Relationships between apolipoprotein E and insulin resistance in patients with obstructive sleep apnoea: a large-scale cross-sectional study.

BACKGROUND: Obstructive sleep apnoea (OSA) is commonly associated with insulin resistance (IR) and dyslipidaemia. Apolipoprotein E (APOE) plays important roles in lipid metabolism. The study aimed to disentangle the multifactorial relationships between IR and APOE based on a large-scale population with OSA. METHODS: A total of 5,591 participants who underwent polysomnography for OSA diagnosis were finally enrolled. We collected anthropometric, fasting biochemical and polysomnographic data for each participant. Linear regression analysis was performed to evaluate the relationships between APOE, IR, and sleep breathing-related parameters. Logistic regression, restricted cubic spline (RCS) and mediation analyses were used to explore relationships between APOE and IR in patients with OSA. RESULTS: Increasing OSA severity was associated with greater obesity, more obvious dyslipidaemia, and higher levels of APOE and IR. APOE was positively correlated with the apnoea-hypopnoea index (AHI), oxygen desaturation index (ODI) and microarousal index (MAI) even after adjusting for age, sex, body mass index, and smoking and drinking levels (ß = 0.107, ß = 0.102, ß = 0.075, respectively, all P < 0.001). The risks of IR increased from the first to fourth quartiles of APOE (odds ratio (OR) = 1.695, 95% CI: 1.425-2.017; OR = 2.371, 95% confidence interval (CI): 2.009-2.816; OR = 3.392, 95% CI: 2.853-4.032, all P < 0.001) after adjustments. RCS analysis indicated non-linear and dose response relationships between APOE, AHI, ODI, MAI and insulin resistance. Mediation analyses showed that HOMA-IR explained 9.1% and 10% of the association between AHI, ODI and APOE. The same trends were observed in men, but not in women. CONCLUSIONS: This study showed that APOE is a risk factor for IR; moreover, IR acts as a mediator between OSA and APOE in men. APOE, IR, and OSA showed non-linear and multistage relationships. Taken together, these observations revealed the complex relationships of metabolic disorders in patients with OSA, which could lead to the development of new treatment modalities and a deeper understanding of the systemic impact of OSA.

Independent relationship between sleep apnea-specific hypoxic burden and glucolipid metabolism disorder: a cross-sectional study.

OBJECTIVES: Obstructive sleep apnea (OSA) is associated with abnormal glucose and lipid metabolism. However, whether there is an independent association between Sleep Apnea-Specific Hypoxic Burden (SASHB) and glycolipid metabolism disorders in patients with OSA is unknown. METHODS: We enrolled 2,173 participants with suspected OSA from January 2019 to July 2023 in this study. Polysomnographic variables, biochemical indicators, and physical measurements were collected from each participant. Multiple linear regression analyses were used to evaluate independent associations between SASHB, AHI, CT90 and glucose as well as lipid profile. Furthermore, logistic regressions were used to determine the odds ratios (ORs) for abnormal glucose and lipid metabolism across various SASHB, AHI, CT90 quartiles. RESULTS: The SASHB was independently associated with fasting blood glucose (FBG) (ß = 0.058, P = 0.016), fasting insulin (FIN) (ß = 0.073, P < 0.001), homeostasis model assessment of insulin resistance (HOMA-IR) (ß = 0.058, P = 0.011), total cholesterol (TC) (ß = 0.100, P < 0.001), total triglycerides (TG) (ß = 0.063, P = 0.011), low-density lipoprotein cholesterol (LDL-C) (ß = 0.075, P = 0.003), apolipoprotein A-I (apoA-I) (ß = 0.051, P = 0.049), apolipoprotein B (apoB) (ß = 0.136, P < 0.001), apolipoprotein E (apoE) (ß = 0.088, P < 0.001) after adjustments for confounding factors. Furthermore, the ORs for hyperinsulinemia across the higher SASHB quartiles were 1.527, 1.545, and 2.024 respectively, compared with the lowest quartile (P < 0.001 for a linear trend); the ORs for hyper-total cholesterolemia across the higher SASHB quartiles were 1.762, 1.998, and 2.708, compared with the lowest quartile (P < 0.001 for a linear trend) and the ORs for hyper-LDL cholesterolemia across the higher SASHB quartiles were 1.663, 1.695, and 2.316, compared with the lowest quartile (P < 0.001 for a linear trend). Notably, the ORs for hyper-triglyceridemia{1.471, 1.773, 2.099} and abnormal HOMA-IR{1.510, 1.492, 1.937} maintained a consistent trend across the SASHB quartiles. CONCLUSIONS: We found SASHB was independently associated with hyperinsulinemia, abnormal HOMA-IR, hyper-total cholesterolemia, hyper-triglyceridemia and hyper-LDL cholesterolemia in Chinese Han population. Further prospective studies are needed to confirm that SASHB can be used as a predictor of abnormal glycolipid metabolism disorders in patients with OSA. TRIAL REGISTRATION: ChiCTR1900025714 { http://www.chictr.org.cn/ }; Prospectively registered on 6 September 2019; China.

