Older adults at greater risk for Alzheimer's disease show stronger associations between sleep apnea severity in REM sleep and verbal memory.

BACKGROUND: Obstructive sleep apnea (OSA) increases risk for cognitive decline and Alzheimer's disease (AD). While the underlying mechanisms remain unclear, hypoxemia during OSA has been implicated in cognitive impairment. OSA during rapid eye movement (REM) sleep is usually more severe than in non-rapid eye movement (NREM) sleep, but the relative effect of oxyhemoglobin desaturation during REM versus NREM sleep on memory is not completely characterized. Here, we examined the impact of OSA, as well as the moderating effects of AD risk factors, on verbal memory in a sample of middle-aged and older adults with heightened AD risk. METHODS: Eighty-one adults (mean age:61.7 ± 6.0 years, 62% females, 32% apolipoprotein E ε4 allele (APOE4) carriers, and 70% with parental history of AD) underwent clinical polysomnography including assessment of OSA. OSA features were derived in total, NREM, and REM sleep. REM-NREM ratios of OSA features were also calculated. Verbal memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT). Multiple regression models evaluated the relationships between OSA features and RAVLT scores while adjusting for sex, age, time between assessments, education years, body mass index (BMI), and APOE4 status or parental history of AD. The significant main effects of OSA features on RAVLT performance and the moderating effects of AD risk factors (i.e., sex, age, APOE4 status, and parental history of AD) were examined. RESULTS: Apnea-hypopnea index (AHI), respiratory disturbance index (RDI), and oxyhemoglobin desaturation index (ODI) during REM sleep were negatively associated with RAVLT total learning and long-delay recall. Further, greater REM-NREM ratios of AHI, RDI, and ODI (i.e., more events in REM than NREM) were related to worse total learning and recall. We found specifically that the negative association between REM ODI and total learning was driven by adults 60 + years old. In addition, the negative relationships between REM-NREM ODI ratio and total learning, and REM-NREM RDI ratio and long-delay recall were driven by APOE4 carriers. CONCLUSION: Greater OSA severity, particularly during REM sleep, negatively affects verbal memory, especially for people with greater AD risk. These findings underscore the potential importance of proactive screening and treatment of REM OSA even if overall AHI appears low.

The role of lncRNAs in intermittent hypoxia and sleep Apnea: A review of experimental and clinical evidence.

In this narrative review, we present a comprehensive assessment on the putative roles of long non-coding RNAs (lncRNAs) in intermittent hypoxia (IH) and sleep apnea. Collectively, the evidence from cell culture, animal, and clinical research studies points to the functional involvement of lncRNAs in the pathogenesis, diagnosis, and potential treatment strategies for this highly prevalent disorder. Further research is clearly warranted to uncover the mechanistic pathways and to exploit the therapeutic potential of lncRNAs, thereby improving the management and outcomes of patients suffering from sleep apnea.

Causal relationship between sleep apnea and non-alcoholic fatty liver disease: A Mendelian randomization study.

BACKGROUND: Observational studies indicate that sleep apnea is associated with non-alcoholic fatty liver disease (NAFLD) and its related metabolic features, independent of confounding factors including obesity. However, the causal relationships remain to be determined. METHODS: Univariable and multivariable Mendelian randomization (MR) analyses were performed to investigate the causal relationship between sleep apnea and NAFLD, along with its typical features including liver function, glycemic traits and lipid profiles. Summary-level data for sleep apnea were obtained from the Finngen consortium (33,423 cases and 307,648 controls). Summary-level data for NAFLD were available from a GWAS meta-analysis (8434 cases and 770,180 controls), and data for 12 NAFLD-related features from corresponding published GWASs. The inverse variance weighted (IVW) analysis was employed as the primary statistical method. Bidirectional MR and CAUSE analysis were conducted to avoid reverse causality and false positive findings. RESULTS: In univariable MR analyses, we found evidence to support a causal effect of genetically predicted sleep apnea on NAFLD (OR = 1.50, 95% CI = 1.18-1.91) and HDL-C (ß = -0.045, 95% CI = -0.090 to -0.001). In reverse MR, genetically predicted serum TG was associated with an increased risk of sleep apnea (OR = 1.07, 95% CI = 1.02-1.12), while genetically predicted HDL-C was associated with a decreased risk of sleep apnea (OR = 0.93, 95% CI = 0.89-0.98). After adjusting body mass index or educational attainment, none of these causal associations were retained. However, CAUSE method and MR analyses focusing on lipoprotein subfractions supported a causal effect of sleep apnea on HDL-C and HDL subfractions. CONCLUSION: This MR study indicated that sleep apnea has no direct causal association with NAFLD, elevated liver enzymes and insulin resistance. Our results showed suggestive inverse associations of genetically predicted sleep apnea on HDL-C and HDL subfractions, indicating that both HDL-C levels and HDL function may be causally implicated in sleep apnea.

