The interplay between X-chromosome functional dosage and circadian regulation in females.

PURPOSE: Biological factors and mechanisms that drive higher prevalence of insomnia in females are poorly understood. This study focused on the neurological consequences of X-chromosome functional imbalances between sexes. METHODS: Benefited from publicly available large-scale genetic, transcriptional and epigenomic data, we curated and contrasted different gene lists: (1) X-liked genes, including assignments for X-chromosome inactivation patterns and disease associations; (2) sleep-associated genes; (3) gene expression markers for the suprachiasmatic nucleus. RESULTS: We show that X-linked markers for the suprachiasmatic nucleus are significantly enriched for clinically relevant genes in the context of rare genetic syndromes and brain waves modulation. CONCLUSION: Considering female-specific patterns on brain transcriptional programs becomes essential when designing health care strategies for mental and sleep illnesses with sex bias in prevalence.

Shared genetic mechanisms underlying association between sleep disturbances and depressive symptoms.

OBJECTIVES: Polygenic scores (PGS) for sleep disturbances and depressive symptoms in an epidemiological cohort were contrasted. The overlap between genes assigned to variants that compose the PGS predictions was tested to explore the shared genetic bases of sleep problems and depressive symptoms. METHODS: PGS analysis was performed on the São Paulo Epidemiologic Sleep Study (EPISONO, N = 1042), an adult epidemiological sample. A genome wide association study (GWAS) for depression grounded the PGS calculations for Beck Depression Index (BDI), while insomnia GWAS based the PGS for Insomnia Severity Index (ISI) and Pittsburg Sleep Quality Index (PSQI). Pearson's correlation was applied to contrast PGS and clinical scores. Fisher's Exact and Benjamin-Hochberg tests were used to verify the overlaps between PGS-associated genes and the pathways enriched among their intersections. RESULTS: All PGS models were significant when individuals were divided as cases or controls according to BDI (R2 = 1.2%, p = 0.00026), PSQI (R2 = 3.3%, p = 0.007) and ISI (R2 = 3.4%, p = 0.021) scales. When clinical scales were used as continuous variables, the PGS models for BDI (R2 = 1.5%, p = 0.0004) and PSQI scores (R2 = 3.3%, p = 0.0057) reached statistical significance. PSQI and BDI scores were correlated, and the same observation was applied to their PGS. Genes assigned to variants that compose the best-fit PGS predictions for sleep quality and depressive symptoms were significantly overlapped. Pathways enriched among the intersect genes are related to synapse function. CONCLUSIONS: The genetic bases of sleep quality and depressive symptoms are correlated; their implicated genes are significantly overlapped and converge on neural pathways. This data suggests that sleep complaints accompanying depressive symptoms are not secondary issues, but part of the core mental illness.

Homocysteine as a predictor of apnea-hypopnea index in obstructive sleep apnea: a longitudinal epidemiological study (EPISONO).

BACKGROUND: Obstructive sleep apnea (OSA) affects nearly 1 billion people globally, and has established links with cardiovascular and neurocognitive complications. Although it has some limitations, the apnea-hypopnea index (AHI) is commonly used to gauge OSA severity and therapeutic response. Homocysteine (Hcy) metabolism, when impaired, can elicit cellular senescence mechanisms that may be shared with OSA. Hence, our objective was to explore the role of Hcy concentrations both as a predictor of AHI values and as a potential risk factor for OSA. METHODS: Involving 1042 volunteers aged 20 to 80 years, the initial study (2007) included polysomnographic evaluations, questionnaires on sleep and general health, as well as biochemical analyses. After an 8-year interval, 715 participants from the initial study were invited for a follow-up assessment in 2015. RESULTS: Our findings showed that Hcy was a predictor for an increased AHI, and AHI increased over time. Individuals with plasma Hcy concentrations ≥ 15 µmol/L experienced an average AHI increase of 7.43 events/hour ([beta coefficient] ß = 7.43; 95%CI 2.73 to 12.13) over time, compared to those with plasma concentrations < 10 µmol/L. A similar trend was apparent in those with plasma Hcy concentrations between 10 ≥ and < 15 µmol/L, who had an AHI increase with an average beta coefficient of 3.20 events/hour (95%CI 1.01 to 5.39) compared to those with plasma Hcy concentrations < 10 µmol/L. CONCLUSIONS: In summary, our study suggests that increased plasma Hcy concentrations could be considered a risk factor for the development of OSA. These findings highlight that elevated plasma Hcy concentrations can predict the severity of OSA, underscoring their correlation with the AHI.

