Prospective findings from the Dongfeng-Tongji cohort: Exposure to various metals, the expression of microRNA-4286, and the incidence of acute coronary syndrome.

Mounting evidence suggests that metal/metalloid exposure is related to the adverse health effects. Our prior investigation revealed a positive relation between the plasma level of microRNA-4286 (miR-4286) and an increased risk of developing acute coronary syndrome (ACS). However, it is a lack of studies evaluating the connection between metal/metalloid exposure and miRNA expression on ACS. In the prospective Dongfeng-Tongji cohort, we performed a nested case-control study. A total of 480 ACS and 480 controls were carefully selected based on similar age, sex, and blood collection time. Using inductively coupled plasma mass spectrometry, we assessed the plasma concentrations of 24 different metals. Quantitative real-time polymerase chain reaction was used to analyze the plasma miR-4286. We examined the relations of plasma metals with miR-4286 levels, the incidence of ACS, and the potential interactions. Using the multivariate conditional logistic regression models, we observed that the adjusted odds ratios (95% confidence intervals [CI]) for incident ACS were 1.79 (1.03, 3.12; P-trend = 0.03), 0.60 (0.41, 0.87; P-trend = 0.008), and 0.66 (0.46, 0.93; P-trend = 0.02), when comparing the extreme tertiles of aluminum, rubidium, and selenium, respectively. There was a relation between the concentration of rubidium in plasma and a decrease in the level of plasma miR-4286 (percent difference [95% CI]: -13.36% [-22.74%, -2.83%]; P-trend = 0.01). Both multiplicative (P interaction = 0.009) and additive interactions (relative excess risk due to interaction [95% CI]: 0.82 [0.59, 1.06]) were noted in our observation regarding the relationship between plasma aluminum and miR-4286 in incident ACS. The findings indicated that plasma aluminum was positively while plasma rubidium and selenium were negatively linked to an increased risk of developing ACS. Plasma aluminum exposure and plasma miR-4286 expression might synergistically affect the incident ACS risk. Controlling aluminum exposure was important for ACS prevention, especially for individuals with high expression of plasma miR-4286.

Mediation of association between benzo[a]pyrene exposure and lung cancer risk by plasma microRNAs: A Chinese case-control study.

Epidemiologic studies have reported the positive relationship of benzo[a]pyrene (BaP) exposure with the risk of lung cancer. However, the mechanisms underlying the relationship is still unclear. Plasma microRNA (miRNA) is a typical epigenetic biomarker that was linked to environment exposure and lung cancer development. We aimed to reveal the mediation effect of plasma miRNAs on BaP-related lung cancer. We designed a lung cancer case-control study including 136 lung cancer patients and 136 controls, and measured the adducts of benzo[a]pyrene diol epoxide-albumin (BPDE-Alb) and sequenced miRNA profiles in plasma. The relationships between BPDE-Alb adducts, normalized miRNA levels and the risk of lung cancer were assessed by linear regression models. The mediation effects of miRNAs on BaP-related lung cancer were investigated. A total of 190 plasma miRNAs were significantly related to lung cancer status at Bonferroni adjusted P < 0.05, among which 57 miRNAs showed different levels with |fold change| > 2 between plasma samples before and after tumor resection surgery at Bonferroni adjusted P < 0.05. Especially, among the 57 lung cancer-associated miRNAs, BPDE-Alb adducts were significantly related to miR-17-3p, miR-20a-3p, miR-135a-5p, miR-374a-5p, miR-374b-5p, miR-423-5p and miR-664a-5p, which could in turn mediate a separate 42.2%, 33.0%, 57.5%, 36.4%, 48.8%, 32.5% and 38.2% of the relationship of BPDE-Alb adducts with the risk of lung cancer. Our results provide non-invasion biomarker candidates for lung cancer, and highlight miRNAs dysregulation as a potential intermediate mechanism by which BaP exposure lead to lung tumorigenesis.

Association between serum pyrethroid insecticide levels and incident type 2 diabetes risk: a nested case-control study in Dongfeng-Tongji cohort.

