Identification of circular RNA hsa_circ_0034621 as a novel biomarker for carotid atherosclerosis and the potential function as a regulator of NLRP3 inflammasome.

BACKGROUND AND AIMS: NLRP3 inflammasome plays a key role in vascular inflammation and atherosclerosis. Circular RNAs (circRNAs) are involved in disease development by regulating gene expression, and have emerged as promising novel disease biomarkers. This study aimed to identify the NLRP3 inflammasome-associated circRNA biomarkers of carotid atherosclerosis. METHODS: Based on the differential expression profiles of circRNAs in patients with carotid artery plaque (CAP) and healthy controls, hsa_circ_0043621, hsa_circ_0051995, and hsa_circ_0123388 were screened and validated using real-time quantitative polymerase chain reaction (RT-qPCR). Potential circRNA-miRNA-mRNA interactions were explored using a luciferase assay. The biological roles of the validated circRNAs were investigated in human umbilical vein endothelial cells (HUVECs) using Western blotting, transwell, and CCK-8 assays. Clinical significance was assessed using receiver operating characteristic (ROC) curves and logistic regression analysis. RESULTS: The expression levels of all candidate circRNAs were significantly higher in patients with CAP than in controls (p<0.05), which was consistent with the results of the microarray analysis. Overexpression of hsa_circ_0043621 significantly increased the expression of NLRP3, induced migration of HUVECs, and inhibited cell proliferation. hsa_circ_0043621 demonstrated reasonable diagnostic accuracy for CAP detection and increased intima-media thickness (IMT). hsa_circ_0043621 upregulation was an independent predictor of an increased risk of CAP and increased IMT. CONCLUSIONS: hsa_circ_0043621 is a valuable circulating biomarker of carotid atherosclerosis and may contribute to its pathogenesis by regulating the NLRP3 inflammasome.

Associations of waist-to-height ratio with the incidence of type 2 diabetes and mediation analysis: Two independent cohort studies.

AIM: To assess the relationship between waist-to-height ratio (WHtR) and the incidence of type 2 diabetes (T2D)/impaired fasting glucose (IFG) and to explore to what extent these associations are mediated by blood pressure, lipids and other indicators related to liver and kidney metabolism. MATERIALS AND METHODS: This study was based on a functional community cohort included 6109 participants which were divided into two sub-cohorts. One sub-cohort included participants with normal fasting glucose (n = 5563), another included IFG individuals at baseline (n = 546). Cox regression models were used to evaluate the relationships of WHtR with T2D/IFG. Four-year time-dependent receiver operating characteristic (ROC) curve and area under curve (AUC) were calculated to estimate the discriminatory power of WhtR and other anthropometric indices on T2D. Mediation analysis was performed to estimate which risk factors mediate the association between WHtR and T2D. RESULTS: Significant positive associations were found between WHtR and the incidence of T2D/IFG in both sub-cohort. WhtR was a useful predictor of T2D (P < 0.05). Mediation analysis showed that HOMA-IR (0.45 %), SBP (5.10 %), triglycerides (11.02 %), creatinine (9.36 %) and combined kidney indicators (17.48 %) partly mediated the effect of WHtR on T2D in men. For women, this association was partly mediated by SBP (13.86 %), HDL (24.54 %), ALT (6.29 %), UA (22.58 %) and combined kidney indicators (39.51 %). CONCLUSIONS: WHtR was an independent risk factor for the development of T2D and IFG. This association was partly mediated by HOMA-IR, SBP, lipids and other liver and kidney metabolism indicators.

Association of serum uric acid with the risk of developing hypertension: A prospective cohort study with mediation analysis.