Leptin moderates the relationship between sleep quality and memory function: A population-based study.

Sleep is crucial for memory, as it promotes its encoding, consolidation, storage, and retrieval. Sleep periods following learning enhance memory consolidation. Leptin, a hormone that regulates appetite and energy balance, also influences memory and neuroplasticity. It plays a neurotrophic role in the hippocampus, enhancing synaptic function and promoting memory processes. Given these associations between sleep, memory, and leptin, this study aimed to evaluate the interplay between sleep quality, memory complaints and leptin levels. Using data from the São Paulo Epidemiologic Sleep Study (EPISONO) 2007 edition, we analyzed data from 881 participants who underwent evaluations for subjective sleep quality (Pittsburgh Sleep Quality Index), memory function (Prospective and Retrospective Memory Questionnaire), body mass index and plasmatic leptin levels. After confirming that subjects with poor sleep quality had more memory complaints in our cohort, we observed that leptin levels were increased in individuals with more memory complaints, but there was no association between leptin levels and sleep quality. Mediation analysis reinforced the direct effect of sleep quality on memory function, but leptin had no indirect effect as mediator over the sleep-memory association. Moderation analysis revealed that leptin acted as a moderator in the relationship between sleep quality and memory, with increased leptin levels enhancing the effect of sleep quality over memory function. These findings underscore the intricate interplay between sleep, memory, and metabolic factors like leptin, shedding light on potential mechanisms through which sleep influences memory and cognitive functions. Further research is needed to elucidate the exact mechanisms underlying these relationships and their implications for overall health and well-being.

How do phases of the menstrual cycle affect sleep? A polysomnographic study of the EPISONO database.

PURPOSE: Our study aimed to evaluate the impact of the menstrual cycle stages, especially menses, on sleep, inflammatory mediators, fatigue, anxiety, depression, and quality of life. METHODS: We used data from the EPISONO study cohort, selecting 96 women who had undergone one-night polysomnography. The women were distributed in three groups according to the time point of the menstrual cycle on the polysomnography night: menses, mid/late follicular phase, and luteal phase. The volunteers completed questionnaires related to sleep quality, daytime sleepiness, insomnia, fatigue, anxiety, depression, and quality of life. Blood samples were collected to analyze interleukin 6, tumor necrosis factor-alpha, and C-reactive protein. RESULTS: Sleep efficiency was statistically higher in women in the mid/late follicular group (89.9% ± 9.6) compared to menstrual (83.0% ± 10.8) and luteal (83.7% ± 12.7) groups. The mid/late follicular group presented a statistically significant reduction in sleep onset latency (7.1 ± 7.1 min) compared to the menstrual (22.3 ± 32.4 min) and luteal groups (15.9 ± 14.7 min). No statistical differences among the three groups were observed in other polysomnographic parameters, inflammatory mediators, daytime sleepiness, insomnia, fatigue, anxiety, depression, and quality of life. CONCLUSIONS: Our findings demonstrate that the mid/late follicular phase might be beneficial for women's sleep, although there were no statistically changes in inflammatory mediators among the groups.

The impact on the quality of life and sleep complaints in a vitiligo sample and the influence of inflammatory cytokines in the interaction between vitiligo and sleep.

INTRODUCTION: Vitiligo is an autoimmune dermatosis that affects quality of life, which englobes sleep quality. Sleep regulates the immune system, including inflammatory cytokines, and other pathways, which may influence vitiligo pathogenesis. OBJECTIVES: To analyze levels of immune serum components (cytokines) in a vitiligo group, and assess whether there was any association with sleep. METHODS: This study comprised 30 vitiligo patients and 26 control individuals. Quality of life and sleep questionnaires were completed [Dermatology Life Quality Index (DLQI), Short-Form Health Survey (SF-36), Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI)]. Seven cytokines have been measured: IFN-γ, interleukin (IL)-4, IL-6, IL-10, IL-17A, IL-12 p40 and TNF-α. RESULTS: The mean age of the vitiligo group was 47.7 years-old, with prevalence of females (66.7 %). Mucosal (70 %), acral (60 %) and focal subtype (53.3 %) predominated. Signs of vitiligo activity were identified in 63.3 % of the disease sample. Total PSQI scores and scores for domain 4 (sleep efficiency) were statistically worse in vitiligo group. The SF-36 and ISI total scores were worse in the vitiligo group, although not statistically significant compared with controls. Four SF-36 domains were statistically worse in vitiligo sample, and the DLQI mean score was mild to moderate (5.57). Cytokine levels were not different between groups, or when associated with PSQI. Higher ISI scores (more severe insomnia) were related to increased IL-17A. Higher IL-4, IL-6 and IL-10 levels were associated with previous phototherapy. CONCLUSIONS: Poor sleep and impaired aspects of quality of life predominated in the vitiligo sample. Insomnia was related to IL-17A increase in vitiligo. Increased levels of IL-4, IL-6 and IL-10 were related to previous ultraviolet B narrow band (UVB-NB) phototherapy, suggesting an interaction of this treatment on immune system. Sleep disruption and the course of vitiligo may have common pathways in respect of circadian cytokines, which may represent an important subject in vitiligo management.

