Protective Role of TRPC3 Gene Polymorphism (rs10518289) in Obstructive Sleep Apnea Hypopnea Syndrome Among Hypertensive Patients.

BACKGROUND Obstructive sleep apnea-hypopnea syndrome (OSAHS) presents a significant health concern, particularly among individuals with essential hypertension (EH). Understanding the genetic underpinnings of this association is crucial for effective management and intervention. We investigated the relationship between TRPC3 gene polymorphisms and susceptibility to OSAHS in patients with EH. MATERIAL AND METHODS We enrolled 373 patients with EH hospitalized at the First Affiliated Hospital of Xinjiang Medical University between April 2015 and November 2017. Patients were categorized into EH (n=74) and EH+OSAHS (n=299) groups according to the apnea-hypopnea index. Sequenom detection technology was used for TRPC3 gene single-nucleotide polymorphism genotyping, including genotypes at rs953691, rs10518289, rs2292232, rs4995894, rs951974, and rs4292355. RESULTS Sex, smoking history, alcohol history, hypertension duration, fasting blood glucose, urea, creatinine, total cholesterol, HDL-C, LDL-C, glycosylated hemoglobin, 24-h mean systolic BP, and 24-h mean diastolic BP were not significantly different between the 2 groups (P>0.05); however, age, BMI, triglyceride levels differed significantly (P<0.05). No significant difference was detected in distribution frequency of polymorphisms of TRPC3 gene between the 2 groups (P>0.05), while genotype, dominant genotype, and recessive genotype at rs10518289 and alleles at rs4292355 differed significantly (P<0.05). Logistic regression analysis showed age, BMI, and CG+GG genotypes at rs10518289 were risk factors for OSAHS in patients with EH. Interaction between TRPC3 (rs10518289) and obesity was not a risk of OSAHS with EH (P>0.05). CONCLUSIONS CC genotype of rs10518289 in the TRPC3 gene could be a protective genetic marker of OSAHS, and CG+GG genotype may be a risk genetic marker of OSAHS with EH.

The causal relationship between depression and obstructive sleep apnea: A bidirectional Mendelian randomization study.

OBJECTIVE: Numerous studies have reported the close association of depression with obstructive sleep apnea (OSA). However, the causal nature and direction remain unclear. This study aimed to identify the genetic causal relationship between depression and OSA using Mendelian randomization (MR). METHODS: Based on publicly available genome-wide association studies data of depression and OSA, we conducted a bidirectional two-sample MR study. The inverse-variance weighted (IVW) was used as the main analysis method. Moreover, multivariable MR was performed to further explore the underlying genetic causality of OSA and depression after adjusting for several potential mediators. RESULTS: The univariable MR analysis revealed a significant causality of depression on the susceptibility of OSA (ORivw = 1.29, 95%CI:1.11,1.50; p < 0.001). This relationship was evidenced by the phenotypes for broad depression (ORivw = 3.30, 95%CI: 1.73, 6.29; p < 0.001), probable major depression (ORivw = 18.79, 95%CI: 5.69, 61.99; p < 0.001), and ICD-10 major depression (ORivw = 23.67, 95%CI: 4.13, 135.74; p < 0.001). In the reverse direction, no significant causal effect of OSA on depression was found. After adjusting for smoking, alcohol use, obesity, type 2 diabetes, insomnia, age, gender, and codeine, most of these results suggested that depression remained significantly and positively associated with OSA. CONCLUSION: These findings may contribute to the understanding of the etiology of depression and OSA and also suggest the clinical significance of controlling depression for the prevention of OSA.

Genetic variant in TNF-α gene and its plasma level in relation to obstructive sleep apnoea in the Pakistani population.

