RESUMO
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.
Assuntos
Apneia Obstrutiva do Sono , Telômero , Glucuronidase/genética , Humanos , Proteínas Klotho , Polissonografia , Apneia Obstrutiva do Sono/genética , Telômero/genéticaRESUMO
Obstructive sleep apnea (OSA) is a common clinical condition associated with increased cardiovascular morbidity and mortality. Recent evidence from clinical studies and animal models suggest that OSA can promote cardiovascular disease by inducing autonomic, hemodynamic, inflammatory and metabolic dysregulation. However, most of the evidence addressing hard endpoints in humans is derived from observational studies. Several challenges have been noted in the pursuit of a comprehensive knowledge base about the impact of OSA including: 1) the precise mechanisms by which OSA causes metabolic and cardiovascular consequences are not clear, which limits our current ability to address potential targets in OSA; 2) several patients with OSA, even with severe forms, present with no or mild daytime symptoms. Beyond the obvious challenges for obtaining good adherence for conventional OSA treatments, there is evidence that symptomatic vs. asymptomatic patients with OSA do not necessarily have the same metabolic and cardiovascular outcomes; and 3) the cardiovascular response to OSA treatment may vary even in those patients with good adherence. In this scenario, there is an obvious need to develop biomarkers in the OSA research area. This review focuses on describing the advances that have occurred so far in exploring potential OSA biomarkers with clear emphasis for the cardiovascular risk. Particular attention will be devoted to discuss molecular biomarkers including the potential role of microRNAs, proteomics and metabolomics. We also discuss the major challenges and perspectives in this growing research field.
Assuntos
Doenças Cardiovasculares/etiologia , Metaboloma , Proteoma , Apneia Obstrutiva do Sono/complicações , Transcriptoma , Biomarcadores/metabolismo , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Perfilação da Expressão Gênica , Fatores de Risco de Doenças Cardíacas , Humanos , Metabolômica , Valor Preditivo dos Testes , Proteômica , Medição de Risco , Apneia Obstrutiva do Sono/genética , Apneia Obstrutiva do Sono/metabolismoRESUMO
BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is associated to intermittent hypoxia (IH) and is an aggravating factor of non-alcoholic fatty liver disease (NAFLD). We investigated the effects of hypoxia in both in vitro and in vivo models of NAFLD. METHODS: Primary rat hepatocytes treated with free fatty acids (FFA) were subjected to chemically induced hypoxia (CH) using the hypoxia-inducible factor-1 alpha (HIF-1α) stabilizer cobalt chloride (CoCl2). Triglyceride (TG) content, mitochondrial superoxide production, cell death rates, cytokine and inflammasome components gene expression and protein levels of cleaved caspase-1 were assessed. Also, Kupffer cells (KC) were treated with conditioned medium (CM) and extracellular vehicles (EVs) from hypoxic fat-laden hepatic cells. The choline deficient L-amino acid defined (CDAA)-feeding model used to assess the effects of IH on experimental NAFLD in vivo. RESULTS: Hypoxia induced HIF-1α in cells and animals. Hepatocytes exposed to FFA and CoCl2 exhibited increased TG content and higher cell death rates as well as increased mitochondrial superoxide production and mRNA levels of pro-inflammatory cytokines and of inflammasome-components interleukin-1ß, NLRP3 and ASC. Protein levels of cleaved caspase-1 increased in CH-exposed hepatocytes. CM and EVs from hypoxic fat-laden hepatic cells evoked a pro-inflammatory phenotype in KC. Livers from CDAA-fed mice exposed to IH exhibited increased mRNA levels of pro-inflammatory and inflammasome genes and increased levels of cleaved caspase-1. CONCLUSION: Hypoxia promotes inflammatory signals including inflammasome/caspase-1 activation in fat-laden hepatocytes and contributes to cellular crosstalk with KC by release of EVs. These mechanisms may underlie the aggravating effect of OSAS on NAFLD. [Abstract word count: 257].
Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Hipóxia/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Hepatopatia Gordurosa não Alcoólica/genética , Apneia Obstrutiva do Sono/genética , Animais , Caspase 1/genética , Deficiência de Colina/genética , Deficiência de Colina/metabolismo , Deficiência de Colina/patologia , Cobalto/toxicidade , Modelos Animais de Doenças , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologia , Ácidos Graxos não Esterificados/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Hipóxia/induzido quimicamente , Hipóxia/metabolismo , Hipóxia/patologia , Inflamassomos/genética , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Interleucina-1beta/genética , Células de Kupffer/metabolismo , Células de Kupffer/patologia , Camundongos , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Ratos , Apneia Obstrutiva do Sono/etiologia , Apneia Obstrutiva do Sono/metabolismo , Apneia Obstrutiva do Sono/patologia , Triglicerídeos/genéticaRESUMO
OBJECTIVE/BACKGROUND: Obstructive sleep apnea (OSA) is a sleep-related breathing disorder that has a complex phenotype. Currently, few genes have been linked with OSA. Thus, the aim of this study was to conduct a genome-wide association study (GWAS) of the apnea-hypopnea index (AHI) variation along time (delta-AHI) in a prospective cohort. METHODS: We used data derived from the São Paulo Epidemiologic Sleep Study (EPISONO) (n = 1074) cohort, which was followed over eight years (n = 712). Our phenotype of interest was delta-AHI and incident OSA. Further, we were interested on the time-dependent effect of genetic variants. Our final GWAS model used delta-AHI as a dependent variable and the SNPs and covariates as independent variables. We also performed a gene-set and pathway analysis. RESULTS: The delta-AHI increased on average 6.1 events/hour (standard deviation = 14.9) over the follow-up. We found two significant and 21 suggestive variants associated with delta-AHI. The strongest association (rs12415421) was observed at ST8SIA6 gene and the other significant hit (rs4731117) was in an intergenic region in linkage disequilibrium with our third hit (rs12669165) in the ASB15 gene. We found an effect of the allele rs12415421 for the OSA incidence. Additionally, we observed that individuals with both risk alleles presented a higher incidence of OSA when compared to those with one or without any risk alleles. CONCLUSIONS: This study has identified genes in these associated regions with delta-AHI, which seem to be involved in growth and stability of muscle and bone. We also observed an effect of both allele frequencies in the incidence of OSA.
Assuntos
Alelos , Estudo de Associação Genômica Ampla , Proteínas/genética , Sialiltransferases/genética , Apneia Obstrutiva do Sono , Adulto , Brasil/epidemiologia , Feminino , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Polissonografia , Estudos Prospectivos , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/genética , Fatores de TempoRESUMO
Obstructive sleep apnea (OSA) has been associated with oxidative stress and various cardiovascular consequences, such as increased cardiovascular disease risk. Quantitative real-time PCR is frequently employed to assess changes in gene expression in experimental models. In this study, we analyzed the effects of chronic intermittent hypoxia (an experimental model of OSA) on housekeeping gene expression in the left cardiac ventricle of rats. Analyses via four different approaches-use of the geNorm, BestKeeper, and NormFinder algorithms; and 2-ΔCt (threshold cycle) data analysis-produced similar results: all genes were found to be suitable for use, glyceraldehyde-3-phosphate dehydrogenase and 18S being classified as the most and the least stable, respectively. The use of more than one housekeeping gene is strongly advised. RESUMO A apneia obstrutiva do sono (AOS) tem sido associada ao estresse oxidativo e a várias consequências cardiovasculares, tais como risco aumentado de doença cardiovascular. A PCR quantitativa em tempo real é frequentemente empregada para avaliar alterações na expressão gênica em modelos experimentais. Neste estudo, analisamos os efeitos da hipóxia intermitente crônica (um modelo experimental de AOS) na expressão de genes de referência no ventrículo cardíaco esquerdo de ratos. Análises a partir de quatro abordagens - uso dos algoritmos geNorm, BestKeeper e NormFinder e análise de dados 2-ΔCt (ciclo limiar) - produziram resultados semelhantes: todos os genes mostraram-se adequados para uso, sendo que gliceraldeído-3-fosfato desidrogenase e 18S foram classificados como o mais e o menos estável, respectivamente. A utilização de mais de um gene de referência é altamente recomendada.
Assuntos
Expressão Gênica , Genes Essenciais , Ventrículos do Coração , Hipóxia/genética , Apneia Obstrutiva do Sono/genética , Animais , Modelos Animais de Doenças , Ventrículos do Coração/fisiopatologia , Hipóxia/fisiopatologia , Masculino , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Valores de Referência , Apneia Obstrutiva do Sono/fisiopatologiaRESUMO
This study aims to determine the relationship between C-reactive protein levels and obstructive sleep apnea syndrome (OSAS). We recruited 30 OSAS patients into the observation group (OSAS group), and subdivided them into mild, moderate and severe groups according to the apnea hypopnea index. In addition, 20 normal individuals were included in the control group. Plasma CRP levels of two groups were measured. As compared with the control group, the CRP levels in the OSAS group were significantly increased (P < 0.05). ANOVA showed that CRP levels in the three subgroups differ; statistically significant differences between the mild and severe OSA patients were observed (P < 0.05). It was hypothesized that OSAS patients show elevated serum CRP levels, and that serum CRP levels are associated with OSAS severity.