Sleep patterns according to genetically determined ethnicity in the population of São Paulo, Brazil.

Sleep is a behavior expressed differently for each individual. However, studies have shown that some ethnic groups express common sleep patterns, which can be observed in different ethnic groups. Previous studies have shown the existence of sleep disparities in populations of different ethnicities. Most of these studies have considered self-reported ethnicity and assessed sleep subjectively. Therefore, the aim of this study was to evaluate sleep disparities in different ethnic groups based on an analysis of genetic ancestry and the use of objective sleep evaluation. To do this, we used data from the São Paulo Epidemiologic Sleep Study (EPISONO), which was undertaken in Brazil, a country that is known for its ethnic/racial diversity. All individuals completed a series of questionnaires, underwent full polysomnography and had their blood collected for DNA extraction. After genotyping and identifying samples with high-quality DNA suitable for genetic analysis, 31 ancestry-informative markers (AIMs) were selected. These markers exhibited substantial allelic frequency differences, enabling the characterization of the three primary founding populations of modern Brazil - Europeans, West-Africans, and Native Americans. Through this analysis, the genetic contribution of each of these ancestral groups was identified in respect of each participant. Based on this, a latent class cluster analysis (LCCA) was performed to define the three clusters that best classified the sample according to ethnic group: African (n = 255), Caucasian (n = 668) and Native American (n = 83). Applying the adjusted model for the confounding variables (age, socio-economic class and sex), statistically significant differences in sleep variables between ethnicities were found. Africans had higher sleep latency compared to the other groups (ß = 4.46, CI = 1.18 to 7.74 and ß = 7.83, CI = 3.50 to 12.15), while Caucasians had longer total sleep time (ß = -16.47, CI = -29.94 to -2.99) and better sleep efficiency (ß = -2.19, CI = -4.35 to -0.02) compared to Africans. Regarding the respiratory arousals index (ß = -1.11, IC = -2.07 to -0.16) and periodic leg movements index (ß = -7.48, CI = -12.08 to -2.88), both were higher among Caucasians compared to Africans. We were able to conclude that genetic ancestry might modulate sleep structure and the occurrence of sleep disorders.

Network analysis of sleep bruxism in the EPISONO adult general population.

Sleep bruxism (SB) has been associated with biological and psychosocial factors. The assessment of SB includes self-report, clinical evaluation, and polysomnography. This study aimed to investigate the associations of self-reported SB with other sleep disorders and demographic, psychological, and lifestyle factors in the adult general population, and to investigate whether self-reported SB and polysomnographically (PSG) confirmed SB provide similar outcomes in terms of their associated factors. We recruited 915 adults from the general population in Sao Paulo, Brazil. All participants underwent a one-night PSG recording and answered questions about sex, age, BMI, insomnia, OSA risk, anxiety, depression, average caffeine consumption, smoking frequency, and alcohol consumption frequency. We investigated the link between SB and the other variables in univariate, multivariate, and network models, and we repeated each model once with self-reported SB and once with PSG-confirmed SB. Self-reported SB was only significantly associated with sex (p = 0.042), anxiety (p = 0.002), and depression (p = 0.03) in the univariate analysis, and was associated with insomnia in the univariate (p < 0.001) and multivariate (ß = 1.054, 95%CI 1.018-1.092, p = 0.003) analyses. Network analysis showed that self-reported SB had a direct positive edge to insomnia, while PSG-confirmed SB was not significantly associated with any of the other variables. Thus, sleep bruxism was positively associated with insomnia only when self-reported, while PSG-confirmed SB was not associated with any of the included factors.

The relationship between irritable bowel syndrome, the gut microbiome, and obstructive sleep apnea: the role of the gut-brain axis.

