Mediation of metabolic syndrome in the association between long-term exposure to particulate matter and incident cardiovascular disease: Evidence from a population-based cohort in Chengdu.

BACKGROUND: Particulate matter (PM) exposure has been linked with cardiovascular disease (CVD) and metabolic syndrome (MetS), the latter characterized by concurrent multiple metabolic disorders. As a result, the mechanisms assumption from PM to CVD through MetS have emerged, thus requiring further epidemiological evidence. This cohort study aimed to assess whether MetS mediates the associations of PM with CVD risk. METHODS: This study included 14,195 participants from the Chengdu cohort of the China Multi-Ethnic Cohort (CMEC) study in 2018. The primary outcome of incident CVD diagnoses was identified using matched hospital records from the Health Information Center of Sichuan Province. Residence-specific levels of PM with aerodynamic diameters of ≤ 1 µm (PM1), ≤ 2.5 µm (PM2.5), and ≤ 10 µm (PM10) were estimated by spatiotemporal models. Causal mediation analyses were applied to evaluate the indirect effect of MetS. RESULTS: Increased exposure levels to PM were significantly associated with MetS and CVD. Mediation analyses indicated that the associations between PM exposure and CVD were mediated by MetS, with the proportion of multiple mediations being 19.3%, 12.1%, and 13.5% for PM1, PM2.5, and PM10, respectively. Further moderated mediation analyses suggested that male, overweight individuals, alcohol drinkers, and those suffering from indoor air pollution may experience more significant adverse effects from PM exposure on CVD via MetS than others. CONCLUSIONS: Our findings suggest that MetS partially mediates the association between long-term exposure to PM and CVD. These mediation effects appear to be amplified by demographic characteristics and unhealthy lifestyles.

Associations of Long-Term Exposure to Fine Particulate Constituents With Cardiovascular Diseases and Underlying Metabolic Mediations: A Prospective Population-Based Cohort in Southwest China.

BACKGROUND: The health effects of particulate matter with an aerodynamic diameter ≤2.5 µm (PM2.5) might differ depending on compositional variations. Little is known about the joint effect of PM2.5 constituents on metabolic syndrome and cardiovascular disease (CVD). This study aims to evaluate the combined associations of PM2.5 components with CVD, identify the most detrimental constituent, and further quantify the mediation effect of metabolic syndrome. METHODS AND RESULTS: A total of 14 427 adults were included in a cohort study in Sichuan, China, and were followed to obtain the diagnosis of CVD until 2021. Metabolic syndrome was defined by the simultaneous occurrence of multiple metabolic disorders measured at baseline. The concentrations of PM2.5 chemical constituents within a 1-km2 grid were derived based on satellite- and ground-based detection methods. Cox proportional hazard models showed that black carbon, organic matter (OM), nitrate, ammonium, chloride, and sulfate were positively associated with CVD risks, with hazard ratios (HRs) ranging from 1.24 to 2.11 (all P<0.05). Quantile g-computation showed positive associations with 4 types of CVD risks (HRs ranging from 1.48 to 2.25, all P<0.05). OM and chloride had maximum weights for CVD risks. Causal mediation analysis showed that the positive association of OM with total CVD was mediated by metabolic syndrome, with a mediation proportion of 1.3% (all P<0.05). CONCLUSIONS: Long-term exposure to PM2.5 chemical constituents is positively associated with CVD risks. OM and chloride appear to play the most responsible role in the positive associations between PM2.5 and CVD. OM is probably associated with CVD through metabolic-related pathways.

Mediation Effect of Obesity on the Association of Age at Menarche With Blood Pressure Among Women in Southwest China.

Background Previous studies have been inconsistent about the association between age at menarche and high blood pressure. Little is known about such association across a wide range of menarcheal ages in less developed ethnic minority regions in China. We aimed to explore the association between age at menarche and high blood pressure (BP; ≥140/90 mm Hg) and to examine the mediating effect of obesity and the moderating effect of menopausal status on this association. Methods and Results A total of 45 868 women from the baseline data of the CMEC (China Multi-Ethnic Cohort) were included in this study. Binary logistic regression was used to analyze the relationship between age at menarche and high BP, and the mediation model was used to evaluate the mediating effects of body mass index and waist circumference on the association of age at menarche with high BP. The mean age at enrollment and age at menarche of participants in our study were 49.3 (SD=10.7) and 14.7 (SD=2.1) years, respectively. Late menarche was associated with a lower risk of high BP (odds ratio, 0.831 [95% CI, 0.728-0.950]). The risk of high BP decreased by 3.1% with each year's delay in the onset of menarche (P for trend <0.001). Body mass index and waist circumference could partially mediate the association of age at menarche and high BP with the indirect effect of body mass index (odds ratio, 0.998 [95% CI, 0.997-0.998]) and waist circumference (odds ratio, 0.999 [95% CI, 0.998-0.999]). In addition, the mediation effects were modified by the status of menopause. Conclusions Women with late menarche have a lower risk of high BP, and obesity could be one of the important mediators. Obesity prevention is an efficient strategy to reduce the association between age at menarche and high BP, especially in premenopausal women.

Role of Liver Enzymes in the Relationship Between Particulate Matter Exposure and Diabetes Risk: A Longitudinal Cohort Study.