Assuntos
Proteína C-Reativa/metabolismo , Apneia Obstrutiva do Sono/sangue , Adulto , Idoso , Proteína C-Reativa/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia , Índice de Gravidade de Doença , Apneia Obstrutiva do Sono/genética , Apneia Obstrutiva do Sono/patologiaRESUMO
BACKGROUND: OSA has a familial aggregation pattern indicating that it can be partially caused by a genetic component. However, the heritability of OSA has been estimated based on the study of families of obese probands of urban populations with established OSA diagnosis. The objective of this genetic-epidemiologic study is to study families ascertained from a general rural population to determine an unbiased estimate of OSA heritability. METHODS: We studied a sample of families living in Baependi, a small rural southeastern Brazilian city. Participants were assessed for anthropometric measurements, physical examination, Epworth Sleepiness Scale, blood samples for glucose and cholesterol determination, and overnight home portable monitoring. RESULTS: We studied 587 participants (399 women) from 91 families, with a median (interquartile range [IQR]) of 4 (2-8) participants per family. The median age of the population was 44 years (IQR, 29-55 years) and median BMI was 25.0 kg/m(2) (IQR, 22.1-28.6 kg/m(2)). OSA, defined by apnea-hypopnea index (AHI) > 5/h, was diagnosed in 18.6% of the sample. Two polygenic models, model I (no covariate effects) and model II (with covariate effects), were fitted to the data in all analyses. Heritability estimates for AHI were 0.23 and 0.25 for model I and II, respectively. Covariates (age, sex, and BMI) showed no significant effects on the heritability estimate for AHI. CONCLUSIONS: The heritability of AHI in a rural population with low levels of obesity is intermediate (25%).
Assuntos
Padrões de Herança , Saúde da População Rural/estatística & dados numéricos , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/genética , Adulto , Fatores Etários , Índice de Massa Corporal , Brasil , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores Sexuais , Apneia Obstrutiva do Sono/diagnósticoRESUMO
BACKGROUND: Obstructive sleep apnea syndrome (OSAS) has a negative impact on health and behavior of millions of individuals worldwide. The pathogenesis of this disorder is a multifactorial process related to a variety of mechanisms, including selective activation of inflammatory response pathways. A number of inflammatory factors, such as IL-6, IL-8, and TNF-α, can be found in high concentrations in subjects with OSAS and may serve as biological markers of this disease. The concentration of these cytokines contributes to weight gain in patients with OSAS and can also modify the risk of obesity-related metabolic disorders, especially insulin resistance. Nevertheless, the mechanisms by which specific genes are associated with these processes are still poorly known. In addition to gene expression studies, investigations aiming at the identification of epigenetic factors associated with OSAS are still scarce in the literature. The documented data support the hypothesis that the molecular changes that mediate inflammatory response are important mechanisms in the pathogenesis of OSAS, sleepiness, insulin resistance, visceral obesity, and cardiovascular disease, perhaps by leading to a more severe OSAS. Often, systemic changes may not be detected in mild OSA; however, molecular changes, which are much more sensitive to the mechanisms of intermittent hypoxia and oxidative stress, may be present. PURPOSE: This review aimed to show an updated view on the studies evaluating the genetic basis of inflammatory response in many aspects of OSAS and to highlight potential research areas not fully explored to date in this field.
Assuntos
Expressão Gênica/genética , Mediadores da Inflamação/metabolismo , Apneia Obstrutiva do Sono/genética , Apneia Obstrutiva do Sono/imunologia , Alelos , Proteína C-Reativa/genética , Quimiocina CCL5/genética , Pressão Positiva Contínua nas Vias Aéreas , Humanos , Interleucina-6/genética , NF-kappa B/genética , Estresse Oxidativo/genética , Polimorfismo Genético/genética , RNA Mensageiro/genética , Apneia Obstrutiva do Sono/terapia , Fator de Necrose Tumoral alfa/genéticaRESUMO
Recent data have indicated that inflammation may have an important correlation with obstructive sleep apnea (OSA). Studies have indicated a relationship between OSA and TNF-α gene polymorphisms. Zinc finger protein 36 (ZFP36) regulates TNF-α mRNAs. However, ZFP36 gene polymorphisms have not been investigated in OSA. Therefore, we conducted the present case-control study to assess whether variances in ZFP36 gene polymorphisms account for differences in TNF-α levels in patients with moderate-to-severe OSA. This case-control study aims to investigate the relationship between genetic variations in the ZFP36 gene and moderate-to-severe OSA. Three common single nucleotide polymorphisms of the ZFP36 gene (rs251864, rs3746083, and rs17879933) were evaluated in a group of patients with moderate-to-severe OSA (N = 408) and in a control group (N = 394) by using TaqMan polymerase chain reaction analysis. The moderate-to-severe OSA group and the control group exhibited significant differences in the distributions of rs251864 and rs17879933 genotypes and alleles (P < 0.05). TNF-α levels were significantly different not only among the three rs251864 genotypes but also between the II genotype and the DD + ID genotypes of rs17879933. However, no significant differences in sleep apnea parameters in the three ZFP36 gene polymorphisms were observed. Logistic regression analyses demonstrated that TNF-α and the three ZFP36 gene polymorphisms were not independently associated with OSA. ZFP36 might be involved in TNF-α regulation. However, ZFP36 gene variants were not independent risk factors for moderate-to-severe OSA.