OBJECTIVE: To assess the link between tumour necrosis factor-alpha -308 guanine/adenine polymorphism and tumour necrosis factor-alpha plasma levels in relation to obstructive sleep apnoea. METHODS: The cross-sectional study was conducted from December 2018 to March 2021 at the sleep clinic of Dow University Hospital, Karachi, on obstructive sleep apnoea patients and healthy controls. Epworth Sleep Scale score was used to determine daytime sleepiness, while full-night polysomnography was carried out for obstructive sleep apnoea confirmation and categorisation according to severity. Blood sample collection was followed by deoxyribonucleic acid extraction and plasma tumour necrosis factor-alpha measurement using enzyme-linked immunosorbent assay. Genotype distribution and allelic frequency were assessed. Data was analysed using SPSS 20. RESULTS: Out of the 225 subjects, with a mean age of 47.68±9.88 years, 132 (58.7%) were males, and 93 (41.3%) were females. Among them, 150 (66.7%) were patients, and 75 (33.3%) were controls. Heterozygous tumour necrosis factor-alpha -308 guanine/adenine genotypes were significantly higher among the patients (p<0.05). Minor allele - 308 adenine showed an association with obstructive sleep apnoea, its severity, higher tumour necrosis factor-alpha levels, neck circumference, excessive daytime sleepiness and the presence of hypertension (p<0.05). CONCLUSIONS: Tumour necrosis factor-alpha -308 adenine allele and higher tumour necrosis factor-alpha levels were found to be linked with obstructive sleep apnoea. The polymorphism also showed an association with hypertension in obstructive sleep apnoea patients.

LncRNA NEAT1 aggravates human microvascular endothelial cell injury by inhibiting the Apelin/Nrf2/HO-1 signalling pathway in type 2 diabetes mellitus with obstructive sleep apnoea.

Long noncoding RNAs (lncRNAs) regulate the progression of type 2 diabetes mellitus complicated with obstructive sleep apnoea (T2DM-OSA). However, the role of the lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1) in T2DM-OSA remains unknown. This study aimed to reveal the function of NEAT1 in T2DM-OSA and the underlying mechanism. KKAy mice were exposed to intermittent hypoxia (IH) or intermittent normoxia to generate a T2DM-OSA mouse model. HMEC-1 cells were treated with high glucose (HG) and IH to construct a T2DM-OSA cell model. RNA expression was detected by qRT-PCR. The protein expression of Apelin, NF-E2-related factor 2 (Nrf2), haem oxygenase-1 (HO-1), and up-frameshift suppressor 1 (UPF1) was assessed using western blot. Cell injury was evaluated using flow cytometry, enzyme-linked immunosorbent assay, and oxidative stress kit assays. RIP, RNA pull-down, and actinomycin D assays were performed to determine the associations between NEAT1, UPF1, and Apelin. NEAT1 expression was upregulated in the aortic vascular tissues of mice with T2DM exposed to IH and HMEC-1 cells stimulated with HG and IH, whereas Apelin expression was downregulated. The absence of NEAT1 protected HMEC-1 cells from HG- and IH-induced damage. Furthermore, NEAT1 destabilized Apelin mRNA by recruiting UPF1. Apelin overexpression decreased HG- and IH-induced injury to HMEC-1 cells by activating the Nrf2/HO-1 pathway. Moreover, NEAT1 knockdown reduced HG- and IH-induced injury to HMEC-1 cells through Apelin. NEAT1 silencing reduced HMEC-1 cell injury through the Apelin/Nrf2/HO-1 signalling pathway in T2DM-OSA.Abbreviations: LncRNAs, long non-coding RNAs; T2DM, type 2 diabetes mellitus; OSA, obstructive sleep apnoea; NEAT1, nuclear paraspeckle assembly transcript 1; IH, intermittent hypoxia; HMEC-1, human microvascular endothelial cells; HG, high glucose; Nrf2, NF-E2-related factor 2; UPF1, up-frameshift suppressor 1; HO-1, haem oxygenase-1; qRT-PCR, quantitative real-time polymerase chain reaction; ELISA, enzyme-linked immunosorbent assay; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; TNF-α, tumour necrosis factor-α; CCK-8, Cell Counting Kit-8; IL-1ß, interleukin-1ß; ROS, reactive oxygen species; MDA, malondialdehyde; SOD, superoxide dismutase; RIP, RNA immunoprecipitation; SD, standard deviations; GSH, glutathione; AIS, acute ischaemic stroke; HMGB1, high mobility group box-1 protein; TLR4, toll-like receptor 4.