Heritability and genetic correlations for sleep apnea, insomnia, and hypersomnia in a large clinical biobank.

RATIONALE: Comorbid insomnia and sleep apnea is reported to have worse outcomes than either condition alone. The local genetic correlations of these disorders are unknown. OBJECTIVES: To identify local genomic regions with heritability for clinically diagnosed sleep apnea and insomnia, and to identify local genetic correlations between these disorders and/or hypersomnia. METHODS: Fifty thousand two hundred seventeen patients of European ancestry were examined. Global and local heritability and genetic correlations for independent regions were calculated, adjusting for obesity and other covariates. RESULTS: Sleep apnea and insomnia were significantly globally heritable and had 118 and 168 genetic regions with local heritability p-values <.05, respectively. One region had a significant genetic correlation for sleep apnea and hypersomnia (p-value = 9.85 × 10-4). CONCLUSIONS: Clinically diagnosed sleep apnea and insomnia have minimal shared genetic architecture, supporting genetically distinct comorbid insomnia and sleep apnea components. However, additional correlated regions may be identified with additional sample size and methodological improvements.

Identification of novel proteins for sleep apnea by integrating genome-wide association data and human brain proteomes.

BACKGROUND: Sleep apnea is regarded as a significant global public health issue. The relationship between sleep apnea and nervous system diseases is intricate, yet the precise mechanism remains unclear. METHODS: In this study, we conducted a comprehensive analysis integrating the human brain proteome and transcriptome with sleep apnea genome-wide association study (GWAS), employing genome-wide association study (PWAS), transcriptome-wide association study (TWAS), Mendelian randomization (MR), and colocalization analysis to identify brain proteins associated with sleep apnea. RESULTS: The discovery PWAS identified six genes (CNNM2, XRCC6, C3orf18, CSDC2, SQRDL, and DGUOK) whose altered protein abundances in the brain were found to be associated with sleep apnea. The independent confirmatory PWAS successfully replicated four out of these six genes (CNNM2, C3orf18, CSDC2, and SQRDL). The transcriptome level TWAS analysis further confirmed two out of the four genes (C3orf18 and CSDC2). The subsequent two-sample Mendelian randomization provided compelling causal evidence supporting the association of C3orf18, CSDC2, CNNM2, and SQRDL with sleep apnea. The co-localization analysis further supported the association between CSDC2 and sleep apnea (posterior probability of hypothesis 4 = 0.75). CONCLUSIONS: In summary, the integration of brain proteomic and transcriptomic data provided multifaceted evidence supporting causal relationships between four specific brain proteins (CSDC2, C3orf18, CNNM2, and SQRDL) and sleep apnea. Our findings provide new insights into the molecular basis of sleep apnea in the brain, promising to advance understanding of its pathogenesis in future research.

An integrated multi-omics analysis of sleep-disordered breathing traits implicates P2XR4 purinergic signaling.

Sleep Disordered Breathing (SDB) is a common disease associated with increased risk for cardiometabolic, cardiovascular, and cognitive diseases. How SDB affects the molecular environment is still poorly understood. We study the association of three SDB measures with gene expression measured using RNA-seq in multiple blood tissues from the Multi-Ethnic Study of Atherosclerosis. We develop genetic instrumental variables for the associated transcripts as polygenic risk scores (tPRS), then generalize and validate the tPRS in the Women's Health Initiative. We measure the associations of the validated tPRS with SDB and serum metabolites in Hispanic Community Health Study/Study of Latinos. Here we find differential gene expression by blood cell type in relation to SDB traits and link P2XR4 expression to average oxyhemoglobin saturation during sleep and butyrylcarnitine (C4) levels. These findings can be used to develop interventions to alleviate the effect of SDB on the human molecular environment.

Gain-of-function mutations in KCNK3 cause a developmental disorder with sleep apnea.