CONTEXT: Particulate matter (PM) is an important risk factor for diabetes. However, its underlying mechanisms remain poorly understood. Although liver-derived biological intermediates may play irreplaceable roles in the pathophysiology of diabetes, few studies have explored this in the association between PM and diabetes. OBJECTIVE: We investigated the role of liver enzymes in mediating the relationship between PM exposure and diabetes. METHODS: We included a total of 7963 participants from the China Multi-Ethnic Cohort. Residential exposure to PM was assessed using a validated spatial-temporal assessment method. Diabetes was diagnosed according to the criteria from American Diabetes Association. Associations between PM, liver enzyme [including alanine aminotransferase (ALT), aspartate aminotransferase, alkaline phosphatase, and γ-glutamyl transpeptidase (GGT)], and diabetes were estimated using multivariable regression models. The function of liver enzymes in the relationship between PM and diabetes was assessed using mediation analysis. RESULTS: PM exposure was positively associated with the odds of diabetes, with odds ratios of 1.32 (95% CI 0.83, 2.09), 1.33 (95% CI 1.07, 1.65), and 1.18 (95% CI 1.02, 1.36) for every 10-µg/m3 increment in ≤1 µm (PM1), ≤2.5 µm (PM2.5), and ≤10 µm (PM10) PM, respectively. ALT (4.47%) and GGT (4.78%) exhibited statistically significant mediation effects on the association between PM2.5 and diabetes, and the ALT (4.30%) also had a mediating role on PM10. However, none of the liver enzymes had a significant mediating effect on PM1. CONCLUSION: The relationship between PM and diabetes is partially mediated by liver enzymes, suggesting that lipid accumulation, oxidative stress, and chronic inflammation in the liver may be involved in its pathogenesis.

Comorbid Depressive and Anxiety Symptoms and Their Correlates Among 93,078 Multiethnic Adults in Southwest China.

Background: Depressive symptoms and anxiety symptoms commonly coexist and severely increases the disease burden worldwide. Little is known about the patterns and correlates of comorbid depressive and anxiety symptoms among the multiethnic populations of China. Methods: This population-based study investigated the comprehensive associations of comorbid depressive and anxiety symptoms with lifestyles, stressful life events, chronic diseases, and physical and mental well-being among 93,078 participants (37,193 men, 55,885 women) aged 30-79 years across seven ethnic groups in Southwest China. Multivariable logistic regression models were used to estimate associations. Results: Overall, 2.9% (2.1% in men and 3.5% in women) participants had comorbid depressive and anxiety symptoms; there was considerable heterogeneity among multiethnic populations. Participants with chronic diseases were more likely to have comorbidity than those without them; people with rheumatic heart disease reported the highest risk, with an odds ratio (OR) of 6.25 and 95% confidence interval (CI) of 4.06-9.62. Having experienced 3 or more stressful life events (OR, 8.43, 95% CI: 7.27-9.77), very poor self-rated health status (OR, 33.60, 95%CI: 25.16-44.87), and very unsatisfied life (OR, 33.30, 95% CI: 23.73-46.74) had strong positive associations with comorbid depressive symptoms and anxiety symptoms, with a dose-response relationship (P < 0.05). High frequency of physical activity had negative associations. All the associations were stronger than depressive symptoms alone or anxiety symptoms alone. Conclusions: Our findings emphasize the need to focus on the vulnerable ethnic groups with comorbid depressive and anxiety symptoms, ultimate for help early prevention and improvement of health equity in the underdevelopment and high urbanization areas.

GCH1 plays a role in the high-altitude adaptation of Tibetans.

Tibetans are well adapted to high-altitude hypoxia. Previous genome-wide scans have reported many candidate genes for this adaptation, but only a few have been studied. Here we report on a hypoxia gene ( GCH1, GTP-cyclohydrolase I), involved in maintaining nitric oxide synthetase (NOS) function and normal blood pressure, that harbors many potentially adaptive variants in Tibetans. We resequenced an 80.8 kb fragment covering the entire gene region of GCH1 in 50 unrelated Tibetans. Combined with previously published data, we demonstrated many GCH1 variants showing deep divergence between highlander Tibetans and lowlander Han Chinese. Neutrality tests confirmed a signal of positive Darwinian selection on GCH1 in Tibetans. Moreover, association analysis indicated that the Tibetan version of GCH1 was significantly associated with multiple physiological traits in Tibetans, including blood nitric oxide concentration, blood oxygen saturation, and hemoglobin concentration. Taken together, we propose that GCH1 plays a role in the genetic adaptation of Tibetans to high altitude hypoxia.

EP300 contributes to high-altitude adaptation in Tibetans by regulating nitric oxide production.

The genetic adaptation of Tibetans to high altitude hypoxia likely involves a group of genes in the hypoxic pathway, as suggested by earlier studies. To test the adaptive role of the previously reported candidate gene EP300 (histone acetyltransferase p300), we conducted resequencing of a 108.9 kb gene region of EP300 in 80 unrelated Tibetans. The allele-frequency and haplotype-based neutrality tests detected signals of positive Darwinian selection on EP300 in Tibetans, with a group of variants showing allelic divergence between Tibetans and lowland reference populations, including Han Chinese, Europeans, and Africans. Functional prediction suggested the involvement of multiple EP300 variants in gene expression regulation. More importantly, genetic association tests in 226 Tibetans indicated significant correlation of the adaptive EP300 variants with blood nitric oxide (NO) concentration. Collectively, we propose that EP300 harbors adaptive variants in Tibetans, which might contribute to high-altitude adaptation through regulating NO production.