Association of the TNF-α-308G>A gene polymorphism with left ventricular geometry and functional abnormalities in obstructive sleep apnea subjects.

OBJECTIVE: Tumor necrosis factor-α (TNF-α) can induce left ventricular remodeling. In this study, we investigated whether the TNF-α-308G>A polymorphism is associated with left ventricular geometry (LVG) and left ventricular functional abnormalities in obstructive sleep apnea (OSA) subjects. METHODS: Two hundred and seventy-eight subjects were enrolled. Echocardiography and genetic data were assessed in all patients. Geometric patterns of the left ventricle were determined from the relative wall thickness and left ventricular mass index (LVMI). Genetic analysis for the TNF-α-308G>A SNP rs1800629 was identified by Sanger sequencing. The correlations of the TNF-α-308G>A polymorphism with LVG and left ventricular function were analyzed by difference analysis and logistic regression. RESULTS: The chi-square test showed that there were differences in genotype distributions among the four groups (p = 0.033), such that the frequency of GA+AA genotypes was significantly higher in the concentric hypertrophy group than in the normal geometry group (p < 0.05). Independent sample T tests showed that the GA+AA genotypes had higher IVST, LVPWT, LVMI, E/e' values, and lower e' values than those of the GG genotype (p < 0.05). Logistic regression analysis showed that the TNF-α-308G>A polymorphism was independently correlated with eccentric hypertrophy (OR = 2.456, p = 0.047) and concentric hypertrophy (OR = 2.456, p = 0.047). CONCLUSION: In OSA patients, the TNF-α-308G>A polymorphism was linked to LVG and abnormal left ventricular diastolic function, suggesting that the TNF-α-308G>A polymorphism may have an important influence on LVG alterations.

Reduction of IL-6, IL-8 and ß2-ADRENOCEPTOR mRNA levels in circulating polymorphonuclear leukocytes after adenotonsillectomy in children with Obstructive Sleep Apnea Syndrome.

BACKGROUND: Obstructive Sleep Apnea Syndrome (OSAS) affects approximately 1-5% of children and is linked to cardiovascular, metabolic, and neurobehavioral complications. Dysregulation of inflammatory process and sympathetic nervous system overstimulation leading to increased catecholamine production may contribute to OSAS pathogenesis. Polymorphonuclear Neutrophils (PMN), key cells in the inflammatory process, express adrenergic receptors, including ß2-adrenergic receptor (ADRB2), which modulate their functions through an autocrine/paracrine loop. In this pilot study, we aimed to investigate the relationship between OSAS severity, ADRB2 expression in PMN and patient's inflammatory profile before and after adenotonsillectomy. PATIENTS/METHODS: In this pilot study we enrolled OSAS pediatric patients in which ADRB2, IL-6 and IL-8 mRNA expression levels were evaluated in circulating PMN by RT-PCR. RESULTS: 9 OSAS pediatric patients, ranged from 3 to 8 years of age, were enrolled in the study. We found that adenotonsillectomy significantly reduced ADRB2 as well as IL-6, IL-8 mRNA expression levels in PMN. CONCLUSIONS: These findings offer valuable insights into the underlying immune and inflammatory mechanisms of OSAS and open the way for the development of novel therapeutic approaches.

Association of modifiable risk factors with obstructive sleep apnea: a Mendelian randomization study.