Elevated serum uric acid (SUA) is associated with the incidence of hypertension, but whether relevant metabolic factors have mediating effects is not certain. Our study was based on a functional community cohort established in Beijing. In 2015, a total of 7482 individuals without hypertension were recruited and followed up until 2019. Multivariate logistic regression analysis was used to investigate the association between SUA and hypertension. Cross-lagged panel analysis and mediation analysis were used to explore the effects of metabolic factors on the association between SUA and incident hypertension. During the average 4-year follow-up, the cumulative incidence of hypertension was 10.9% (n = 580). SUA was an independent risk factor for hypertension, and the RRs (95% CI) for subjects with baseline SUA levels in quartile 2, quartile 3 and quartile 4 were 1.20 (0.88-1.63), 1.50 (1.10-2.05), and 1.57 (1.11-2.22) compared to those in quartile 1, respectively. The cross-lagged panel analysis showed that the increases in Cr, TG, LDL, ALT, AST and WBC occurred after SUA increased (P < 0.001). Among these factors, TG, WBC and ALT played an intermediary role in both men (TG: 14.76%; WBC: 11.61%; ALT: 15.93%) and women (TG: 14.55%; WBC: 8.55%; ALT: 6.89%). The elevated SUA concentration was an independent risk factor for hypertension in the Chinese population, and TG, WBC and ALT had important mediating effects on the association between SUA and hypertension.

The effects of short-term exposure to air pollution on mortality in Baotou, China, during 2015-2019.

Air pollution was considered one of the main causes linked to increased morbidity and mortality around the world. This study aimed to estimate the effect of air pollutants on daily death in Baotou city of Inner Mongolia. Daily deaths data were provided by Baotou Centers for Disease Control and Prevention for the years 2015-2019 (Baotou CDC). The air pollutants, PM2.5, PM10, NO2, SO2, CO and maximum 8-h average concentrations of O3, came from the eight environmental monitoring stations in Baotou city. Time-series plots were used to exploit the trend of air pollutants at calendar time. Generalized additive model was used to estimate the effect of air pollutants on daily death. Restricted cubic spline was employed to investigate non-line relationships between air pollutants and daily death. After adjusting the meteorological factors, non-accidental daily deaths were related to PM2.5 (ER = 0.074%) and PM10 (ER = 0.023%), respectively. In stratified analysis, population aged over 65 years and females were more sensitive to air pollutants exposure and warm season might make people more susceptible to air pollutants compared with cold season. PM2.5 and PM10 increase the risk of non-accidental and cardiovascular daily death, but not respiratory daily death.

Association between surrogate indicators of insulin resistance and risk of type 2 diabetes combined with hypertension among Chinese adults: two independent cohort studies.

BACKGROUND: Type 2 diabetes (T2D) combined with hypertension has a higher risk of developing cardiovascular diseases. This study aimed to investigate the relationships between the surrogate indicators of insulin resistance (TyG, TG/HDL, and Mets-IR) with the risk of T2D combined with hypertension. METHODS: This study is based on a functional community cohort from Beijing and the China Health and Retirement Longitudinal Study, comprising 4234 and 4658 participants respectively. Cox proportional hazards models and restricted cubic spline regression were performed to assess the link between TyG, TG/HDL, and Mets-IR with T2D combined with hypertension. The cross-lagged panel analysis and the mediation analysis were used to examine the temporal relationship between insulin resistance and obesity and their temporal relationship with follow-up T2D combined with hypertension. RESULTS: In multivariable-adjusted models, higher TyG was associated with a higher risk of developing T2D combined with hypertension, the hazard ratios (95% confidence interval) were 3.46 (2.43-4.93) and 2.02 (1.67-2.44), in two cohorts respectively. A similar positive association was shown for Mets-IR, the hazard ratios (95% confidence interval) were 1.04 (1.03-1.06) and 1.05 (1.03-1.07), in two cohorts respectively. However, the association between TG/HDL with T2D combined with hypertension was different in two cohorts. The restricted cubic spline regression showed a linear association between TyG and T2D combined with hypertension (P-nonlinear > 0.05). The cross-lagged path coefficient from baseline BMI to follow-up TyG index was significantly greater than the path coefficient from baseline TyG to follow-up BMI. TyG partially mediated the effect of BMI on the risk of T2D combined with hypertension and the percentage of mediated association was estimated at 41.58% and 48.41% in two cohorts, respectively. CONCLUSION: These findings indicated positive associations between TyG and Mets-IR with the risk of T2D combined with hypertension in two cohorts. In addition, BMI change may precede TyG index change, and the TyG index plays a mediating role in BMI induced T2D combined with hypertension.