Sleep apnea is a common disorder that represents a global public health burden. KCNK3 encodes TASK-1, a K+ channel implicated in the control of breathing, but its link with sleep apnea remains poorly understood. Here we describe a new developmental disorder with associated sleep apnea (developmental delay with sleep apnea, or DDSA) caused by rare de novo gain-of-function mutations in KCNK3. The mutations cluster around the 'X-gate', a gating motif that controls channel opening, and produce overactive channels that no longer respond to inhibition by G-protein-coupled receptor pathways. However, despite their defective X-gating, these mutant channels can still be inhibited by a range of known TASK channel inhibitors. These results not only highlight an important new role for TASK-1 K+ channels and their link with sleep apnea but also identify possible therapeutic strategies.

Self-reported symptoms of sleep-disordered breathing and risk of cardiovascular diseases: Observational and Mendelian randomization findings.

Sleep-disordered breathing may increase the risk of cardiovascular diseases, but observational findings are inconclusive. We investigated whether sleep-disordered breathing-related symptoms are associated with risk of several cardiovascular diseases using data from a cohort study and by performing Mendelian randomization analyses. The cohort study included 43,624 adults (56-94 years old) who completed questionnaires regarding symptoms of snoring and cessation of breathing, lifestyle habits and health characteristics. Participants were followed up for incident cardiovascular diseases and death over 8 years through linkage to the Swedish National Patient and Death Registers. The Mendelian randomization analyses were conducted using single-nucleotide polymorphisms robustly associated with sleep apnea in a recent genome-wide association study and summary-level data for major cardiovascular diseases from large-scale consortia. In the cohort study, an increased risk of atrial fibrillation was observed in participants who reported both snoring and cessation of breathing (hazard ratio [95% confidence interval] = 1.16 [1.03-1.30]) compared with those without sleep-disordered breathing symptoms. There was no association between sleep-disordered breathing symptoms and risk of myocardial infarction, heart failure, aortic valve stenosis or abdominal aortic aneurysm in multivariable analyses. Mendelian randomization analyses showed no association of genetic liability to sleep apnea with myocardial infarction, heart failure or atrial fibrillation, but revealed a suggestive association with coronary artery disease (odds ratio [95% confidence interval] = 1.24 [1.02-1.52]).

Analysis of nocturnal, hypoxia-induced miRNAs in sleep apnea patients.

INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is associated with an increased cardiovascular risk. The underlying mechanisms are largely unclear. MicroRNAs (miRNAs) are RNAs circulating in the blood that can be released into the bloodstream during hypoxia. In the present study, we investigate if OSAS-induced hypoxia results in a release of miRNAs that may mediate OSAS-associated cardiovascular damage. METHODS: Blood was sampled from 23 OSAS patients before and after a polygraphically monitored night. Total circulating RNA was isolated from the plasma and quantified using real-time qPCR. Using a Taqman miRNA array, the levels of 384 different miRNAs were compared between evening and morning after polysomnography. The most highly upregulated miRNA (miRNA-505) and four additionally upregulated miRNAs (miRNA-127, miRNA-133a, miRNA-145, and miRNA-181a) were then quantified in a bigger patient cohort individually. RESULTS: Apnea/Hypopnea-Index (AHI) was evaluated and averaged at 26 per hour on nocturnal polygraphy. In an initial miRNA array, a total of 4 miRNAs were significantly regulated. A significant increase of miRNA-145 was observed in the larger patient cohort. No significant changes in concentration were detected for miRNA-127, miRNA-133a, miRNA-181a, and miRNA-505 in this larger cohort. CONCLUSION: OSAS results in the nocturnal release of miRNAs into the bloodstream. Our collected data may indicate a hypoxia-induced release of miRNAs into the bloodstream of OSAS-patients. In vitro experiments are needed to confirm the secretion of these miRNAs under hypoxia and evaluate the effect on the cardio vasculature.

Sleep Disordered Breathing, Obesity and Atrial Fibrillation: A Mendelian Randomisation Study.