Pyrethroid insecticides have been extensively used worldwide, but few studies explored the prospective association between pyrethroid exposure and incident type 2 diabetes (T2D). We conducted a nested case-control study of 2012 paired cases and controls, and measured eight pyrethroid insecticides in the baseline sera. We used conditional logistic regression models to estimate odds ratios (ORs) with 95% confidence intervals, and constructed multiple-pollutant models to investigate the association of pyrethroid mixture with incident T2D risk. The median concentrations (detection rates) were 3.53 µg/L (92.45%), 0.52 µg/L (99.80%), 1.16 µg/L (90.61%) and 1.43 µg/L (99.95%) for permethrin, cypermethrin, fenvalerate, and deltamethrin, respectively. Compared to participants with serum fenvalerate levels in the first quartile, the multivariable-adjusted ORs of incident T2D were 1.20 (95% CI 0.86-1.67), 1.41 (0.97-2.05), and 2.29 (1.27-4.11) for the second, third and fourth quartile (P trend = 0.01). Spline analysis further confirmed the positive association between serum fenvalerate levels and incident T2D risk (P for overall association = 0.006). Furthermore, mixture models revealed a positive association of pyrethroid mixture with incident T2D risk, with serum fenvalerate ranked as the top contributor (proportion of relative contribution: > 70%). We found that high concentrations of serum pyrethroid insecticides were significantly associated with an increased risk of incident T2D. The elevated risk was largely explained by fenvalerate. Further investigations are urgently needed to confirm our findings and elucidate the underlying mechanisms, given the widespread use of pyrethroids and the global pandemic of diabetes.

Plasma metal concentrations and their interactions with genetic susceptibility on homocysteine levels.

Limited studies have evaluated the associations of multiple metal exposures with homocysteine (Hcy) levels, which were independent risk factor for cardiovascular disease (CVD). Furthermore, the interactions between genetic variants and plasma metals in relation to Hcy levels were largely unknown. We aimed to explore the associations of multiple plasma metals (including metalloids arsenic [As] and selenium [Se]) with Hcy levels and whether their associations were modified by genetic susceptibility. We included 2989 participants from the baseline of the Dongfeng-Tongji cohort (DFTJ cohort) and conducted a cross-sectional study to explore the associations of 17 plasma metals with serum Hcy levels. Both multi-variable linear regression model (single-metal model) and LASSO penalized regression model (multiple-metal model) were used to identify the Hcy-associated metals. The weighted genetic risk score (GRS) was calculated based on 18 established Hcy-associated genetic variants. For metals that were associated with Hcy, we further assessed the gene-metal interactions on Hcy levels. Among 17 metals, plasma molybdenum (Mo), strontium (Sr), and Zinc (Zn) were positively associated with Hcy levels, whereas Se was inversely associated with Hcy levels in both single- and multiple-metal models. We also observed that the genetic predisposition to Hcy significantly modified the association between plasma Se and serum Hcy levels (P for interaction = 0.003), while no significant gene-metal interactions were found for Mo, Sr, and Zn (all P for interactions > 0.05). These findings provide novel insight into the associations of the plasma concentrations of Mo, Se, Sr and Zn with Hcy levels and address the importance of Se as a potential upstream modifiable factor for the personalized prevention of elevated Hcy levels and CVD.

Single-Cell RNA Sequencing Reveals the Heterogeneity of Infiltrating Immune Cell Profiles in the Hepatic Cystic Echinococcosis Microenvironment.

Human cystic echinococcosis, caused by the larval stage of Echinococcus granulosus sensu lato, has been reported a near-cosmopolitan zoonotic disease. Various infiltrating immune cells gather around the lesion and produce a lesion microenvironment; however, cellular composition and heterogeneity in hepatic cystic echinococcosis lesion microenvironments are incompletely understood. Here, 81,865 immune cells isolated from peripheral blood, perilesion liver tissue, and adjacent normal liver tissue from four cystic echinococcosis patients were profiled using single-cell RNA sequencing. We identified 23 discrete cell populations and found distinct differences in infiltrating immune cells between tissue environments. Despite the significant similarity between perilesion and adjacent normal liver tissue-resident immune cells, the cellular proportions of type 2 innate lymphoid cells (ILC2s) and plasmacytoid dendritic cells (pDCs) were higher in perilesion liver tissue. Interestingly, the immunosuppressive gene NFKBIA was upregulated in these cells. Seven subsets of CD4+ T cell populations were found, and there were more regulatory-CD4+ T cells (Treg-CD4+) and Th2-CD4+ T cells in perilesion tissue than in adjacent normal tissue. There was close contact between CD4+ T cells and ILC2s and pDCs, which caused upregulation of genes related to positive immune activity in adjacent normal liver tissue. However, expression of genes related to immunosuppression, especially the immune inhibitory checkpoint gene NKG2A/HLA-E, was obviously higher in perilesion tissue, suggesting that cellular interaction resulted in an inhibitory microenvironment in the cystic echinococcosis (CE) lesion. This work offers new insights into the transcriptional heterogeneity of infiltrating immune cells in hepatic cystic echinococcosis lesion microenvironments at a single-cell level and provides potential target signatures for diagnosis and immunotherapies.