CircRNA hsa_circ_0071336 is associated with type 2 diabetes through targeting the miR-93-5p/GLUT4 axis.

Glucose transporter 4 (GLUT4) is a dominant regulator of whole-body glucose homeostasis. Accumulating evidence has shown that circular RNAs (circRNAs) play significant roles in the pathogenesis of disease. The aim of the present study was to identify the circRNA that can be used as a novel biomarker for type 2 diabetes (T2D) through regulating GLUT4. Based on previous microarray analysis comparing T2D cases and healthy controls, hsa_circ_0071336, which was predicted to be a regulator of GLUT4 by acting as a competitive endogenous RNAs (ceRNA) to sponge miR-93-5p, was selected for further validation. The clinical significance of circulating hsa_circ_0071336 was investigated in a large independent cohort. The results showed that circulating hsa_circ_0071336 was significantly downregulated in blood in T2D and had a high diagnostic accuracy for discriminating T2D and impaired fasting glucose (IFG) from healthy controls. Low expression of circ_0071336 was an independent predictor of T2D, IFG and insulin resistance. A luciferase reporter assay and western-blot analysis indicated that miR-93-5p was a direct target of hsa_circ_0071336, and miR-93-5p may negatively regulate the expression of GLUT4. The expression levels of hsa_circ_007136 were negatively related to miR-93-5p expression and positively correlated with the mRNA expression of GLUT4 in adipose tissues. In conclusion, hsa_circRNA_0071336 can be considered as a potential novel and stable biomarker for T2D and its early detection. hsa_circ_0071336 regulates the GLUT4 expression by sponging miR-93-5p and maybe involved in the pathogenesis of T2D. These findings may unveil new targets for the prevention, diagnosis and treatment of T2D.

Short-term effects of gaseous air pollutants on outpatient visits for respiratory diseases: a case-crossover study in Baotou, China.

Air pollution is a major public health problem throughout the world. Although there have been several studies in this field, most of them have focused on particulate matter and only covered a few key cities. This study aimed to assess a potential association between exposure to gaseous air pollutants and outpatient visits for respiratory diseases in Baotou, China. Daily outpatient visits for respiratory diseases and daily averages of air pollutants and meteorological parameters from 2015 to 2020 were obtained. Time-stratified case-crossover design and restricted cubic splines were used to perform the analyses. Stratified analyses were performed in different hospital departments and districts. Significant association between the concentrations of air pollutants and outpatient visits for respiratory diseases was observed. The odds ratios of outpatient visits for respiratory diseases associated with per 10 µg/m3 increases in concentrations of NO2 and SO2, and per 10 mg/m3 increases in concentrations of CO were 1.033 (95% CI: 1.018 to 1.049), 0.965 (95% CI: 0.954 to 0.976), and 1.038 (95% CI: 1.006 to 1.071), respectively. Short-term exposure to NO2, SO2, and CO was positively associated with outpatient visits for respiratory diseases, with stronger effects among children. The relationship between O3 and respiratory diseases varied at different concentrations.

Gender-specific predictive ability for the risk of hypertension incidence related to baseline level or trajectories of adiposity indices: a cohort study of functional community.

BACKGROUND: Early prevention of hypertension is important for global cardiovascular disease morbidity and mortality. This study aims to explore better predictors for hypertension incidence related to baseline level or trajectories of adiposity indices, as well as the gender-specific effect. METHODS: 6085 subjects from a functional community cohort in urban Beijing participated in our study. Restricted cubic splines were used to estimate nonlinear associations of body mass index (BMI) and waist-to-height ratio (WHtR) as continuous variable with risk of hypertension. Stepwise logistic regression model was performed to estimate the relative risks (RRs) of adiposity indices and metabolic status, adjusted for covariates. Nomogram models and receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive power of BMI trajectory groups and WHtR trajectory groups on hypertension incidence. Further, all analysis were performed by gender. RESULTS: The risk of hypertension incidence was related to BMI trajectory groups (persistent overweight: RR = 1.88, 95% CI: 1.48-2.37; persistent obesity: RR = 2.79, 95% CI: 2.18-3.56; persistent the highest: RR = 4.30, 95% CI: 3.20-5.78) and WHtR trajectory groups (persistent medium: RR = 2.69, 95% CI: 2.07-3.50; persistent high: RR = 3.85, 95% CI: 2.92-5.09; increasing to higher: RR = 7.00, 95% CI: 4.96-9.89). In total population, BMI trajectories and WHtR trajectories showed similar ability to predict the risk of hypertension incidence with AUC 0.723 and 0.726, respectively. After stratified by gender, both BMI trajectories and WHtR trajectories showed higher power in female than male (BMI trajectories: 0.762 vs. 0.661; WHtR trajectories: 0.768 vs. 0.661). CONCLUSIONS: BMI and WHtR trajectories have higher predictive power for hypertension incidence compared to baseline data. Females are more vulnerable to obesity than males.