Universal inter-molecular radical transfer reactions on metal surfaces.

On-surface synthesis provides tools to prepare low-dimensional supramolecular structures. Traditionally, reactive radicals are a class of single-electron species, serving as exceptional electron-withdrawing groups. On metal surfaces, however, such species are affected by conduction band screening effects that may even quench their unpaired electron characteristics. As a result, radicals are expected to be less active, and reactions catalyzed by surface-stabilized radicals are rarely reported. Herein, we describe a class of inter-molecular radical transfer reactions on metal surfaces. With the assistance of aryl halide precursors, the coupling of terminal alkynes is steered from non-dehydrogenated to dehydrogenated products, resulting in alkynyl-Ag-alkynyl bonds. Dehalogenated molecules are fully passivated by detached hydrogen atoms. The reaction mechanism is unraveled by various surface-sensitive technologies and density functional theory calculations. Moreover, we reveal the universality of this mechanism on metal surfaces. Our studies enrich the on-surface synthesis toolbox and develop a pathway for producing low-dimensional organic materials.

T266M variants of ANGPTL4 improve lipid metabolism by modifying their binding affinity to acetyl-CoA carboxylase in obstructive sleep apnea.

BACKGROUND: Angiopoietin-like protein 4 (ANGPTL4) is recognized as a crucial regulator in lipid metabolism. Acetyl-CoA carboxylases (ACACAs) play a role in the ß-oxidation of fatty acids. Yet, the functions of ANGPTL4 and ACACA in dyslipidemia of obstructive sleep apnea (OSA) remain unclear. METHODS: This study included 125 male OSA subjects from the Shanghai Sleep Health Study (SSHS) who were matched for age, body mass index (BMI), and lipid profile. Serum ANGPTL4 levels were measured via ELISA. The ANGPTL4 T266M variants of 4455 subjects along with their anthropometric, fasting biochemical, and standard polysomnographic parameters were collected. Linear regression was used to analyze the associations between quantitative traits and ANGPTL4 T266M. Molecular docking and molecular dynamic simulation were employed to compare the effects of the wild-type ANGPTL4 and its T266M mutation on ACACA. RESULTS: Serum ANGPTL4 levels significantly decreased with increasing OSA severity (non-OSA: 59.6 ± 17.4 ng/mL, mild OSA: 50.0 ± 17.5 ng/mL, moderate OSA: 46.3 ± 15.5 ng/mL, severe OSA: 19.9 ± 14.3 ng/mL, respectively, p = 6.02 × 10-16). No associations were found between T266M and clinical characteristics. Molecular docking indicated that mutant ANGTPL4 T266M had stronger binding affinity for the ACACA protein, compared with wild-type ANGPTL4. In terms of protein secondary structure, mutant ANGTPL4 T266M demonstrated greater stability than wild-type ANGPTL4. CONCLUSIONS: Serum ANGTPL4 levels were significantly decreased in OSA patients, particularly among individuals with severe OSA. Although functional ANGTPL4 T266M variants were not associated with lipid levels in OSA, ANGTPL4 T266M could enhance binding affinity for the ACACA protein, potentially regulating lipid metabolism.