BACKGROUND: The risk factors involved in obstructive sleep apnea (OSA) have not been clearly identified yet. We attempted to systematically investigate genetically predicted modifiable risk factors and lifestyle behaviors associated with OSA. METHODS: The association between 34 risk factors and OSA was evaluated using the two-sample Mendelian randomization (MR). Genetic variants for risk factors were acquired from European-descent genome-wide studies. Data sources for OSA were extracted from FinnGen study with 16,761 cases and 201,194 controls. The primary analysis chosen was the inverse-variance weighted method. RESULTS: MR analyses provide evidence of genetically predicted poor overall health rating (odds ratio (OR), 2.82; 95% confidence interval (CI), 1.95-4.08), nap during day (OR, 2.01; 95% CI, 1.37-2.93), high body mass index (BMI) (OR, 1.14; 95% CI, 1.09-1.19), increased body fat mass (OR, 1.83; 95% CI, 1.83-2.05), elevated body water mass (OR, 1.50; 95% CI, 1.31-1.70) and hypertension (OR, 1.81; 95% CI, 1.34-2.45) were associated with higher OSA risk, while high education level (OR, 0.55; 95% CI, 0.40-0.75) correlated with reduced OSA risk. Suggestive evidence was obtained for smoking and waist-to-hip ratio (WHR) with higher OSA odds, and vigorous physical activity, and HDL cholesterol with lower OSA odds. After adjusting for BMI using multivariable MR analysis, the effects of smoking, WHR, vigorous physical activity, and HDL-cholesterol were fully attenuated. CONCLUSIONS: This MR study indicates that overall health rating, nap during day, BMI, body fat mass, body water mass, hypertension, and education are causally associated with the risk of OSA, which means that these modifiable risk factors are key targets for OSA prevention.

[The association of renalase single-nucleotide polymorphisms rs2576178 and rs10887800 with hypertension in patients with obstructive sleep apnea].

Objective: To evaluate the associations between the renalase single-nucleotide polymorphisms rs2576178 and rs10887800 and the risk of hypertension in OSA patients. Methods: A total of 3, 570 male OSA subjects diagnosed via standard polysomnography were included in this retrospective study. We recorded anthropometric, genomic, and polysomnographic parameters and blood pressure levels. All subjects were divided into four groups based on quartiles of the apnea-hypopnea index (AHI). The relationships between rs2576178 and rs10887800 and the risk of hypertension were evaluated using the binary logistic regression, and haplotype analysis. Results: In the bottom AHI quartile, rs10887800 was significantly associated with the risk of hypertension according to the dominant model [odds ratio(OR)=0.691, 95% confidence interval (CI)=0.483-0.990, P=0.044] even after adjustment for age, sex, and the body mass index. The G-A haplotype was associated with a co-effect of the two SNPs, namely, the risk of hypertension decreased (OR=0.879, 95%CI=0.784-0.986, P=0.028). Conclusions: We find no association between single rs2576178 or rs10887800 variants with the risk of hypertension in our OSA population. But, the synergistic effect of the two polymorphisms is associated with the risk of hypertension in OSA patients.

[Obstructive sleep apnea and type 2 diabetes: a bidirectional Mendelian randomization study].

