The genetic etiology of periodic limb movement in sleep.

STUDY OBJECTIVES: Periodic limb movement in sleep is a common sleep phenotype characterized by repetitive leg movements that occur during or before sleep. We conducted a genome-wide association study (GWAS) of periodic limb movements in sleep (PLMS) using a joint analysis (i.e., discovery, replication, and joint meta-analysis) of four cohorts (MrOS, the Wisconsin Sleep Cohort Study, HypnoLaus, and MESA), comprised of 6843 total subjects. METHODS: The MrOS study and Wisconsin Sleep Cohort Study (N = 1745 cases) were used for discovery. Replication in the HypnoLaus and MESA cohorts (1002 cases) preceded joint meta-analysis. We also performed LD score regression, estimated heritability, and computed genetic correlations between potentially associated traits such as restless leg syndrome (RLS) and insomnia. The causality and direction of the relationships between PLMS and RLS was evaluated using Mendelian randomization. RESULTS: We found 2 independent loci were significantly associated with PLMS: rs113851554 (p = 3.51 × 10-12, ß = 0.486), an SNP located in a putative regulatory element of intron eight of MEIS1 (2p14); and rs9369062 (p = 3.06 × 10-22, ß = 0.2093), a SNP located in the intron region of BTBD9 (6p12); both of which were also lead signals in RLS GWAS. PLMS is genetically correlated with insomnia, risk of stroke, and RLS, but not with iron deficiency. Pleiotropy adjusted Mendelian randomization analysis identified a causal effect of RLS on PLMS. CONCLUSIONS: Because PLMS is more common than RLS, PLMS may have multiple causes and additional studies are needed to further validate these findings.

The reproducibility of clinical OSA subtypes: a population-based longitudinal study.

PURPOSE: The identification of subgroups of obstructive sleep apnea (OSA) is critical to understand disease outcome and treatment response and ultimately develop optimal care strategies customized for each subgroup. In this sense, we aimed to perform a cluster analysis to identify subgroups of individuals with OSA based on clinical parameters in the Epidemiological Sleep Study of São Paulo city (EPISONO). We aimed to analyze whether or not subgroups remain after 8 years, since there is not any evidence showing if these subtypes of clinical presentation of OSA in the same population can change overtime. METHODS: We used data derived from EPISONO cohort, which was followed over 8 years after baseline evaluation. All individuals underwent polysomnography, answered questionnaires, and had their blood collected for biochemical examinations. OSA was defined according to AHI ≥ 15 events/h. Cluster analysis was performed using latent class analysis (LCA). RESULTS: Of the 1042 individuals in the EPISONO cohort, 68% agreed to participate in the follow-up study (n = 712), and 704 were included in the analysis. We were able to replicate the OSA 3-cluster solution observed in previous studies: disturbed sleep, minimally symptomatic and excessively sleepy in both baseline (36%, 45% and 19%, respectively) and follow-up studies (42%, 43%, and 15%, respectively). The optimal cluster solution for our sample based on Bayesian information criterion (BIC) was 2 cluster for baseline (disturbed sleep and excessively sleepy) and 3 clusters for follow-up (disturbed sleep, minimally symptomatic, and excessively sleepy). A total of 45% of the participants migrated clusters between the two evaluations (and the factor associated with this was a greater delta-AHI (B = - 0.033, df = 1, p = 0.003). CONCLUSIONS: The results replicate and confirm previously identified clinical clusters in OSA which remain in the longitudinal analysis, with some percentage of migration between clusters.

Aging biological markers in a cohort of antipsychotic-naïve first-episode psychosis patients.

Schizophrenia is a severe and multifactorial disorder with an unknown causative pathophysiology. Abnormalities in neurodevelopmental and aging processes have been reported. Relative telomere length (RTL) and DNA methylation age (DMA), well-known biomarkers for estimating biological age, are both commonly altered in patients with schizophrenia compared to healthy controls. However, few studies investigated these aging biomarkers in first-episode psychosis (FEP) and in antipsychotic-naïve patients. To cover the existing gap regarding DMA and RTL in FEP and antipsychotic treatment, we aimed to verify whether those aging markers could be associated with psychosis and treatment response. Thus, we evaluated these measures in the blood of FEP antipsychotic-naïve patients and healthy controls (HC), as well as the response to antipsychotics after 10 weeks of treatment with risperidone. RTL was measured in 392 subjects, being 80 FEP and 312 HC using qPCR, while DMA was analyzed in a subset of 60 HC, 60 FEP patients (antipsychotic-naïve) and 59 FEP-10W (after treatment) using the "Multi-tissue Predictor"and the Infinium HumanMethylation450 BeadChip Kit. We observed diminished DMA and longer RTL in FEP patients before treatment compared to healthy controls, indicating a decelerated aging process in those patients. We found no statistical difference between responder and non-responder patients at baseline for both markers. An increased DMA was observed in patients after 10 weeks of treatment, however, after adjusting for blood cell composition, no significant association remained. Our findings indicate a decelerated aging process in the early phases of the disease.