Past Shift Work and Incident Coronary Heart Disease in Retired Workers: A Prospective Cohort Study.

Present shift work has been associated with coronary heart disease (CHD) among employed workers, but it remains unclear whether shift work performed in the past is still associated with CHD in retired workers. We recruited 21,802 retired workers in Shiyan, China, in 2008-2010 and 2013 and followed them for CHD events occurring up to December 31, 2018. Retired workers with longer durations of past shift work (rounded to 0.25 years) had higher CHD risks (for those with ≤5.00, 5.25-10.00, 10.50-20.00, and >20.00 years of past shift work, hazard ratios were 1.05 (95% confidence interval (CI): 0.94, 1.16), 1.08 (95% CI: 0.94, 1.25), 1.23 (95% CI: 1.07, 1.42), and 1.28 (95% CI: 1.08, 1.51), respectively). The association was substantially higher among service or sales workers than among manufacturing or manual-labor workers (for every 5-year increase in past shift work, hazard ratio = 1.11 (95% CI: 1.05, 1.16) vs. hazard ratio = 1.02 (95% CI: 0.98, 1.06)). Moreover, the risk was lower among those who were physically active than among their inactive counterparts (P for interaction = 0.019). Longer duration of past shift work was associated with higher risk of incident CHD among these retired workers, especially those from the service or sales sectors. Physical exercise might be beneficial in reducing the excess risk.

Th1/Th2/Th17 cytokine profile in hepatic cystic Echinococcosis patients with different cyst stages.

AIMS: The study aimed to investigate possible correlation between expression level of Th1/Th2/Th17-type profile and cyst viability in the systemic and local immunity of hepatic cystic Echinococcosis (CE) patients. METHODS AND RESULTS: Expression of Th1-type interleukin (IL)-2, interferon (IFN)-γ, tumour necrosis factor (TNF)-α, Th2-type IL-4, IL-6, IL-10 and Th17-type IL-17A was examined in the serum and liver samples of hepatic CE patients with different cyst stages. Compared with healthy controls, Th1/Th2/Th17-type cytokines were significantly increased in the serum of hepatic CE patients. Moreover, expression of these cytokines was also at higher level in the inflammatory cell band of peri-lesion liver (PL) tissues than that in the adjacent normal (AN) liver tissues. Interestingly, elevation of Th1-type and Th17-type cytokines was more evident in PL tissues of patients with inactive cysts. Relatively, Th2-type cytokines were predominant in PL tissues of patients with active cysts. CONCLUSION: Our findings provide new insights that Th1/Th2/Th2-type cytokine profile was associated with cyst stages. In hepatic CE patients with inactive cysts, Th1 and Th17-type cytokines were predominant. Comparatively, Th2-type cytokines were more evident in hepatic CE patients with active cysts, which may provide basis for the immune response diversity in hepatic CE patients with different cyst stages.

The air quality changes and related mortality benefits during the coronavirus disease 2019 pandemic in China: Results from a nationwide forecasting study.

Air quality changes during the coronavirus disease 2019 (COVID-19) pandemic in China has attracted increasing attention. However, more details in the changes, future air quality trends, and related death benefits on a national scale are still unclear. In this study, a total of 352 Chinese cities were included. We collected air pollutants (including fine particulate matter [PM2.5], inhalable particulate matter [PM10], nitrogen dioxide [NO2], and ozone [O3]) data for each city from January 2015 to July 2020. Convolutional neural network-quantile regression (CNN-QR) forecasting model was used to predict pollutants concentrations from February 2020 to January 2021 and the changes in air pollutants were compared. The relationships between the socioeconomic factors and the changes and the avoided mortality due to the changes were further estimated. We found sharp declines in all air pollutants from February 2020 to January 2021. Specifically, PM2.5, PM10, NO2, and O3 would drop by 3.86 µg/m3 (10.81%), 4.84 µg/m3 (7.65%), 0.55 µg/m3 (2.18%), and 3.14 µg/m3 (3.36%), respectively. The air quality changes were significantly related to many of the socioeconomic factors, including the size of built-up area, gross regional product, population density, gross regional product per capita, and secondary industry share. And the improved air quality would avoid a total of 7237 p.m.2.5-related deaths (95% confidence intervals [CI]: 4935, 9209), 9484 p.m.10-related deaths (95%CI: 5362, 13604), 4249 NO2-related deaths (95%CI: 3305, 5193), and 6424 O3-related deaths (95%CI: 3480, 9367), respectively. Our study shows that the interventions to control COVID-19 would improve air quality, which had significant relationships with some socioeconomic factors. Additionally, improved air quality would reduce the number of non-accidental deaths.

Association of age and viral factors with high-risk HPV persistence: A retrospective follow-up study.