Assuntos
Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , Apneia Obstrutiva do Sono/genética , Tristetraprolina/genética , Fator de Necrose Tumoral alfa/genética , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Frequência do Gene , Genótipo , Humanos , Inflamação , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Polissonografia , RNA Mensageiro/metabolismo , Fatores de Risco , Índice de Gravidade de Doença , Transdução de Sinais , Apneia Obstrutiva do Sono/metabolismo , Apneia Obstrutiva do Sono/patologia , Tristetraprolina/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVE: Obstructive sleep apnea syndrome is mainly characterized by intermittent hypoxia (IH) during sleep, being associated with several complications. Exposure to IH is the most widely used animal model of sleep apnea, short-term IH exposure resulting in cognitive and neuronal impairment. Pigment epithelium-derived factor (PEDF) is a hypoxia-sensitive factor acting as a neurotrophic, neuroprotective, and antiangiogenic agent. Our study analyzed performance on learning and cognitive tasks, as well as PEDF gene expression and PEDF protein expression in specific brain structures, in rats exposed to long-term IH. METHODS: Male Wistar rats were exposed to IH (oxygen concentrations of 21-5%) for 6 weeks-the chronic IH (CIH) group-or normoxia for 6 weeks-the control group. After CIH exposure, a group of rats were allowed to recover under normoxic conditions for 2 weeks (the CIH+N group). All rats underwent the Morris water maze test for learning and memory, PEDF gene expression and PEDF protein expression in the hippocampus, frontal cortex, and temporal cortex being subsequently assessed. RESULTS: The CIH and CIH+N groups showed increased PEDF gene expression in the temporal cortex, PEDF protein expression remaining unaltered. PEDF gene expression and PEDF protein expression remained unaltered in the frontal cortex and hippocampus. Long-term exposure to IH did not affect cognitive function. CONCLUSIONS: Long-term exposure to IH selectively increases PEDF gene expression at the transcriptional level, although only in the temporal cortex. This increase is probably a protective mechanism against IH-induced injury.
OBJETIVO: A síndrome da apneia obstrutiva do sono caracteriza-se principalmente por episódios de hipóxia intermitente (HI) durante o sono e associa-se a diversas complicações. A exposição à HI é o mais usado modelo animal de apneia do sono, e protocolos de curta duração causam diversos prejuízos cognitivos e neuronais. Pigment epithelium-derived factor (PEDF, fator derivado do epitélio pigmentado) é um fator neurotrófico, neuroprotetor e antiangiogênico sensível à hipóxia celular. Nosso estudo analisou o desempenho em tarefas cognitivas e de aprendizagem, bem como a expressão do gene PEDF e da proteína PEDF em estruturas cerebrais específicas em ratos expostos a HI de longa duração. MÉTODOS: Ratos Wistar foram expostos a HI (21-5% de oxigênio) durante 6 semanas - o grupo HI crônica (HIC) - ou a normóxia durante 6 semanas - o grupo controle. Após a exposição à HIC, um grupo de ratos foi exposto a normóxia durante 2 semanas (o grupo HIC+N). Todos os animais foram submetidos ao labirinto aquático de Morris para avaliação de memória e aprendizado; avaliou-se também a expressão do gene PEDF e da proteína PEDF no hipocampo e nos córtices frontal e temporal. RESULTADOS: Os grupos HIC e HIC+N apresentaram um aumento de expressão do gene PEDF no córtex temporal, porém sem aumento dos níveis proteicos. A expressão do gene PEDF e da proteína PEDF manteve-se inalterada nas demais estruturas. A exposição de longa duração à HI não afetou a função cognitiva. CONCLUSÕES: A exposição de longa duração à HI aumenta seletivamente a expressão do gene PEDF ao nível transcricional, embora apenas no córtex temporal. Esse aumento é provavelmente um mecanismo de proteção contra a HI.