Association between insulin resistance and incidence of carotid atherosclerotic plaque: A cohort study.

BACKGROUND AND AIMS: There is limited evidence on the association between insulin resistance (IR) and carotid plaque was reported in prospective study. We aimed to exploit the relationship between IR and carotid plaque in a prospective cohort study. METHODS AND RESULTS: The study was performed in a functional community cohort in urban Beijing. In 2015, a total of 7061 individuals without intima-media thickness (IMT) thickening and carotid artery plaque were recruited and followed up until 2019. Restricted cubic spline was conducted to exploit the dose-response relationship between carotid plaque and baseline HOMA-IR or TyG index as continuous variables. Logistic regression was used to analyze the associations between carotid plaque and HOMA-IR or TyG index. During the average 4 years follow-up, 589 subjects developed carotid plaque. Both HOMA-IR and TyG index showed significant linear dose-response relationship on carotid plaque (p < 0.001). The RRs (95%CI) for subjects with baseline HOMA-IR in quartile 2, quartile 3 and quartile 4 were 1.52 (1.14-2.04), 1.86 (1.40-2.46), and 2.55 (1.94-3.35) compared to quartile 1, respectively. Compared to the first quartile of TyG, the RRs (95%CI) for subjects in quartile 2, quartile 3 and quartile 4 were 1.43 (1.08-1.90), 1.59 (1.20-2.12), and 1.69 (1.26-2.25), respectively. In total population, the predictive ability of HOMA-IR for carotid plaque was significantly better than that of TyG index (p = 0.025). CONCLUSION: IR is an independent risk factor of carotid plaque. Both HOMA-IR and TyG has significant predictive ability for carotid plaque.

Association of household solid fuel use and long-term exposure to PM2.5 with arthritis in middle-aged and older population in China: A cohort study.

Air pollutants are common modifiable risk factors for arthritis. To explore the longitudinal effects of air pollution on arthritis based on a cohort study in middle-aged and elder people of China. Data was obtained from the China Health and Retirement Longitudinal Study (CHARLS) from 2011 to 2018. A total of 7449 participants aged 45 years and older were involved in our study. The generalized linear mixed models were conducted to examine the separate and joint effects of household air pollution and outdoor air pollution on arthritis, respectively. We found a strong significant association between air pollution and arthritis incidence. Individuals cooking primarily with solid fuel were more likely in higher risk of arthritis compared with cleaner fuel (OR= 1.15; 95% CI: 1.08-1.23). The group-based trajectory model identified four trajectory groups, compared with group "High-Decreasing rapidly", adjusted ORs of incident arthritis for group "Middle-Decreasing moderately", "Low-Decreasing slowly" and "Low-Stably" were 1.36 (95% CI, 1.03-1.79), 1.36 (95% CI, 1.01-1.83) and 1.81 (95% CI, 1.30-2.52), respectively. These associations were generally higher in participants younger than 65 years. In addition, solid fuel use and PM2.5 exposure had additive and multiplicative effects on arthritis. The results suggested that solid fuel use and long-term PM2.5 exposure were associated with a higher incidence of arthritis. Therefore, it is necessary to restrict solid fuel use to reduce household air pollution and make stronger environmental protection policies to reduce PM2.5 concentration.

Effect of Metabolite Levels on Type 2 Diabetes Mellitus and Glycemic Traits: A Mendelian Randomization Study.