Obstructive sleep apnea and the retina: a review.

CITATION: This review's objective was to synthesize the literature on the repercussions of obstructive sleep apnea (OSA) in the retinal vascular system. Two independent investigators conducted a search using the MEDLINE/PubMed database using the following terms: sleep apnea syndrome, obstructive sleep apnea, retina, vascular tortuosity, central serous chorioretinopathy, diabetes mellitus, and subfoveal choroidal thickness. Patients with OSA present increased vascular tortuosity compared with patients without OSA, decreased parafoveal and peripapillary vessel density, and increased retinal vein occlusion incidence. In central serous chorioretinopathy patients and patients who are poor responders to intravitreal anti-VEGF (-vascular endothelial growth factor) treatment for macular edema, OSA is more frequent. Macular choroidal thickness alterations are controversial, and OSA may worsen diabetic maculopathy, thus being a risk factor for diabetic retinopathy, proliferative diabetic retinopathy, and macular edema. OSA is a prevalent syndrome with many systemic vascular changes. The retina and choroid are the most affected ocular structures, with primarily vascular changes. New noninvasive technologies such as optical coherence tomography and optical coherence tomography angiography could help to better understand retinal structures and help clarify the ophthalmological repercussions of OSA. CITATION: Nakayama LF, Tempaku PF, Bergamo VC, et al. Obstructive sleep apnea and the retina: a review. J Clin Sleep Med. 2021;17(9):1947-1952.

Klotho genetic variants mediate the association between obstructive sleep apnea and short telomere length.

The core features of obstructive sleep apnea (OSA) can potentially contribute to the acceleration of telomere shortening mechanisms. Other factor associated with telomeres is Klotho gene as it can negatively regulates telomerase activity. Noteworthy, KLOTHO protein level has recently been associated with OSA. In this sense, it was plausible to hypothesize that OSA would be associated with short telomere length and those with OSA plus risk single nucleotide polymorphisms (SNPs) in Klotho gene would present even shorter telomere length. As part of the EPISONO cohort, 1042 individuals answered questionnaires, underwent polysomnography and had blood collected for DNA extraction. OSA was defined according to AHI≥ 15 events/hour. Leukocyte telomere length (LTL) was measured through real-time polymerase chain reaction (qPCR) and Klotho SNPs were genotyped by array. Mediation analyses considered the presence of SNPs in Klotho gene and how this interaction can affect OSA and its consequence in telomere length. All the analyses were corrected for multiple comparisons. LTL was significantly shorter in OSA compared to controls in a severity-dependent manner (B = 0.055; CI = 0.007-0.102; p = 0.02). Among the 43 Klotho SNPs analyzed, we observed that 4 SNPs (rs525014, rs7982726, rs685417 and rs9563124) significantly mediated the association between OSA and short LTL. Klotho gene opens a new venue in OSA research since it can contribute in the increase of knowledge of the mechanisms involved in the consequences of short telomeres in individuals with OSA.

Sleep deprivation decreases the reproductive capacity by affecting the arrival of morulas in the uterus.

A previous animal study by our group found that sleep deprivation during preimplantation was associated with decreased pregnancy maintenance. Given its impact on human society, we aimed in the current study to assess whether sleep deprivation affects blastocyst gene expression and/or the implantation process. For this, pregnant mice (gestational day 0 [GD 0]) were assigned into paradoxical sleep deprivation (SD, 72 hr; multiple platform method) and, a control (CT) group. Animals were euthanized on GD 3.5 and blood, uterus (embryos) and fallopian tube were collected. Then, 89% of CT presented blastocysts in the uterus versus 25% from SD group. Compared to CT, SD presented lighter relative uterus weight, increased plasma concentrations of corticosterone and testosterone, decreased concentrations of progesterone and luteinizing hormone, but no statistical differences in plasma concentrations of 17ß-estradiol and follicle stimulating hormone. There were no differences in uterus and blastocyst gene expression related to embryo implantation and development, and no alteration in blastocysts global DNA methylation. Considering this, the decreased pregnancy maintenance after sleep deprivation seems not to be associated with implantation losses or developmental problems related to the blastocysts. It is likely that complications in morula development and/or its movement through the fallopian tubes affect the pregnancy rate, since only 25% of SD females presented a blastocyst on the GD 3.5. In fact, three out of four females without blastocysts in the uterus presented morula in the fallopian tubes due to a phase delay. Additionally, we suggest that the observed hormonal changes may play a role in this outcome.