Sleep disruption, especially that resulting from obstructive sleep apnea (OSA) - a widely prevalent sleep disorder - can lead to important systemic repercussions. We raise a subject of current interest, namely the possible relationship between sleep in general, OSA, and irritable bowel syndrome (IBS), an intestinal disease that can be made worse by stressful events. The intermittent hypoxia caused by OSA can induce alterations in the gut microbiota, which can lead to the dysregulation of the gut-brain axis and the worsening of IBS. This may be considered to be a circular relationship, with OSA playing a crucial role in the worsening of bowel symptoms, which in turn have a negative effect on sleep. Thus, based on previous evidence, we suggest that improving sleep quality could be a key to disrupting this relationship of IBS aggravation and OSA.

Can intraoral and facial photos predict obstructive sleep apnea in the general and clinical population?

STUDY OBJECTIVES: This study aimed to evaluate and compare measurements of standardized craniofacial and intraoral photographs between clinical and general population samples, between groups of individuals with an apnea-hypopnea index (AHI) ≥ 15 and AHI < 15, and their interaction, as well as the relationship with the presence and severity of obstructive sleep apnea (OSA). METHODS: We used data from 929 participants from Sleep Apnea Global Interdisciplinary Consortium, in which 309 patients from a clinical setting and 620 volunteers from a general population. RESULTS: AHI ≥ 15 were observed in 30.3% of the total sample and there were some interactions between facial/intraoral measures with OSA and both samples. Mandibular volume (p < 0.01) and lateral face height (p = 0.04) were higher in the AHI ≥ 15 group in the clinical sample compared to the AHI ≥ 15 group in the general population and AHI < 15 group in the clinical sample. When adjusted for sex and age, greater mandible width (p < 0.01) differed both in the clinical and in the general population samples, reflecting AHI severity and the likelihood of OSA. The measure of smaller tongue curvature (p < 0.01) reflected the severity and probability of OSA in the clinical sample and the higher posterior mandibular height (p = 0.04) showed a relationship with higher AHI and higher risk of OSA in the general population. When adjusted for sex, age, and body mass index, only smaller tongue curvature (p < 0.01) was associated with moderate/severe OSA. CONCLUSIONS: Measures of greater tongue and mandible were associated with increased OSA risk in the clinical sample and craniofacial measurement was associated in the general population sample.

Sleep and quality of life in kidney transplant recipients with and without non-melanoma skin cancer: a comparative study.

Non-melanoma skin cancer (NMSC) is prevalent in kidney transplant recipients (KTR), related to the immunosuppressive effects of anti-rejection therapy. Sleep disturbances can alter the immune system and enhance oxidative stress, which may increase the risk of carcinogenesis. This study aimed to analyze the quality of life and sleep in KTR with and without NMSC. Participants answered a set of questionnaires, the WHOQOL-bref, the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), the Berlin Questionnaire and self-reported chronotype. The total sample was distributed in the following groups: KTR with NMSC (n = 42), KTR without NMSC (n = 43) and healthy controls (n = 41). The mean scores of the questionnaires were not statistically significant, except for 3 domains of PSQI (sleep quality, sleep latency and daily consequences of poor sleep). The KTR with NMSC and control group presented worse sleep quality. Worse sleep latency and more daytime consequences were found in KTR groups. All groups had a numerical predominance of low-quality sleep (PSQI) and greater sleepiness (EES). Higher risk of obstructive sleep apnea was not observed and the evening-type chronotype was most frequent. In the WHOQOL, compromised physical domain was observed in KTR. Significant results were reached in few aspects of quality of life and sleep comparing KTR and controls. All groups presented excessive daytime sleepiness and low-sleep quality.

Lipid metabolism and neuromuscular junction as common pathways underlying the genetic basis of erectile dysfunction and obstructive sleep apnea.

Erectile dysfunction (ED) incidence is higher in patients with obstructive sleep apnea (OSA). Studies have suggested that ED and OSA may activate similar pathways; however, few have investigated the links between their underlying genotypic profiles. Therefore, we conducted an in-silico analysis to test whether ED and OSA share genetic variants of risk and to identify any molecular, cellular and biological interactions between them. Two gene lists were manually curated through a literature review based on a PUBMED search, which resulted in one gene list associated with ED (total of 205 genes) and the other with OSA (total of 2622 genes). Between those gene sets, 35 were common for both lists (Fisher exact test, p-value = 0.027). The Protein-protein interaction (PPI) analysis using the intersect list as input showed that 3 of them had direct interactions (LPL, DGKB and PLCB1). In addition, the biological function of the genes contained in the intersect list suggested that pathways related to lipid metabolism and the neuromuscular junction were commonly found in the genetic basis of ED and OSA. From the shared genes between both conditions, the biological pathways highlighted in this study may serve as preliminary findings for future functional investigations on OSA and ED association.