Objective: This study aims to explore the causal relationship between obstructive sleep apnea (OSA) and type 2 diabetes (T2D) using bidirectional Mendelian randomization (MR). Methods: The genetic data related to OSA were obtained from the FinnGen Biobank (Ncase=16, 761, Ncontrol=201, 194) in the Genome-wide association study (GWAS). Three single nucleotide polymorphism (SNP) were screened out as instrumental variable (IV) of OSA. The genetic data related to T2D were derived from a large Meta-analysis of GWAS (Ncase=62, 892, Ncontrol=596, 424), 114 SNP were selected as IV of T2D. Multiple MR methods were used for analysis and inverse variance weighted (IVW) was performed as main method. The sensitivity of MR analytic results was analyzed using MR-Egger and other methods, and the IV was evaluated using F-value statistics. Results: MR analysis showed that OSA was significantly associated with increased risk of T2D (OR=2.016, 95%CI: 1.185-3.429, P<0.05). There was no significant relationship between T2D and OSA risk (OR=1.030, 95%CI: 0.980-1.082, P=0.238). There was heterogeneity in both-way results (OSA➝T2D, P=1.808×10-11; T2D➝OSA, P=1.729×10-7), and no horizontal pleiotropy (OSA➝T2D, P=0.477; T2D➝OSA, P=0.349). IV of OSA and T2D-selected in the study were strong instrumental variables (F statistics of OSA=20.543; F statistics of T2D=30.117). Conclusion: Our results supported that OSA was a risk factor for T2D, but T2D had no significant impact on the incidence of OSA. Blood glucose monitoring and diabetes screening in OSA patients might be beneficial to the early detection and intervention of T2D.

PSGL-1: a novel immune checkpoint driving T-cell dysfunction in obstructive sleep apnea.

Introduction: Although higher incidence of cancer represents a major burden for obstructive sleep apnea (OSA) patients, the molecular pathways driving this association are not completely understood. Recently, the adhesion receptor P-selectin glycoprotein-1 (PSGL 1) has been identified as a novel immune checkpoint, which are recognized major hallmarks in several types of cancer and have revolutionized cancer therapy. Methods: The expression of PSGL-1 and its ligands VISTA and SIGLEC-5 was assessed in the leucocytes of OSA patients and control subjects exploring the role of intermittent hypoxia (IH) using in vitro models. In addition, PSGL-1 impact on T-cells function was evaluated by ex vivo models. Results: Data showed PSGL-1 expression is upregulated in the T-lymphocytes from patients with severe OSA, indicating a relevant role of hypoxemia mediated by intermittent hypoxia. Besides, results suggest an inhibitory role of PSGL-1 on T-cell proliferation capacity. Finally, the expression of SIGLEC-5 but not VISTA was increased in monocytes from OSA patients, suggesting a regulatory role of intermittent hypoxia. Discussion: In conclusion, PSGL-1 might constitute an additional immune checkpoint leading to T-cell dysfunction in OSA patients, contributing to the disruption of immune surveillance, which might provide biological plausibility to the higher incidence and aggressiveness of several tumors in these patients.

Intermittent Hypoxia Mediates Cancer Development and Progression Through HIF-1 and miRNA Regulation.

INTRODUCTION: There is still a debate for the link between obstructive sleep apnoea (OSA) and cancer. The mechanisms underlying this causality are poorly understood. Several miRNAs are involved in cancer development and progression with expression being influenced by hypoxia. The aims of this work were (i) to compare miRNAs expression in controls versus patients affected by OSA without or with cancer (ONCO-OSA) and (ii) in colorectal cancer cells exposed to intermittent hypoxia (IH), to evaluate miRNAs impact on tumor progression in vitro. METHODS: We detected miRNAs by qRT-PCR in patients' sera and in CaCo2 cells exposed to 2-32h of IH with or without acriflavine (ACF), a HIF-1 inhibitor. Viability and transwell invasion test were applied to investigate the proliferation and migration of CaCo2 exposed to IH and treated with miRNA inhibitors or acriflavine. HIF-1α activity was evaluated in CaCo2 cells after IH. RESULTS: The levels of miR-21, miR-26a and miR-210 increased in OSA and ONCO-OSA patients compared to controls. MiR-23b increased in ONCO-OSA patients, and miR-27b and miR-145 increased in OSA but not ONCO-OSA patients. MiR-21, miR-26a, miR-23b and miR-210 increased in cells after IH. IH stimulated cell proliferation and migration. This effect was reduced after either miRNA inhibition or acriflavine treatment. MiRNA inhibition reduces HIF-1α gene expression. Conversely, acriflavine reduced the expression of these miRNAs. CONCLUSIONS: We identified a signature of miRNAs, induced by the IH environment. They could be implicated in cancer development and progression through a regulatory loop involving HIF-1.

