadian timing when the contribution of abnormal sleep variability (amount) and sleep regularity (timing) to obesity and its associated adverse cardiometabolic health outcomes appears to increase. The aim of this study was to summarize findings from studies conducted in adolescents examining both sleep variability and regularity in relation to obesity and cardiometabolic health. Gaps in research and potential causal pathways that future studies should examine are highlighted. Results: Nightly deviations in sleep duration and sleep midpoint appear to contribute to the development of obesity and associated adverse cardiometabolic outcomes in youth. Studies show that increased sleep variability and irregularity are associated with obesity, decreased physical activity, dysregulated eating and inadequate diet, metabolic dysfunction, impaired cardiac autonomic balance, and elevated blood pressure in adolescents. Conclusions: A stable circadian timing of sleep is essential to the overall physical well-being of youth. Emerging evidence supports that sleep variability and circadian misalignment, including sleep irregularity, contribute to adverse obesity-related health outcomes early on in adolescence. Future studies should focus on the underlying behavioral and biological mechanisms in the causal pathway between day-to-day deviations in the amount and timing of sleep and obesity.
Introduction Adolescence is associated with a delay in the circadian timing of sleep. However, social factors prevent adolescents from adapting to a later sleep-wake pattern, leading to different forms of circadian misalignment that may increase the risk of cardiovascular and mental health disorders. Several GWAS have identified genes associated with sleep and circadian phenotypes, however, little is known regarding the epigenetic basis and significance of sleep timing and its regularity in adolescence. Methods We analyzed data from 230 adolescents from the Penn State Child Cohort follow-up study who provided a blood sample for DNA extraction and had complete at-home 7-night (at least 3) actigraphy (ACT) data. ACT-measured sleep midpoint was calculated as the intra-individual mean of the 7-night midpoint (zeroed to midnight) of the sleep period. ACT-measured sleep regularity was calculated as the intra-individual standard deviation of the 7-night sleep midpoint. Epigenome-wide single nucleotide resolution of DNA methylation in cytosine-phosphate-guanine (CpG) sites and surrounding regions were obtained from peripheral leukocytes. This study focuses on methylation sites in GWAS-informed genes previously associated with sleep and circadian phenotypes. Linear regression assessed the association between sleep midpoint and sleep regularity with site-specific methylation levels, adjusting for sex, age, race/ethnicity, body mass index, and psychotropic medication use. Using the Benjamini & Hochberg method to adjust for a false discovery rate. Adjusted p-values are reported as q-values. Results Sleep midpoint was not associated with a significant change in methylation at any of the measured intragenic sites. Sleep regularity was significantly associated with differential methylation at 238 intragenic sites in 147 genes with an adjusted p<0.05, of which, three sites were within GWAS-informed sleep/circadian-related genes. Higher sleep irregularity was associated with hypermethylation in MAD1L1 (q=2.4x10-2) and with hypomethylation in CALN1 (q=3.8 x 10-4) and ZNF618 (q=3.8 x 10-2). Conclusion Sleep irregularity is associated with altered DNA methylation in genes previously identified in GWAS of sleep/circadian phenotypes. Our data provides evidence for a potential epigenetic link between sleep irregularity and genes involved in neurocognitive functioning (CALN1), internalizing disorders (MAD1L1) and blood pressure (ZNF618). Support (If Any) National Institutes of Health (R01HL136587, R01MH118308, UL1TR000127)
Introduction: Although obesity, insufficient sleep and sleep apnea are known risk factors for elevated blood pressure, the circadian timing of sleep is also involved in metabolic and blood pressure regulation. As a result, sleep irregularity, which is highly prevalent in adolescents, may be a potential risk factor for obesity-related adverse cardiovascular outcomes. Hypothesis: We hypothesize that greater sleep irregularity increases the impact of visceral adiposity on elevated blood pressure in adolescents. Methods: We analyzed cross-sectional data from the Penn State Child Cohort follow-up study, a random population-based sample of 303 adolescents (16.2 ± 2.2 year old; 47.5% female; 