Do nocturnal asthma attacks influence sleep parameters and inflammatory markers? A cross-sectional population-based study.

PURPOSE: To evaluate the effects of nocturnal asthma on sleep parameters and inflammatory markers according to the severity of the condition in participants in the São Paulo Epidemiologic Sleep Study (EPISONO). METHODS: Data from the 2007 and 2018 editions of the EPISONO study were utilized. Subjects completed validated sleep and respiratory questionnaires, underwent nocturnal polysomnography and spirometry tests, and provided blood samples for the assessment of inflammatory parameters. RESULTS: Of 72 participants (67% women), 53% (n = 38) had intermittent nocturnal asthma symptoms and 47% (n = 34) had persistent asthma (mild, moderate, and severe). Individuals with persistent nocturnal symptoms had a higher body mass index (BMI), were more likely to have respiratory symptoms, and had worse lung function, a higher apnea-hypopnea index (AHI), and higher desaturation index than individuals with intermittent nocturnal symptoms. Positive associations were identified between nocturnal asthma and obstructive sleep apnea (OSA). A higher frequency of OSA was observed in participants with persistent asthma and participants with OSA were more likely to have persistent than intermittent asthma. However, there were no significant differences between the immunological parameters of those with intermittent or persistent asthma. CONCLUSIONS: This study highlights the relevance of nocturnal symptoms as a valuable indicator of asthma severity. The findings also add to the existing body of evidence linking nocturnal asthma and OSA.

The relationship between neurodevelopmental transcriptional programs and insomnia: From Rubinstein-Taybi syndrome into energy metabolism.

Neurodevelopmental disorders (NDD) are characterized by cognitive, emotional, and/or motor skills impairment since childhood, and sleep disturbances are a common comorbidity. Rubinstein-Taybi syndrome (RSTS), a rare genetic syndrome associated with NDD, is caused by CREBBP haploinsufficiency. This gene encodes an acetyltransferase with crucial role on the establishment of transcriptional programs during neurodevelopment. Although insomnia has been reported in RSTS patients, the convergent mechanisms between this sleep disturbance and CREBBP loss-of-function are not fully understood. We tested weather the genetic architecture underlying CREBBP regulatory targets and insomnia-associated genes is significantly shared. We then identified the biological pathways enriched among these shared genes. The intersection between CREBBP regulatory targets and genes associated with insomnia included 7 overlapping genes, indicating significantly more overlap than expected by chance. An over-representation analysis on these intersect genes identified pathways related to mitochondrial activity. This finding indicates that the transcriptional programs established by CREBBP might impact insomnia-related biological pathways through the modulation of energy metabolism. The overlapping gene set and biological pathways highlighted by this study may serve as a primer for new functional investigations of shared molecular mechanisms between insomnia and CREBBP regulatory targets.

Endocrine and Epigenetic Regulation as Common Pathways Underlying the Genetic Basis of Sleep Traits and Longevity.

The amount of sleep needed over one's lifespan is age dependent and not sleeping enough or sleeping in excess is associated with increased morbidity and mortality. Yet, the convergent molecular mechanisms that link longevity and sleep are largely unknown. We performed a gene enrichment study that (1) identified genes associated with both longevity and sleep traits and (2) determined molecular pathways enriched among these shared genes. We manually curated two sets of genes, one associated with longevity and aging and the other with sleep traits (e.g., insomnia, narcolepsy, sleep duration, chronotype, among others), with both gene lists heavily driven by hits from recent large-scale Genome-Wide Association Studies. There were 47 overlapping genes between the gene list associated with sleep traits (1064 genes total) and the genes associated with longevity (367 genes total), indicating significantly more overlap than expected by chance. An overrepresentation analysis identified enriched pathways that suggest endocrine and epigenetic regulation as potential shared mechanisms between sleep traits and longevity. Concordantly, functional network analysis retrieved two clusters, being one associated with proteins of nuclear functions and the other, with extracellular proteins. This overlapping gene set, and the highlighted biological pathways may serve as preliminary findings for new functional investigations of sleep and longevity shared genetic mechanisms.