Implications of obstructive sleep apnea in lung adenocarcinoma: A valuable omission in cancer prognosis and immunotherapy.

Lung adenocarcinoma (LUAD) is a highly invasive malignant tumor with poor prognosis, and there is growing evidence that obstructive sleep apnea (OSA) could significantly promotes the risk of LUAD. In order to improve the treatment outcomes of patients with LUAD and OSA, we aim to screen OSA-related genes that may potentially affect LUAD and to discover a high sensitivity prognostic signature that can stratify LUAD/OSA patients and to further accurately identify LUAD patients who might respond to immunotherapy. Molecular subtypes classified by the prognostic signature did not belong to any previously reported subtypes of LUAD. The tumor microenvironment (TME), mutation, and so on, were significantly distinct between patients within different risk groups or clusters. Combined with gene set variation analysis (GSVA) and drug susceptibility analysis, patients in the low-risk group (The vast majority of patients belonging to cluster2 by molecular subtyping) were not suitable for immunotherapy due to T-cell exhaustion caused by long-term inflammatory response; the question of how to reverse T-cell exhaustion may be a primary consideration. Cluster3 patients had the highest benefit from immunotherapy, and although cluster1 patients had the worst prognosis, they were more sensitive to traditional chemotherapeutic drugs. Animal experiments showed that chronic intermittent hypoxia (CIH) could not only significantly promote the tumor growth of LUAD, but also increase the expression levels of risk genes. This risk model may contribute greatly to the evaluation of prognosis, molecular characteristics, and treatment modalities of LUAD/OSA, and could be further translated into clinical applications to ameliorate the treatment dilemmas.

Smoking, Coffee Consumption, Alcohol Intake, and Obstructive Sleep Apnea: A Mendelian Randomization Study.

BACKGROUND: Previous studies revealed that obstructive sleep apnea (OSA) and smoking, alcohol consumption, and coffee intake are closely related. This study aimed to evaluate the causal effect between these factors and OSA. METHODS: The published genome-wide association study data (GWAS) provided genetic tools. We conducted a univariable two-sample Mendelian Randomization (MR) to estimate the causal effect between smoking initiation, never smoking, alcohol consumption, coffee intake, and coffee consumption with the risk of incidence OSA. Inverse variance weighting (IVW) was used as the main method for effect evaluation, and other MR methods were used for sensitivity analysis. After adjusting for body mass index (BMI), hypertension, and diabetes respectively by multivariable MR (MVMR), we further evaluate the causal effect of these factors on OSA. RESULTS: Under univariable MR analysis, we observed that smoking initiation was associated with an increased risk of incidence OSA (OR 1.326, 95% CI 1.001-1.757, p =0.049). Never smoking was associated with decreased risk of OSA (OR 0.872, 95% CI 0.807-0.942, p <0.001). Coffee intake and coffee consumption was associated with an increased incidence of OSA (OR 1.405, 95% CI 1.065-1.854, p =0.016) and (OR 1.330, 95% CI 1.013-1.746, p =0.040). Further multivariate MR showed that the causal relationship between never smoking and OSA existed but not coffee consumption, after adjusting for diabetes and hypertension. However, the all results did not support causality after adjusting for BMI. CONCLUSION: This two-sample MR study showed that genetically predicted smoking and higher coffee intake are causally associated with an increased risk of OSA.

Pathophysiological mechanisms and therapeutic approaches in obstructive sleep apnea syndrome.