Association between multiple sleep dimensions in obstructive sleep apnea and an early sign of atherosclerosis.

STUDY OBJECTIVES: We investigated the associations between multiple sleep dimensions in obstructive sleep apnea (OSA) and carotid intima-media thickness (CIMT), an early sign of atherosclerosis, in participants from the Shanghai Sleep Health Study. METHODS: We performed secondary analysis of SSHS in a group of subjects who underwent ultrasound evaluation from 2018 to 2022. Multiple sleep dimensions were measured using standard polysomnography. CIMT was measured from ultrasound images as an early sign of atherosclerosis. Multivariable-adjusted linear regression and logistic regression analyses were performed to detect associations between sleep traits in OSA and CIMT. RESULTS: CIMT was found to increase with increasing severity of OSA (P < .001). When adjusted for conventional risk factors, microarousal index and hypoxic burden were positively correlated with CIMT, while slow-wave sleep and mean apnea-hypopnea event duration showed a negative correlation with CIMT (all P < .01). In binary logistic regression analysis, participants with a high microarousal index, less slow-wave sleep, higher hypoxic burden, and shorter mean apnea-hypopnea event duration showed a higher prevalence of thick CIMT with no evidence of interaction by age, sex, or body mass index (P-interaction > .05). CONCLUSIONS: Patients with more severe sleep fragmentation, more severe hypoxemia, and increased arousability were more likely to have increased CIMT after adjusting for potential confounders. It is important to evaluate novel indices of sleep fragmentation, hypoxemia, and arousability in OSA for early detection and prevention of cardiovascular disease, including stroke. CLINICAL TRIAL REGISTRATION: Registry: Chinese Clinical Trial Registry; Name: Establishing Bio-bank and Cohort of OSAHS in Hospital-based Population; URL: http://www.chictr.org.cn/showproj.aspx?proj=43057; Identifier: ChiCTR1900025714. CITATION: Huang W, Zhou E, Zhang J, et al. Association between multiple sleep dimensions in obstructive sleep apnea and an early sign of atherosclerosis. J Clin Sleep Med. 2024;20(7):1093-1104.

Synthesis of Large-Scale High-Quality Metal-Organic Frameworks on Cu(100) via Hierarchical Dehydrogenation Reactions.

Thermal stimulus has been considered as a promising strategy for controlling on-surface reactions, allowing the formation of diverse products on metal substrates. Here, we successfully achieve hierarchical dehydrogenation reactions of amino groups on a Cu(100) surface. By carefully adjusting the experimental parameters, we synthesize large-scale and low-defect density surface metal-organic frameworks on copper surfaces. Our work sheds light on a controllable route for the synthesis of high-quality metal-organic coordination supramolecular structures via on-surface chemistry.

Constructing Two-Dimensional Distorted Kagome Lattices on Ag(111).

Two-dimensional (2D) tessellation of organic species acquired increased interest recently because of their potential applications in physics, biology, and chemistry. Herein, we successfully synthesized the chiral distorted Kagome lattice p3 (333) with bicomponent precursors on Ag(111). Scanning tunneling microscopy and density functional calculation studies reveal that the networks are formed by multiple intermolecular hydrogen bonds. The network structures can be rationally tuned by adjusting the stoichiometric ratio of the reaction precursors. Our study provides new strategies to synthesize complex low-dimensional nanostructures on metal surfaces.

The use of the sleep apnea-specific hypoxic burden to predict obstructive sleep apnea hypopnea syndrome: Evidence from a large cross-sectional study.