Leukocyte telomere length variation in different stages of schizophrenia.

Recent research has demonstrated that telomere maintenance might be a key integrating point for the cumulative effect of genetic and environmental factors in patients with first-episode psychosis (FEP) and schizophrenia (SCZ). Eighty-one participants with antipsychotic-naïve FEP, 173 with SCZ and 438 HC were enrolled in this study. Psychiatric diagnosis was assessed using the Semi-Structured Clinical Interview for DSM-IV Axis-I (SCID-I). The Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale (YMRS) and Calgary Depression Scale for Schizophrenia (CDSS) were used to measure symptoms severity. Telomere length (TL) was determined using a multiplex qPCR assay. After adjustment for age, years of education, and smoking status, we found that patients with SCZ had longer TL (relative ratio (RR) = 1.08) than the HC group (RR = 1.00, Wald χ2 = 12.48, p = 0.002). Further, non-remitted SCZ patients presented longer TL (RR = 1.00) compared to remitted SCZ (RR = 0.88, Wald χ2 = 7.20, p = 0.007). TL in patients also correlated to psychopathology assessment in terms of total (p = 0.003) and positive PANSS scores (p = 0.001). No correlation with negative PANSS, YMRS, and CDSS or effects of medication was found on TL. Although the exact pathways underlying longer TL in SCZ patients remain unclear, these findings raise more questions than answers and suggest that TL may be of immense value on SCZ progression. Further studies are required to investigate the association of TL in FEP and SCZ.

Characterization of bimodal chronotype and its association with sleep: A population-based study.

The circadian system coordinates internal events in a daily schedule to make sure that the body systems are synchronized to environmental time and internal cues. One important behavioral aspect of the circadian system is the chronotype. It is usually assessed through subjective questionnaires, being the Horne-Ostberg Morningness-Eveningness Questionnaire (MEQ) one of the most used. It classifies individuals into three major categories: morning, evening, and intermediate types. Recently, it has been hypothesized the existence of a fourth chronotype, the bimodal type, through an algorithm derived from the MEQ responses. Bimodals answer as morning-types in some questions, and as evening-types in others, resulting in an intermediate total score. To better characterize this phenotype, the present study aimed to detect and characterize the frequency of the bimodal chronotype in the EPISONO, a large population-based cohort, as well as to verify the association between bimodality and sleep parameters and genetic variation in the PER3 gene. Of the 1,042 individuals who participated of the EPISONO, 857 had MEQ filled correctly. We found that 16% of our sample were bimodal types. We observed that bimodal individuals were significantly younger and had lower body mass index. The association between PER3 VNTR genotype and gender with bimodal chronotype was not significant. However, we found an association between bimodality and Epworth Sleepiness Scale (EES) and apnea-hypopnea index (AHI). We did not find a statistically significant difference between bimodals and intermediate non-bimodals for the studied variables. Lastly, it was observed that the most significant predictors for bimodal chronotype were female gender, AHI, and EES. In conclusion, the present work provides more evidence that the bimodal type might have to be considered when classifying chronotype and its association with young age and sleepiness may be due to the influence of social and environmental factors.

Shorter leukocyte telomere length in patients at ultra high risk for psychosis.

Telomere length attrition has been demonstrated in schizophrenia but not in individuals in ultra high risk (UHR) for psychosis. The present study aimed to compare the leukocyte telomere length (TL) between patients at UHR for psychosis and healthy controls (HC). Twenty-two participants with UHR and 88 HC were enrolled in this study. Telomere lengths were determined using a multiplex qPCR assay. After adjustment for age, sex, ethnicity, and education, patients in UHR, compared with HC groups, had shorter telomere length (RR: 0.929, p=0.031). Shorter leukocyte telomere length in UHR could represent early signs of accelerated aging in this population.