Obstructive sleep apnea syndrome (OSAS) is a common breathing disorder in sleep in which the airways narrow or collapse during sleep, causing obstructive sleep apnea. The prevalence of OSAS continues to rise worldwide, particularly in middle-aged and elderly individuals. The mechanism of upper airway collapse is incompletely understood but is associated with several factors, including obesity, craniofacial changes, altered muscle function in the upper airway, pharyngeal neuropathy, and fluid shifts to the neck. The main characteristics of OSAS are recurrent pauses in respiration, which lead to intermittent hypoxia (IH) and hypercapnia, accompanied by blood oxygen desaturation and arousal during sleep, which sharply increases the risk of several diseases. This paper first briefly describes the epidemiology, incidence, and pathophysiological mechanisms of OSAS. Next, the alterations in relevant signaling pathways induced by IH are systematically reviewed and discussed. For example, IH can induce gut microbiota (GM) dysbiosis, impair the intestinal barrier, and alter intestinal metabolites. These mechanisms ultimately lead to secondary oxidative stress, systemic inflammation, and sympathetic activation. We then summarize the effects of IH on disease pathogenesis, including cardiocerebrovascular disorders, neurological disorders, metabolic diseases, cancer, reproductive disorders, and COVID-19. Finally, different therapeutic strategies for OSAS caused by different causes are proposed. Multidisciplinary approaches and shared decision-making are necessary for the successful treatment of OSAS in the future, but more randomized controlled trials are needed for further evaluation to define what treatments are best for specific OSAS patients.

Integrative Analysis and Experimental Validation of Competing Endogenous RNAs in Obstructive Sleep Apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is highly prevalent yet underdiagnosed. This study aimed to develop a predictive signature, as well as investigate competing endogenous RNAs (ceRNAs) and their potential functions in OSA. METHODS: The GSE135917, GSE38792, and GSE75097 datasets were collected from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database. Weighted gene correlation network analysis (WGCNA) and differential expression analysis were used to identify OSA-specific mRNAs. Machine learning methods were applied to establish a prediction signature for OSA. Furthermore, several online tools were used to establish the lncRNA-mediated ceRNAs in OSA. The hub ceRNAs were screened using the cytoHubba and validated by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Correlations between ceRNAs and the immune microenvironment of OSA were also investigated. RESULTS: Two gene co-expression modules closely related to OSA and 30 OSA-specific mRNAs were obtained. They were significantly enriched in the antigen presentation and lipoprotein metabolic process categories. A signature that consisted of five mRNAs was established, which showed a good diagnostic performance in both independent datasets. A total of twelve lncRNA-mediated ceRNA regulatory pathways in OSA were proposed and validated, including three mRNAs, five miRNAs, and three lncRNAs. Of note, we found that upregulation of lncRNAs in ceRNAs could lead to activation of the nuclear factor kappa B (NF-κB) pathway. In addition, mRNAs in the ceRNAs were closely correlated to the increased infiltration level of effector memory of CD4 T cells and CD56bright natural killer cells in OSA. CONCLUSIONS: In conclusion, our research opens new possibilities for diagnosis of OSA. The newly discovered lncRNA-mediated ceRNA networks and their links to inflammation and immunity may provide potential research spots for future studies.

Adult-onset obstructive sleep apnea and pediatric pharyngoplasty in 22q11.2 deletion syndrome.