OBJECTIVES: Obstructive sleep apnea hypopnea syndrome (OSA) is an independent risk factor for neurocognitive and behavioral problems and cardiovascular and metabolic morbidities, ultimately increasing mortality. However, OSA diagnosis is time-consuming, labor-intensive, and expensive. We evaluated the predictive utility of the sleep apnea-specific hypoxic burden (SASHB) in terms of OSA and the severity thereof in Han Chinese individuals. METHODS: From January 2019 to July 2022, subjects with suspected OSA were recruited in the sleep center of the Shanghai Sixth People's Hospital during sleep evaluation via standard polysomnography. Basic anthropometric measurements and polysomnographic indicators were collected; SASHB was calculated based on the SpO2 trends of apnea or hypopnea events. Models predictive of OSA were established via logistic regression in the experimental group and verified in an independent group by drawing receiver operating characteristic (ROC) curves. RESULTS: A total of 2303 subjects with suspected OSA (1200 in the experimental group and 1103 in the validation group) were included. SASHB was positively correlated with the apnea-hyponea index (AHI) in all subjects (r = 0.823, P < 0.001). SASHB distinguished OSA from non-OSA subjects in both the experimental group {area under the curve (AUC) 0.948 [0.934∼0.962]} and the validation group (AUC 0.931 [0.913∼0.949]). SASHB predicted OSA severity well, better than did the neck, waist, or hip circumference; the lowest or mean oxygen saturation; and the Epworth sleepiness scale score. CONCLUSION: SASHB predicted OSA both accurately and efficiently in a Chinese Han population. Further studies are warranted to verify our findings in community samples.

Anthropometric Determinants of Autonomic Control in Obstructive Sleep Apnea: A Large-Scale Study.

OBJECTIVE: Autonomic dysfunction is an independent risk factor for cardiovascular disease (CVD). Both obesity and obstructive sleep apnea (OSA) are associated with heart rate variability (HRV) (a hall marker of sympathetic arousal) and increased risk of CVD. This study aims to investigate whether anthropometric parameters could predict reduced HRV in adult OSA during wakefulness. STUDY DESIGN: Cross-sectional study. SETTING: Sleep center of Shanghai Jiao Tong University Affiliated Sixth Hospital from 2012 to 2017. METHODS: Total of 2134 subjects (503 non-OSA and 1631 OSA) were included. Anthropometric parameters were recorded. HRV was recorded during a 5-minute wakefulness period and analyzed by using time-domain method and frequency-domain method. Multiple step-wise linear regressions were performed to determine significant predictors of HRV with and without adjustments. Multiplicative interactions between gender, OSA, and obesity on HRV were also determined and evaluated. RESULTS: Waist circumference (WC) was significant negative determinant of root mean square of successive NN intervals (ß = -.116, p < .001) and high-frequency power (ß = -.155, p < .001). Age was the strongest determining factor of HRV. Significant multiplicative interactions between obesity and OSA on HRV, gender, and obesity on cardiovascular parameters were observed. CONCLUSION: Anthropometric parameters could predict reduced HRV during wakefulness in patients with OSA, especially WC was the strongest influenceable factor. Obesity and OSA had significant multiplicative interaction on HRV. Gender and obesity had significant multiplicative interaction on cardiovascular parameters. Early intervention for obesity, especially centripetal obesity, may improve reduction of autonomic function and risk of CVD.

The Associations of Platelet Activation and Coagulation Parameters with Obstructive Sleep Apnoea: A Large-Scale Observational Study.