OBJECTIVE: To assess the causal associations of plasma levels of metabolites with type 2 diabetes mellitus (T2DM) and glycemic traits. METHODS: Two-sample mendelian randomization (MR) was conducted to assess the causal associations. Genetic variants strongly associated with metabolites at genome-wide significance level (P < 5 × 10-8) were selected from public genome-wide association studies, and single-nucleotide polymorphisms of outcomes were obtained from the Diabetes Genetics Replication and Meta-analysis consortium for T2DM and from the Meta-Analyses of Glucose and Insulin-related Traits Consortium for fasting glucose, insulin, and glycated hemoglobin (HbA1c). The Wald ratio and inverse-variance weighted methods were used for analyses, and MR-Egger was used for sensitivity analysis. RESULTS: The ß estimates per 1-SD increase of arachidonic acid (AA) level was 0.16 (95% CI, 0.078-0.242; P < 0.001). Genetic predisposition to higher plasma AA levels were associated with higher fasting glucose levels (ß 0.10 [95% CI, 0.064-0.134], P < 0.001), higher HbA1c levels (ß 0.04 [95% CI, 0.027-0.061]), and lower fasting insulin levels (ß -0.025 [95% CI, -0.047 to -0.002], P = 0.033). Besides, 2-hydroxybutyric acid (2-HBA) might have a positive causal effect on glycemic traits. CONCLUSIONS: Our findings suggest that AA and 2-HBA may have causal associations on T2DM and glycemic traits. This is beneficial for clarifying the pathogenesis of T2DM, which would be valuable for early identification and prevention for T2DM.

Identification of Circulating hsa_circ_0063425 and hsa_circ_0056891 as Novel Biomarkers for Detection of Type 2 Diabetes.

CONTEXT: Circular RNAs (circRNAs), which are involved in the development of diseases by regulating gene expression, have become promising novel biomarkers for diseases. OBJECTIVE: The aim of the present study was to identify the circulating circRNA biomarkers for early detection of type 2 diabetes (T2D). METHODS: The circRNA expression profiles were screened by microarray and compared between 5 new T2D cases and 5 healthy controls. The expression of candidate circRNAs that may be involved in the insulin phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway were validated by RT-qPCR in a second sample with 30 T2D cases and 30 controls. The association between circRNAs and T2D and their clinical significances were further assessed by logistic regression model, correlation analysis, and ROC curve in a large cohort comprising 313 subjects. The microRNA (miRNA) targets of circRNAs were verified by dual-luciferase reporter assay and RNA immunoprecipitation assay. RESULTS: Low expressed circ_0063425 and hsa_circ_0056891 were independent predictors of T2D, impaired fasting glucose (IFG), and insulin resistance. The 2-circRNA panel had a high diagnostic accuracy for discriminating T2D and IFG from healthy controls, especially when body mass index was integrated. miR-19a-3p and miR-1-3p were identified as the miRNA targets of hsa_circ_0063425 and hsa_circ_0056891, respectively. Significant positive correlations were found between the expression levels of AKT and hsa_circ_0063425, PI3K and hsa_circ_0056891, in the total sample and subgroups stratified by glucose levels. CONCLUSION: Downregulated hsa_circ_0063425 and hsa_circ_0056891 might contribute to the pathogenesis of T2D. They are valuable circulating biomarkers for early detection of T2D, which may be involved in regulation of PI3K/AKT signaling.

hsa_circ_0111707 Is Associated With Risk of Stress-Related Type 2 Diabetes via Sponging miR-144-3p.