Revisão sistemática sobre a epidemiologia das doenças cardiovasculares e respiratórias e suas associações com a poluição do ar em Vitória/ES / Epidemiology of cardiovascular and respiratory diseases and its associations with air pollution in Vitória, Brazil: a systematic review

Introdução: A poluição do ar é um importante fator ambiental relacionado a doenças crônicas não transmissíveis, como doenças cardiovasculares e respiratórias. Essa relação torna-se importante em cidades com alta atividade industrial, como Vitória/ES. Esta pesquisa utilizou três revisões sistemáticas (RSs) distintas para avaliar a epidemiologia das doenças cardiovasculares (RS1), a epidemiologia das doenças respiratórias (RS2) e a associação entre poluição do ar e doenças cardiorrespiratórias (RS3) na cidade de Vitória. Métodos: A busca bibliográfica considerou três bases de dados (PubMed, Scopus e LILACS). Foi estabelecida uma quantidade mínima de três estudos para a condução de metanálises. A heterogeneidade de cada análise foi calculada pelo índice I2. Resultados: A busca bibliográfica resultou em 1.205 registros, dos quais 27 foram incluídos ­ 17 na RS1, cinco na RS2 e cinco na RS3. Apenas dois desfechos puderam ser avaliados por meio de metanálises: prevalência de hipertensão e prevalência de asma em crianças. Estima-se uma prevalência de 34% (IC95%: 24-45) de hipertensão e de 12% (IC95%: 1-32) de asma em crianças. Os poluentes mais avaliados foram MP10 e SO2, para os quais não se pôde realizar metanálises. Todas as análises apresentaram baixo número de registros incluídos e alta heterogeneidade. Conclusão: Há poucos dados disponíveis sobre a associação de doenças cardiorrespiratórias e poluição ambiental em Vitória. A heterogeneidade, a diversidade de desfechos e a baixa quantidade de estudos impediram a condução de análises mais profundas e limitaram o poder de síntese e conclusão dessas revisões, impossibilitando uma avaliação adequada dos objetivos propostos. São necessários mais estudos epidemiológicos com amostras de grande porte e representativas para que se tenha resultados conclusivos sobre a relação entre poluição ambiental e doenças cardiorrespiratórias em Vitória (AU)

Introduction: Air pollution is an important environmental factor related to chronic non-transmittable diseases, including cardiovascular and respiratory diseases. This relationship is especially relevant in cities with high industrial activity, such as Vitória, Brazil. This research used three systematic reviews (SRs) to evaluate the epidemiology of cardiovascular diseases (SR1), the epidemiology of respiratory diseases (RS2), and the association between air pollution and cardiorespiratory diseases (RS3) in Vitória, Brazil. Methods: A bibliographic search was conducted in three independent databases (PubMed, Scopus and LILACS). A minimum amount of three studies was established to perform meta-analyses. Heterogeneity was calculated using the I2 index. Results: The bibliographic search retrieved 1205 references, of which 27 were included ­ 17 in SR1, five in SR2, and five in SR3. Only two outcomes could be evaluated through meta-analysis: prevalence of hypertension and prevalence of asthma in children. The most frequently evaluated pollutants were PM10 and SO2. The estimated prevalence of hypertension was 34% (CI95%: 24-45) and of asthma in children was 12% (CI95%: 1-32). All analyses had a limited number of included references and showed high heterogeneity. Conclusions: There are limited data available regarding the association of cardiorespiratory diseases and air pollution in Vitória, Brazil. The heterogeneity, the diversity of outcomes, and the limited number of studies hampered the performance of a more detailed analysis and limited the conclusions of these reviews, preventing a proper appraisal of the proposed aims. Further epidemiological studies with bigger and more representative sample sizes are needed to generate conclusive data about the relationship between air pollution and cardiorespiratory diseases in Vitória, Brazil (AU)

The effect of the severity of obstructive sleep apnea syndrome on telomere length.

Aging is associated with an increase in the prevalence of obstructive sleep apnea syndrome (OSAS) as well as the shortening of telomeres. It is known that OSAS-related factors are stimuli that can contribute to the acceleration of cellular senescence. Thus, the present study aimed to compare the leukocyte telomere length (LTL) between OSAS patients and controls, as well as to verify the correlation between LTL and sleep parameters. We used DNA extracted of 928 individuals from EPISONO to measure the LTL by the quantitative real-time polymerase chain reaction. All individuals were subjected to one full-night polysomnography. LTL was significantly shorter in OSAS patients compared to controls. The results showed negative correlations between LTL and the following variables: apnea-hypopnea index, respiratory disturbance index, desaturation index and wake after sleep onset. LTL was positively correlated with sleep efficiency, total sleep time, basal, minimum and maximum oxygen saturation. Lastly, it was observed that OSAS severity was associated with shorter LTL even after adjusting for sex, age, years of schooling, body mass index, diabetes, stroke and heart attack. In conclusion, our study indicates the presence of an association between LTL and OSAS and a significant impact of severity of OSAS in telomeres shortening.