Objectives: Obstructive sleep apnoea (OSA) is associated with an increased risk of cardiovascular disease, with alterations in coagulability suspected as the mediating factor. This study explored blood coagulability and breathing-related parameters during sleep in patients with OSA. Design: Cross-sectional observational study. Setting. Shanghai Sixth People's Hospital. Participants. 903 patients diagnosed by standard polysomnography. Main Outcome and Measures. The relationships between coagulation markers and OSA were evaluated using Pearson's correlation, binary logistic regression, and restricted cubic spline (RCS) analyses. Results: The platelet distribution width (PDW) and activated partial thromboplastin time (APTT) decreased significantly with increasing OSA severity (both p < 0.001). PDW was positively associated with the apnoea-hypopnea index (AHI), oxygen desaturation index (ODI), and microarousal index (MAI) (ß = 0.136, p < 0.001; ß = 0.155, p < 0.001; and ß = 0.091, p = 0.008, respectively). APTT was negatively correlated with AHI (ß = -0.128, p < 0.001) and ODI (ß = -0.123, p = 0.001). PDW was negatively correlated with percentage of sleep time with oxygen saturation below 90%(CT90) (ß = -0.092, p = 0.009). The minimum arterial oxygen saturation (SaO2) correlated with PDW (ß = -0.098, p = 0.004), APTT (ß = 0.088, p = 0.013), and prothrombin time (PT) (ß = 0.106, p = 0.0003). ODI was risk factors for PDW abnormalities (odds ratio (OR) = 1.009, p = 0.009) after model adjustment. In the RCS, a nonlinear dose-effect relationship was demonstrated between OSA and the risk of PDW and APTT abnormalities. Conclusion: Our study revealed nonlinear relationships between PDW and APTT, and AHI and ODI, in OSA, with AHI and ODI increasing the risk of an abnormal PDW and thus also the cardiovascular risk. This trial is registered with ChiCTR1900025714.

Changes in the oral and nasal microbiota in pediatric obstructive sleep apnea.

Background: Several clinical studies have demonstrated that pediatric obstructive sleep apnea (OSA) is associated with dysbiosis of airway mucosal microbiota. However, how oral and nasal microbial diversity, composition, and structure are altered in pediatric OSA has not been systemically explored. Methods: 30 polysomnography-confirmed OSA patients with adenoid hypertrophy, and 30 controls who did not have adenoid hypertrophy, were enrolled. Swabs from four surface oral tissue sites (tongue base, soft palate, both palatine tonsils, and adenoid) and one nasal swab from both anterior nares were collected. The 16S ribosomal RNA (rRNA) V3-V4 region was sequenced to identify the microbial communities. Results: The beta diversity and microbial profiles were significantly different between pediatric OSA patients and controls at the five upper airway sites. The abundances of Haemophilus, Fusobacterium, and Porphyromonas were higher at adenoid and tonsils sites of pediatric patients with OSA. Functional analysis revealed that the differential pathway between the pediatric OSA patients and controls involved glycerophospholipids and amino acid metabolism. Conclusions: In this study, the oral and nasal microbiome of pediatric OSA patients exhibited certain differences in composition compared with the controls. However, the microbiota data could be useful as a reference for studies on the upper airway microbiome.

Heparan sulfate regulates IL-21 bioavailability and signal strength that control germinal center B cell selection and differentiation.

In antibody responses, mutated germinal center B (BGC) cells are positively selected for reentry or differentiation. As the products from GCs, memory B cells and antibody-secreting cells (ASCs) support high-affinity and long-lasting immunity. Positive selection of BGC cells is controlled by signals received through the B cell receptor (BCR) and follicular helper T (TFH) cell-derived signals, in particular costimulation through CD40. Here, we demonstrate that the TFH cell effector cytokine interleukin-21 (IL-21) joins BCR and CD40 in supporting BGC selection and reveal that strong IL-21 signaling prioritizes ASC differentiation in vivo. BGC cells, compared with non-BGC cells, show significantly reduced IL-21 binding and attenuated signaling, which is mediated by low cellular heparan sulfate (HS) sulfation. Mechanistically, N-deacetylase and N-sulfotransferase 1 (Ndst1)-mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength. Ndst1 is down-regulated in BGC cells and up-regulated in ASC precursors, suggesting selective desensitization to IL-21 in BGC cells. Thus, specialized biochemical regulation of IL-21 bioavailability and signal strength sets a balance between the stringency and efficiency of GC selection.

Influence of Molecular Configurations on the Desulfonylation Reactions on Metal Surfaces.

