Background Academic pressure is a prevalent stressor among Chinese adolescents and is often linked to anxiety symptoms, although the underlying mechanism remains unclear. This study aimed to investigate the association between NR3C1 gene methylation, academic pressure, and anxiety symptoms among Chinese adolescents. Methods This nested-case control study included 150 adolescents (boys: 38.7%; baseline age: 12–17 years) from a school-based longitudinal study of Chinese adolescents. Cases (n = 50) were defined as those with anxiety symptoms at both baseline and follow-up, while controls (n = 100) were randomly selected from those without anxiety symptoms at both timepoints. The cases and controls were 1:2 matched by age. Academic pressure, anxiety symptoms, and potential covariates were measured using a self-report questionnaire. Peripheral whole blood samples were collected from each participant for the detection of cortisol level (i.e., morning serum cortisol level) and DNA methylation. The methylation analysis included a total of 27 CpG units at the NR3C1 promoter region. Results The final adjusted models showed that students with heavy academic pressure at baseline were at a higher risk of anxiety symptoms at follow-up compared to those with mild academic pressure (β estimate: 6.24 [95% CI: 3.48 ~ 9.01]). After adjusting for covariates, the methylation level of one CpG unit (NR3C1-16 CpG10) in NR3C1 differed significantly between cases and controls (F = 6.188, P = 0.014), and the difference remained significant after correction for multiple testing (P < 0.025). The adjusted regression models showed that moderate (β estimate = 0.010 [95% CI: 0.000 ~ 0.020], P = 0.046) and heavy (β estimate = 0.011 [95% CI: 0.001 ~ 0.020], P = 0.030) academic pressure were significantly associated with the methylation level of NR3C1-16 CpG 10. Further mediation analysis demonstrated that the association of academic pressure and anxiety symptoms was significantly mediated by the methylation of NR3C1-16 CpG 10 (β estimate for indirect effect = 0.11 [95% CI: 0.005 ~ 0.32]; indirect/total effect = 8.3%). Conclusion The present study suggests that NR3C1-16 CpG 10 DNA methylation might be a potential mechanism that partially explains the lasting effects of academic pressure on subsequent anxiety symptoms among adolescents. Further studies with larger sample sizes are recommended to replicate this finding.

Background Although the association between social isolation and the risk of subsequent cardiovascular disease (CVD) is well documented, most studies have only assessed social isolation at a single time point, and few studies have considered the association using repeatedly measured social isolation. Objective This study aimed to examine the association between social isolation trajectories and incident CVD in a large cohort of middle-aged and older adults. Methods This study used data from 4 waves (wave 1, wave 2, wave 3, and wave 4) of the China Health and Retirement Longitudinal Study. We defined the exposure period as from June 2011 to September 2015 (from wave 1 to wave 3) and the follow-up period as from September 2015 to March 2019 (wave 4). On the basis of the inclusion and exclusion criteria, our final analytic sample included 8422 individuals who had no CVD in the China Health and Retirement Longitudinal Study in waves 1 to 3 and were fully followed up in wave 4. Social isolation was ascertained using an extensively used questionnaire at 3 consecutive, biennial time points from waves 1 to 3, and individuals were assigned to 3 predefined social isolation trajectories based on their scores at each wave (consistently low, fluctuating, and consistently high). Incident CVD included self-reported physician-diagnosed heart disease and stroke combined. Cox proportional hazard models estimated the associations of social isolation trajectories with risks of incident CVD, adjusting for demographics, health behaviors, and health conditions. Results Of the 8422 participants (mean age 59.76, SD 10.33 years at baseline), 4219 (50.09%) were male. Most of the participants (5267/8422, 62.54%) had consistently low social isolation over time and 16.62% (1400/8422) of the participants had consistently high social isolation over the exposure period. During the 4-year follow-up, 746 incident CVDs occurred (heart disease: 450 cases and stroke: 336 cases). Compared with individuals with consistently low social isolation, those with fluctuating social isolation (adjusted hazard ratio 1.27, 95% CI 1.01-1.59) and consistently high social isolation (adjusted hazard ratio 1.45, 95% CI 1.13-1.85) had higher risks for incident CVD after adjusting for demographics (ie, age, sex, residence, and educational level), health behaviors (ie, smoking status and drinking status), and health conditions (ie, BMI; history of diabetes, hypertension, dyslipidemia, chronic kidney disease; use of diabetes medications, hypertension medications, and lipid-lowering therapy; and depressive symptoms scores). Conclusions In this cohort study, middle-aged and older adults with fluctuating and consistently high social isolation exposure had higher risks of the onset of CVD than those without the exposure. The findings suggest that routine social isolation screenings and efforts to improve social connectedness merit increased attention for preventing CVD among middle-aged and older adults.

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BACKGROUND Although the association between social isolation and the risk of subsequent cardiovascular disease (CVD) is well documented, most studies have only assessed social isolation at a single time point, and few studies have considered the association using repeatedly measured social isolation. OBJECTIVE This study aimed to examine the association between social isolation trajectories and incident CVD in a large cohort of middle-aged and older adults. METHODS This study used data from 4 waves (wave 1, wave 2, wave 3, and wave 4) of the China Health and Retirement Longitudinal Study. We defined the exposure period as from June 2011 to September 2015 (from wave 1 to wave 3) and the follow-up period as from September 2015 to March 2019 (wave 4). On the basis of the inclusion and exclusion criteria, our final analytic sample included 8422 individuals who had no CVD in the China Health and Retirement Longitudinal Study in waves 1 to 3 and were fully followed up in wave 4. Social isolation was ascertained using an extensively used questionnaire at 3 consecutive, biennial time points from waves 1 to 3, and individuals were assigned to 3 predefined social isolation trajectories based on their scores at each wave (consistently low, fluctuating, and consistently high). Incident CVD included self-reported physician-diagnosed heart disease and stroke combined. Cox proportional hazard models estimated the associations of social isolation trajectories with risks of incident CVD, adjusting for demographics, health behaviors, and health conditions. RESULTS Of the 8422 participants (mean age 59.76, SD 10.33 years at baseline), 4219 (50.09%) were male. Most of the participants (5267/8422, 62.54%) had consistently low social isolation over time and 16.62% (1400/8422) of the participants had consistently high social isolation over the exposure period. During the 4-year follow-up, 746 incident CVDs occurred (heart disease: 450 cases and stroke: 336 cases). Compared with individuals with consistently low social isolation, those with fluctuating social isolation (adjusted hazard ratio 1.27, 95% CI 1.01-1.59) and consistently high social isolation (adjusted hazard ratio 1.45, 95% CI 1.13-1.85) had higher risks for incident CVD after adjusting for demographics (ie, age, sex, residence, and educational level), health behaviors (ie, smoking status and drinking status), and health conditions (ie, BMI; history of diabetes, hypertension, dyslipidemia, chronic kidney disease; use of diabetes medications, hypertension medications, and lipid-lowering therapy; and depressive symptoms scores). CONCLUSIONS In this cohort study, middle-aged and older adults with fluctuating and consistently high social isolation exposure had higher risks of the onset of CVD than those without the exposure. The findings suggest that routine social isolation screenings and efforts to improve social connectedness merit increased attention for preventing CVD among middle-aged and older adults.