It remains unclear whether the association between obstructive sleep apnoea (OSA), a form of sleep-disordered breathing (SDB), and atrial fibrillation (AF) is causal or mediated by shared co-morbidities such as obesity. Existing observational studies are conflicting and limited by confounding and reverse causality. We performed Mendelian randomisation (MR) to investigate the causal relationships between SDB, body mass index (BMI) and AF. Single-nucleotide polymorphisms associated with SDB (n = 29) and BMI (n = 453) were selected as instrumental variables to investigate the effects of SDB and BMI on AF, using genetic association data on 55,114 AF cases and 482,295 controls. Primary analysis was conducted using inverse-variance weighted MR. Higher genetically predicted SDB and BMI were associated with increased risk of AF (OR per log OR increase in snoring liability 2.09 (95% CI 1.10-3.98), p = 0.03; OR per 1-SD increase in BMI 1.33 (95% CI 1.24-1.42), p < 0.001). The association between SDB and AF was not observed in sensitivity analyses, whilst associations between BMI and AF remained consistent. Similarly, in multivariable MR, SDB was not associated with AF after adjusting for BMI (OR 0.68 (95% CI 0.42-1.10), p = 0.12). Higher BMI remained associated with increased risk of AF after adjusting for OSA (OR 1.40 (95% CI 1.30-1.51), p < 0.001). Elevated BMI appears causal for AF, independent of SDB. Our data suggest that the association between SDB, in general, and AF is attributable to mediation or confounding from obesity, though we cannot exclude that more severe SDB phenotypes (i.e., OSA) are causal for AF.

Sleep-disordered breathing-related symptoms and risk of stroke: cohort study and Mendelian randomization analysis.

BACKGROUND: Sleep-disordered breathing (SDB) may contribute to development of stroke. However, findings are inconclusive. We investigated whether SDB-related symptoms are associated with incidence of stroke and its types in a general community sample of adult men and women as well as to perform Mendelian randomization (MR) analysis. METHODS: We used data from a cohort of 41,742 Swedish adults (56-94 years of age) who completed questionnaires regarding snoring, cessation of breathing, lifestyle and health characteristics. Participants were followed up for incident stroke and death over 8 years through linkage to the Swedish Registers. Hazard ratios, adjusted for potential confounders, were estimated by Cox proportional hazards regression. MR analyses were performed using single-nucleotide polymorphisms associated with sleep apnea at the genome-wide significance level and summary-level data for stroke and its subtypes from consortia and a meta-analysis of Genome-Wide Association Studies. RESULTS: In the cohort study, symptoms of disturbing snoring and/or cessation of breathing were associated with increased risk of total stroke (hazard ratio 1.12, 95% confidence interval 1.02-1.24) and intracerebral hemorrhage (hazard ratio 1.59, 95% confidence interval 1.23-2.05) but not with ischemic stroke or subarachnoid hemorrhage. MR analyses showed no association of genetic liability to sleep apnea with the risk of overall stroke or any specific types of stroke or ischemic stroke subtypes. CONCLUSIONS: SDB-related symptoms were associated with increased risk of total stroke, specifically intracerebral hemorrhage, in the observational analyses but not in the MR analyses. There was limited evidence of an association of SDB with ischemic stroke and subarachnoid hemorrhage.

H3K23/H3K36 hypoacetylation and HDAC1 up-regulation are associated with adverse consequences in obstructive sleep apnea patients.

The aim of this study is to determine the roles of global histone acetylation (Ac)/methylation (me), their modifying enzymes, and gene-specific histone enrichment in obstructive sleep apnea (OSA). Global histone modifications, and their modifying enzyme expressions were assessed in peripheral blood mononuclear cells from 56 patients with OSA and 16 matched subjects with primary snoring (PS). HIF-1α gene promoter-specific H3K36Ac enrichment was assessed in another cohort (28 OSA, 8 PS). Both global histone H3K23Ac and H3K36Ac expressions were decreased in OSA patients versus PS subjects. H3K23Ac expressions were further decreased in OSA patients with prevalent hypertension. HDAC1 expressions were higher in OSA patients, especially in those with excessive daytime sleepiness, and reduced after more than 6 months of continuous positive airway pressure treatment. H3K79me3 expression was increased in those with high C-reactive protein levels. Decreased KDM6B protein expressions were noted in those with a high hypoxic load, and associated with a higher risk for incident cardiovascular events or hypertension. HIF-1α gene promoter-specific H3K36Ac enrichment was decreased in OSA patients versus PS subjects. In vitro intermittent hypoxia with re-oxygenation stimuli resulted in HDAC1 over-expression and HIF-1α gene promoter-specific H3K36Ac under-expression, while HDAC1 inhibitor, SAHA, reversed oxidative stress through inhibiting NOX1. In conclusions, H3K23/H3K36 hypoacetylation is associated with the development of hypertension and disease severity in sleep-disordered breathing patients, probably through up-regulation of HDAC1, while H3K79 hypermethylation is associated with higher risk of cardiovascular diseases, probably through down-regulation of KDM6B.