On-surface synthesis is a powerful methodology for the fabrication of low-dimensional functional materials. The precursor molecules usually anchor on different metal surfaces via similar configurations. The activation energies are therefore solely determined by the chemical activity of the respective metal surfaces. Here, we studied the influence of the detailed adsorption configuration on the activation energy on different metal surfaces. We systematically studied the desulfonylation homocoupling for a molecular precursor on Au(111) and Ag(111) and found that the activation energy is lower on inert Au(111) than on Ag(111). Combining scanning tunneling microscopy observations, synchrotron radiation photoemission spectroscopy measurements, and density functional theory calculations, we elucidate that the phenomenon arises from different molecule-substrate interactions. The molecular precursors anchor on Au(111) via Au-S interactions, which lead to weakening of the phenyl-S bonds. On the other hand, the molecular precursors anchor on Ag(111) via Ag-O interactions, resulting in the lifting of the S atoms. As a consequence, the activation barrier of the desulfonylation reactions is higher on Ag(111), although silver is generally more chemically active than gold. Our study not only reports a new type of on-surface chemical reaction but also clarifies the influence of detailed adsorption configurations on specific on-surface chemical reactions.

Associations between common sleep disturbances and cardiovascular risk in patients with obstructive sleep apnea: A large-scale cross-sectional study.

Objectives: Studies have shown that obstructive sleep apnea (OSA) is inextricably linked with cardiovascular diseases (CVD). However, the roles of certain common sleep disturbances, such as low slow-wave sleep, excessive daytime sleepiness and short sleep duration, in the pathogenesis and progression of CVD in patients with OSA have not been determined. Therefore, we conducted a large cross-sectional study to explore the effect of low slow-wave sleep, excessive daytime sleepiness and short sleep duration on the risk of CVD in patients with OSA. Methods: Subjects were consecutively enrolled to participate in the sleep center of Shanghai Jiao Tong University Affiliated Sixth People's Hospital. All OSA patients were diagnosed by standard polysomnography, while controls were all simple snorers. A total of 4,475 participants were strictly recruited. The Framingham Risk Score were employed to assess the 10-year risk of CVD, and logistic regression was used to measure the association between sleep disturbances and the moderate-to-high CVD risk. Results: In the whole cohort, OSA, excessive daytime sleepiness, and low slow-wave sleep were all risk factors for the moderate-to-high 10-year CVD risk (odds ratio [OR] = 3.012, 95% confidence interval [CI] 2.418-3.751; OR = 1.407, 95% CI: 1.228-1.613, and OR = 0.973,95% CI: 0.967-0.980), but sleep duration did not contribute significantly to that risk. Whether in patients with OSA and controls, low SWS (<12.8%) could increase the risk of CVD. Subjective excessive daytime sleepiness would significantly increase the risk of CVD only in patients with severe OSA. Conclusion: It is important to pay more attention to the impact of sleep on cardiovascular health. Patients with sleep disturbances should adopt a healthy lifestyle and undergo regular follow-up of cardiovascular indicators to prevent cardiovascular complications. Trial registration: [http://www.chictr.org.cn/showproj.aspx?proj=43057], identifier [ChiCTr1900025714].

Prevalence, characteristics, and respiratory arousal threshold of positional obstructive sleep apnea in China: a large scale study from Shanghai Sleep Health Study cohort.