Introduction: Chronic stress plays an important role in the development of type 2 diabetes (T2D). Circular RNAs (circRNAs) play significant roles in regulating the pathogenesis of diseases by regulating gene expression. The aim of the present study was to identify the association between hsa_circ_0111707 and stress-related T2D. Methods: The present study was performed based on a three-part design. The association between hsa_circ_0111707 in peripheral blood mononuclear cells (PBMCs) and T2D and stress-related variables were assessed in a cross-sectional study. The causal relationship of hsa_circ_0111707 on T2D was further investigated in a nested case-control study. miR-144-3p as the miRNA target of hsa_circ_0111707 was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Results: The relative expression of hsa_circ_0111707 was significantly lower in the T2D and impaired fasting glucose (IFG) cases in comparison with controls. The hsa_circ_0111707 expression was significantly negatively correlated with miR-144-3p expression and plasma cortisol concentration and positively correlated with NR3C1 expression. In addition, hsa_circ_0111707 expression was negatively correlated with scores of "demands at work" and "insecurity at work" of Copenhagen Psychosocial Questionnaire (COPSOQ). Decreased hsa_circ_0111707 expression was associated with increased risk of T2D development. Functional analysis demonstrated that hsa_circ_0111707 functions as a sponge for miR-144-3p. Conclusion: hsa_circ_0111707 is associated with risk of T2D development via sponging miR-144-3p. hsa_circ_0111707 in PBMCs can be considered a potential biomarker of stress-related T2D.

Reciprocal associations between job strain and depression: A 2-year follow-up study from the Survey of Health, Ageing and Retirement in Europe.

BACKGROUND: A growing number of people suffered from depression. This study examined the depression prevalence in workers across 10 European countries plus Israel and the reciprocal associations between job strain and depression. METHODS: The study population consisted of 7,879 workers aged 50-63 years at baseline (2004) from the Survey of Health, Ageing, and Retirement in Europe (SHARE). Job demands (physical or psychosocial) and job control variables were derived from the Job Content Questionnaire (JCQ). Two 4-category job strains (physical and psychosocial) were obtained based on the cross-tabulation of these dichotomized demands and control variables. There were 4,284 depression-free, 3,259 high physical strain-free and 3,195 high psychosocial strain-free participants at baseline who were followed up for 2 years to detect incident depression, high physical job strain, or high psychosocial strain, respectively. The reciprocal associations between job strain and depression were analyzed by multivariate logistic regression and multivariate multilevel logistic regression adjusting for potential confounders. RESULTS: The prevalence of depression varied from the lowest 12.5% in Germany to the highest 27.2% in France. Compared to individuals with low strain, a significantly higher risk of depression were found in individuals with high physical strain (OR = 1.39) and high psychosocial strain (OR = 1.55), after adjusting for potential confounders. Depression at baseline was not significantly associated with subsequent high job strain. Similar results were observed from multilevel models that took into consideration of the potential country-level influences. CONCLUSIONS: The prevalence of depression varies across countries in Europe. Avoiding high job strain may be an effective preventive strategy to prevent depression epidemic.

Reciprocal relationship between psychosocial work stress and quality of life: the role of gender and education from the longitudinal study of the Survey of Health, Ageing and Retirement in Europe.

OBJECTIVE: To investigate the reciprocal relationship between psychosocial work stress and quality of life (QoL) and to examine whether the relationship can be moderated by gender or education. DESIGN: Longitudinal, population-based study. SETTING: The Survey of Health, Ageing and Retirement in Europe (SHARE). PARTICIPANTS: The study population was derived from the SHARE, and there were 2006 participants with good QoL at baseline, 1109 with high job control and 1072 with high job reward, respectively, who were followed up for 2 years to detect incidence of poor QoL, low job control and low job reward. MAIN OUTCOME MEASURES: Logistic regression models were employed to explore the reciprocal relationship between psychological work stress and QoL. Stratification analyses by gender and education were performed. RESULTS: Participants with low reward (OR=1.53, 95% CI 1.26 to 1.88) and low control (OR=1.40, 95% CI 1.14 to 1.71) at baseline were at higher risk of poor QoL over the 2-year follow-up. The combination of low reward and low control further increased the risk (OR=1.90, 95% CI 1.46 to 2.48). Stratified analyses revealed that these associations were more pronounced among those who had high levels of education. Further, individuals with poor QoL were at significantly higher risk of having low reward (OR=2.14, 95% CI 1.55 to 2.96) but not low control (OR=1.33, 95% CI0.98 to 1.79) at the 2-year follow-up, especially among those who had medium levels of education. No gender differences were found. CONCLUSIONS: There is a reciprocal relationship between psychological work stress and poor QoL. Education may play an important role in the relationship.