Epigenetic Alterations in Pediatric Sleep Apnea.

Pediatric obstructive sleep apnea has significant negative effects on health and behavior in childhood including depression, failure to thrive, neurocognitive impairment, and behavioral issues. It is strongly associated with an increased risk for chronic adult disease such as obesity and diabetes, accelerated atherosclerosis, and endothelial dysfunction. Accumulating evidence suggests that adult-onset non-communicable diseases may originate from early life through a process by which an insult applied at a critical developmental window causes long-term effects on the structure or function of an organism. In recent years, there has been increased interest in the role of epigenetic mechanisms in the pathogenesis of adult disease susceptibility. Epigenetic mechanisms that influence adaptive variability include histone modifications, non-coding RNAs, and DNA methylation. This review will highlight what is currently known about the phenotypic associations of epigenetic modifications in pediatric obstructive sleep apnea and will emphasize the importance of epigenetic changes as both modulators of chronic disease and potential therapeutic targets.

Sleep disordered breathing in patients with Prader willi syndrome: Impact of underlying genetic mechanism.

INTRODUCTION: Sleep-disordered breathing (SDB) is common in children with PWS. In the current study, we aimed to evaluate the severity of SDB in patients with PWS using polysomnography (PSG), and assess the effect of the underlying genetic mechanism on PSG parameters. METHODS: Children with PWS, referred to our sleep laboratory between March 2016 and January 2020 were enrolled. PSG parameters, demographic data, body mass index (BMI), and symptoms related to SDB were recorded. The effect of non-invasive ventilation strategies and the outcome of therapy on PSG parameters were evaluated. RESULTS: In our study, 64.5% of the patients had severe sleep apnea syndrome (total apnea hypopnea index (AHI) ≥10 events/hour). 22.6% had significantly high (>5 events/hour) central sleep apnea. Patients with a deletion had significantly lower initial and mean SaO2, longer sleep time SaO2 under 90%, oxygen desaturation % and total AHI when compared to those with uniparental disomy. PSG parameters were similar between patients who did or didn't receive growth hormone treatment. CONCLUSION: The majority of the PWS patients had severe sleep apnea syndrome characterized mainly by hypopneas which were accompanied by central apneas. There was a more severe impact on oxygen parameters and total AHI in patients with deletions.

AT1a-dependent GABAA inhibition in the MnPO following chronic intermittent hypoxia.

Chronic intermittent hypoxia (CIH) is associated with diurnal hypertension, increased sympathetic nerve activity (SNA), and increases in circulating angiotensin II (ANG II). In rats, CIH increases angiotensin type 1 (AT1a) receptor expression in the median preoptic nucleus (MnPO), and pharmacological blockade or viral knockdown of this receptor prevents CIH-dependent increases in diurnal blood pressure. The current study investigates the role of AT1a receptor in modulating the activity of MnPO neurons following 7 days of CIH. Male Sprague-Dawley rats received MnPO injections of an adeno-associated virus with an shRNA against the AT1a receptor or a scrambled control. Rats were then exposed to CIH for 8 h a day for 7 days. In vitro, loose patch recordings of spontaneous action potential activity were made from labeled MnPO neurons in response to brief focal application of ANG II or the GABAA receptor agonist muscimol. In addition, MnPO K-Cl cotransporter isoform 2 (KCC2) protein expression was assessed using Western blot. CIH impaired the duration but not the magnitude of ANG II-mediated excitation in the MnPO. Both CIH and AT1a knockdown also impaired GABAA-mediated inhibition, and CIH with AT1a knockdown produced GABAA-mediated excitation. Recordings using the ratiometric Cl- indicator ClopHensorN showed CIH was associated with Cl- efflux in MnPO neurons that was associated with decreased KCC2 phosphorylation. The combination of CIH and AT1a knockdown attenuated reduced KCC2 phosphorylation seen with CIH alone. The current study shows that CIH, through the activity of AT1a receptors, can impair GABAA-mediated inhibition in the MnPO and contribute to sustained hypertension.