PURPOSE: To evaluate the prevalence, characteristics, and respiratory arousal threshold (ArTH) of Chinese patients with positional obstructive sleep apnea (POSA) according to the Cartwright Classification (CC) and Amsterdam Positional Obstructive Sleep Apnea Classification (APOC). METHODS: A large-scale cross-sectional study was conducted in our sleep center from 2007 to 2018 to analyze the clinical and polysomnography (PSG) data of Chinese POSA patients. Low ArTH was defined based on PSG indices. RESULTS: Of 5,748 OSA patients, 36.80% met the CC criteria, and 42.88% the APOC criteria, for POSA. The prevalence of POSA was significantly higher in women than men (40.21% and 46.52% vs. 36.13% and 42.18% for CC and APOC, respectively). Chinese POSA patients had a lower apnea hypopnea index (AHI) and lower oxygen desaturation index, shorter duration of oxygen saturation (SaO2) < 90%, and a higher mean SaO2 and higher lowest SaO2 value compared to subjects with non-positional OSA (NPOSA). More than 40% of the POSA patients had a low ArTH; the proportion was extremely high in the supine-isolated-POSA (si-POSA) group and APOC I group. In multivariate logistic regression analyses, higher mean SaO2 and lower AHI during sleep were positive predictors of POSA. CONCLUSIONS: According to the CC and APOC criteria, more than 1/3 of our Chinese subjects with OSA had POSA. Chinese POSA patients had less severe OSA and nocturnal hypoxia. Compared to NPOSA patients, significantly more patients with POSA had a low ArTH. A low ArTH may be an important endotype in the pathogenesis of POSA, especially in patients with si-POSA and APOC I. Further studies are necessary to develop personalized management strategies for POSA patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry; URL: http://www.chictr.org.cn ; No. ChiCTR1900025714 (retrospectively registered).

Genome-Wide Association Study of Obstructive Sleep Apnea and Objective Sleep-related Traits Identifies Novel Risk Loci in Han Chinese Individuals.

Rationale: Previous genetic studies of obstructive sleep apnea (OSA) have limitations in terms of precise case definition, integrated quantitative traits, and interpretation of genetic functions; thus, the heritability of OSA remains poorly explained. Objectives: To identify novel genetic variants associated with OSA and objective sleep-related traits and to explore their functional roles. Methods: A genome-wide association study was performed in 20,590 Han Chinese individuals (5,438 OSA and 15,152 control samples). Human samples and point mutation knockin mice were used for follow-up investigation of gene functions. Measurements and Main Results: Two characteristic study-wide significant loci (P < 2.63 × 10-9) for OSA were identified: the PACRG intronic variant rs6455893 on 6q26 (odds ratio [OR] = 1.62; 95% confidence interval [CI], 1.39-1.89; P = 6.98 × 10-10) and the missense variant rs3746804 (p.Pro267Leu) in the riboflavin transporter SLC52A3 on 20p13 (OR = 0.83; 95% CI, 0.79-0.88; P = 7.57 × 10-10). In addition, 18 genome-wide significant loci associated with quantitative OSA and objective sleep-related traits were identified, 5 of which exceeded the study-wide significance threshold. Rs3746804 was associated with elevated serum riboflavin concentrations, and the corresponding mutation in mice increased riboflavin concentrations, suggesting that this variant may facilitate riboflavin uptake and riboflavin-dependent physiological activity. Conclusions: We identified several novel genome-wide significant loci associated with OSA and objective sleep-related traits. Our findings provide insight into the genetic architecture of OSA and suggest that SLC52A3 might be a therapeutic target, whereas riboflavin might be a therapeutic agent.

Effects of Chronic Intermittent Hypoxia and Chronic Sleep Fragmentation on Gut Microbiome, Serum Metabolome, Liver and Adipose Tissue Morphology.

Chronic intermittent hypoxia (CIH) and chronic sleep fragmentation (CSF) are two cardinal pathological features of obstructive sleep apnea (OSA). Dietary obesity is a crucial risk intermediator for OSA and metabolic disorders. Gut microbiota affect hepatic and adipose tissue morphology under conditions of CIH or CSF through downstream metabolites. However, the exact relationship is unclear. Herein, chow and high-fat diet (HFD)-fed mice were subjected to CIH or CSF for 10 weeks each and compared to normoxia (NM) or normal sleep (NS) controls. 16S rRNA amplicon sequencing, untargeted liquid chromatography-tandem mass spectrometry, and histological assessment of liver and adipose tissues were used to investigate the correlations between the microbiome, metabolome, and lipid metabolism under CIH or CSF condition. Our results demonstrated that CIH and CSF regulate the abundance of intestinal microbes (such as Akkermansia mucinphila, Clostridium spp., Lactococcus spp., and Bifidobacterium spp.) and functional metabolites, such as tryptophan, free fatty acids, branched amino acids, and bile acids, which influence adipose tissue and hepatic lipid metabolism, and the level of lipid deposition in tissues and peripheral blood. In conclusion, CIH and CSF adversely affect fecal microbiota composition and function, and host metabolism; these findings provide new insight into the independent and synergistic effects of CIH, CSF, and HFD on lipid disorders.