21.5% racial/ethnic minority) who had complete at-home 7-night (at least 5) actigraphy (ACT) data and in-lab dual-energy X-ray absorptiometry (DEXA) scan and polysomnography (PSG) data. ACT-measured sleep duration and sleep midpoint were calculated as the intra-individual mean of the 7-night total sleep time and the midpoint (zeroed to midnight) of the sleep period, respectively. ACT-measured sleep regularity was calculated as the intra-individual standard deviation of the 7-night sleep midpoint. DEXA-measured visceral adipose tissue (VAT) was the primary predictor. Systolic (SBP) and diastolic (DBP) blood pressure, measured three times in the seated position, were the primary outcomes. Multivariable linear regression models tested sleep midpoint and sleep regularity as effect modifiers of VAT on SBP/DBP levels, while simultaneously adjusting for sex, race/ethnicity, age, ACT-measured sleep duration and PSG-measured apnea/hypopnea index. Results: Significant interactions were found between sleep regularity and VAT on SBP (p-interaction=0.009) and DBP (p-interaction=0.039), while not between mean sleep midpoint and VAT (p-interactions=0.210 and 0.883). These findings remained valid even after further adjusting for body mass index percentile (p-interactions=0.006 and 0.034). Among adolescents with high sleep irregularity (≥ 45 minutes; n=124), each standard deviation increase in VAT was associated with a 5.55 (0.91) and 3.07 (0.70) mmHg increase in SBP and DBP, respectively (both p<0.001). Among those with low sleep irregularity (< 45 minutes; n=179) VAT was not significantly associated with SBP [0.69 (0.99), p=0.488] or DBP [0.04 (0.77), p=0.956]. Conclusions: An irregular circadian timing of sleep may increase the impact of visceral adiposity on elevated blood pressure in adolescents. These data support that sleep irregularity, independent of sleep apnea and insufficient sleep, may contribute to the development of cardiovascular sequelae associated with central obesity.
Introduction The circadian timing of sleep, including its variability, has emerged as an important contributor to obesity and cardiovascular health, such as elevated blood pressure. Adolescence is a particularly vulnerable period for circadian misalignment, which may express differently if youth are in school or on free-days. We examined whether deviations in sleep midpoint increase the impact of visceral adiposity on elevated blood pressure in adolescents as a function of being entrained to school or not. Methods We analyzed cross-sectional data from the Penn State Child Cohort follow-up study, a random population-based sample of 303 adolescents (16.2 ± 2.2 y; 47.5% female; 21.5% minority). Actigraphy-measured sleep midpoint was calculated as the midpoint (zeroed to midnight) of the sleep period for weekdays (5-nights) and weekends (2-nights). Actigraphy-measured sleep regularity was calculated as the intra-individual standard deviation of the 5-night weekdays sleep midpoint. Visceral adipose tissue (VAT) was measured via dual-energy X-ray absorptiometry scan. Systolic (SBP) and diastolic (DBP) blood pressure was measured three times in the seated position. Multivariable linear regression models were stratified by “in school” and “on break” to test sleep midpoint and sleep regularity as effect modifiers of VAT on SBP/DBP levels. Analyses were adjusted for sex, race/ethnicity, age, actigraphy-measured sleep duration and polysomnography-measured apnea/hypopnea index. Results When participants were studied while “in school”, significant interactions were found between VAT and weekdays sleep midpoint on SBP (p-interaction=0.027) and DBP (p-interaction=0.046), so that the later the sleep midpoint on school days, the greater the association of VAT with SBP/DBP. When participants were studied while “on break”, a significant interaction was found between VAT and weekdays sleep regularity on SBP (p-interaction=0.039), so that the higher the sleep irregularity on weekdays, the greater the association of VAT with SBP. No other significant interactions were found. Conclusion A delayed and an irregular sleep midpoint during school days and during breaks, respectively, best identified those adolescents with greater cardiovascular risk associated with visceral obesity. These data suggest that not only the circadian timing of sleep contributes to adverse cardiovascular outcomes but its distinct biomarkers require measurement under different entrainment conditions in adolescents. Support (If Any) National Institutes of Health (R01HL136587, UL1TR000127)
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