OBJECTIVE/BACKGROUND: We aimed to evaluate adult-onset obstructive sleep apnea (OSA) and related risk factors, including history of pediatric palatal/pharyngeal surgery to remediate velopharyngeal dysfunction, in 22q11.2 deletion syndrome (22q11.2DS). PATIENTS/METHODS: Using a retrospective cohort design and standard sleep study-based criteria, we determined presence of adult-onset OSA (age ≥16 years) and relevant variables through comprehensive chart review in a well-characterized cohort of 387 adults with typical 22q11.2 microdeletions (51.4% female, median age 32.3, interquartile range 25.0-42.5, years). We used multivariate logistic regression to identify independent risk factors for OSA. RESULTS: Of the 73 adults with sleep study data, 39 (53.4%) met criteria for OSA at median age 33.6 (interquartile range 24.0-40.7) years, indicating a minimum OSA prevalence of 10.1% in this 22q11.2DS cohort. History of pediatric pharyngoplasty (odds ratio 2.56, 95% confidence interval 1.15-5.70) was a significant independent predictor of adult-onset OSA, while accounting for other significant independent predictors (asthma, higher body mass index, older age), and for male sex. An estimated 65.5% of those prescribed continuous positive airway pressure therapy were reported as adherent. CONCLUSIONS: In addition to factors of known importance in the general population, delayed effects of pediatric pharyngoplasty may contribute to risk of adult-onset OSA in individuals with 22q11.2DS. The results support increased index of suspicion for OSA in adults with a 22q11.2 microdeletion. Future research with this and other homogeneous genetic models may help to improve outcomes and to better understand genetic and modifiable risk factors for OSA.

Identification of Novel Biomarkers for Abdominal Aortic Aneurysm Promoted by Obstructive Sleep Apnea.

BACKGROUND: We sought to find new biomarkers for abdominal aortic aneurysms (AAA) caused by chronic intermittent hypoxia (CIH). METHODS: The AAA mice model was created using Ang II. The mice were divided into normoxic and CIH groups. The structure of AAA was observed using abdominal ultrasonography, Elastica van Gieson (EVG), and hematoxylin and eosin (HE) staining. The expression of ɑ-SMA was investigated using immunohistochemistry. The novel biomarkers were screened using bioinformatics analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to verify the expression of novel genes in both normal oxygen and CIH. RESULTS: CIH appears to cause greater aortic dilation, higher AAA incidence, lower survival rate, thicker vessel wall, and more brittle elastic lamellae when compared to controls. The immunohistochemistry results showed that the expression of ɑ-SMA in the CIH group was reduced significantly. Four novel genes, including Homer2, Robo2, Ehf, and Asic1, were found to be differentially expressed between normal oxygen and CIH using qRT-PCR, indicating the same trend as bioinformatics analysis. CONCLUSIONS: We discovered that CIH could hasten the occurrence and progression of AAA. Four genes (Homer2, Robo2, Ehf, and Asic1) may be novel biomarkers for AAA, which could aid in the search for new therapies for patients with AAA caused by CIH.

Causal associations of obstructive sleep apnea with cardiovascular disease: a Mendelian randomization study.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) had been associated with various cardiovascular diseases (CVDs) in observational studies, but causal inferences have not been confirmed. We used the Mendelian randomization (MR) study to explore the potential causal association between OSA with CVDs in the general population. METHODS: We performed a two-sample MR analysis using five gene-wide significant single-nucleotide polymorphisms associated with OSA at genome-wide significance from the FinnGen study (N = 217 955) and 12 cardiovascular diseases from the UK Biobank and the genetic consortia. The inverse-variance weight was chosen as the primary analysis and was complemented by various sensitivity analyses. The study design applied univariable MR, multivariable MR, and mediation analysis. RESULTS: MR analyses provide evidence of genetically predicted OSA on the risk of heart failure (odds ratio [OR],1.26; 95% confidence interval [CI],1.08 to 1.47), hypertension (OR,1.24; 95%CI, 1.11 to 1.39) and atrial fibrillation (OR,1.21; 95%CI,1.12 to 1.31). Multivariable MR indicated the adverse effect of OSA on heart failure persisted after adjusting BMI, smoking, drinking, and education (IVW OR,1.13; 95%CI, 1.01 to 1.27). However, the significance of hypertension and atrial fibrillation was dampened. Mediation analyses suggest that the causal association between OSA and heart failure is mediated in part by Apolipoprotein B, with a mediated portion of 9%. CONCLUSIONS: This study suggested that genetically predicted OSA is a potential causal risk factor for heart failure based on a large-scale population. Nevertheless, further studies regarding ancestral diversity are needed to confirm the causal association between OSA and CVDs.