Multiple genetic variations of chronic rhinosinusitis with nasal polyps are associated with respiratory parameters in men with obstructive sleep apnea.

PURPOSE: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) have a higher risk of obstructive sleep apnea (OSA). However, the relationship between CRSwNP and OSA remains unclear. The aim of this research study was to evaluate the association of multiple single nucleotide polymorphism (SNP) variations in CRSwNP with sleep- and breath-related parameters in men with OSA. METHODS: We included eight CRSwNP SNPs in 2320 participants after strict screening. For each participant, the genetic risk score (GRS) was calculated based on the cumulative effect of multiple genetic variants of CRSwNP. A bivariate correlation analysis was used to assess the relationship between CRSwNP genetic polymorphisms and polysomnography parameters in men with OSA. Logistic regression analyses were used to assess the relationship between the risk of OSA and CRSwNP genetic polymorphisms. RESULTS: In moderate OSA, rs28383314 was related to the oxygen desaturation index, and rs4807532 was positively associated with the microarousal index (r = 0.09, P = 0.03 and r = 0.11, P = 0.01, respectively). The CRSwNP GRS was positively correlated with the oxygen desaturation index and cumulative time percentage with SpO2 < 90% in moderate OSA (r = 0.13, P < 0.001 and r = 0.1, P = 0.01, respectively). There was no association between the CRSwNP GRS and the risk of OSA (OR = 1.007; 95% CI, 0.973-1.042; P = 0.702). CONCLUSION: In men with moderate OSA, single CRSwNP genetic variations correlated with sleep-related parameters, and the cumulative effects of CRSwNP genetic variations were associated with the hypoxic index. CRSwNP may be a predisposing condition for sleep disorders in men with moderate OSA.

The Impact of Glycolipid Metabolic Disorders on Severity Stage-Specific Variation of Cardiac Autonomic Function in Obstructive Sleep Apnea: A Data-Driven Clinical Study.

BACKGROUND: Cardiac autonomic dysfunction (CAD) is a common pathology in cardiovascular diseases; however, the role of glycolipid metabolic disorders in CAD development in obstructive sleep apnea (OSA) remains poorly understood. METHODS: In total, 4152 patients with suspected OSA were recruited in our sleep center. Metabolic characteristics including anthropometric and glycolipid data were collected. Heart rate variability (HRV) was measured to assess the risk of CAD; its dose-response relationship with OSA severity was evaluated via restricted cubic spline (RCS) analysis. A segmented multivariate linear regression (SMLR) model was used to evaluate the roles of metabolic variables in different stages of OSA. RESULTS: The RCS showed that CAD risk increased in a nonlinear relationship pattern with OSA severity, from slow fluctuation at earlier stages to rapid change in later stages. After integrating the clinical definition and RCS selected knots, we obtained the new four OSA severity stages. SMLR model showed that the overall value of glycolipid variables for prediction of HRV abnormalities was greater than the value of OSA variables at earlier stages, while OSA variables were more effective predictors in more severe stages. The discordance in respective relationship of HRV with metabolic and OSA variables sheds the light how metabolic disorders promoted the development of CAD in OSA, the later further in turn deteriorates cardiac function. CONCLUSION: These results are indicative of stage-specific involvement of glycolipid metabolic factors underlying CAD nonlinear changes in patients with OSA. Early control glycolipid disorders may help the control of CAD development in patients with OSA.