OBJECTIVE: Cervical HR-HPV persistence is the main risk factor for cervical cancer. We aimed to investigate the association of age and viral factors with HR-HPV persistence. METHODS: From 2010 to 2017, 343,128 women underwent 390,411 tests performed by the Cervista HR-HPV assay (Data C3) and 157,123 women underwent 206,505 tests performed by the GenoArray HR-HPV assay (Data G14) in nine medical centers located in central and eastern China. We combined the test results and identified 9234 HPV-specific baseline-negative records for time-to-event analyses. The study endpoint event was defined as clearance of type/group-specific HPV. Therefore, hazard ratio (HR) < 1 indicated a higher risk of HPV persistence, which is contrary to the common meaning of HR. RESULTS: The median persistence time was 375 and 541.5 days for Data C3 and Data G14, respectively. For every 5-year increase in age, a 15% (95% confidence interval [CI], 11%-19%) decrease in the clearance rate was observed only after 400 days of infection. For each additional co-infected HPV, the HR was 1.80 (95% CI, 1.63-1.97) on infection initiation but decreased by 22% (95% CI, 18%-26%) every 100 days. The HR of infection recurrence was 0.48 (95% CI, 0.32-0.72). The findings were consistent across different populations and test methods and were robust in sensitivity analysis. CONCLUSIONS: We found a time-dependent association of age and viral factors with HPV clearance. Older age reduced HPV clearance only after 400 days of infection. Co-infection promoted HPV clearance in the beginning, but the effect attenuated and reversed as infection persisted. Recurrent same-type infection cleared slower than the previous one.

Associations of Plasma Metabolites With Risks of Incident Stroke and Its Subtypes in Chinese Adults.

BACKGROUND: Metabolomics studies have identified various metabolic markers associated with stroke risk, yet much uncertainty persists regarding heterogeneity in these associations between different stroke subtypes. We aimed to examine metabolic profiles associated with incident stroke and its subtypes in Chinese adults. METHODS AND RESULTS: We performed a nested case-control study within the Dongfeng-Tongji cohort, including 1029 and 266 incident cases of ischemic stroke (IS) and hemorrhagic stroke (HS), respectively, with a mean follow-up period of 6.1±2.3 years. Fifty-five metabolites in fasting plasma were measured by ultra-high-performance liquid chromatography-mass spectrometry. We examined the associations of metabolites with the risks of total stroke, IS, and HS, with a focus on the comparison of associations of plasma metabolite with IS and HS, using conditional logistic regression. We found that increased levels of asymmetrical/symmetrical dimethylarginine and glutamate were significantly associated with elevated risk of total stroke (odds ratios and 95%, 1.20 [1.08-1.34] and 1.22 [1.09-1.36], respectively; both Benjamini-Hochberg-adjusted P <0.05). When examining stroke subtypes, asymmetrical/symmetrical dimethylarginine was nominally associated with both IS and HS (odds ratios [95% CIs]: 1.16 [1.03-1.31] and 1.39 [1.07-1.81], respectively), while glutamate was associated with only IS (odds ratios [95% CI]: 1.26 [1.11-1.43]). The associations of glutamate with IS risk were significantly stronger among participants with hypertension and diabetes than among those without these diseases (both P for interaction <0.05). CONCLUSIONS: This study validated the positive associations of asymmetrical/symmetrical dimethylarginine and glutamate with stroke risk, mainly that of IS, in a Chinese population, and revealed a novel unanimous association of with both IS and HS. Our findings provided potential intervention targets for stroke prevention.

Sleep Duration, Midday Napping, and Serum Homocysteine Levels: A Gene-Environment Interaction Study.

The associations of sleep duration and midday napping with homocysteine (Hcy) levels, and whether these sleep behaviors modify the association between genetic predisposition and Hcy levels, has yet to be investigated. We included 19,426 participants without severe health conditions at baseline from the Dongfeng−Tongji cohort. In a subgroup of 15,126 participants with genetic data, a genetic risk score (GRS) based on 18 Hcy-related loci was constructed to test the gene−sleep interactions in Hcy. Hcy levels were higher in subjects with a long sleep duration (≥9 h) and midday napping (>90 min), as compared to those who reported a moderate sleep duration (7 to <8 h) and midday napping (1−30 min) (all p values < 0.05). A long sleep duration and midday napping showed a joint effect in increasing Hcy (p for trend < 0.001). Significant interactions regarding Hcy levels were observed for a long sleep duration with GRS and MTHFR rs1801133, and long midday napping with DPEP1 rs12921383 (all p values for interaction < 0.05). Overall findings indicated that a long sleep duration and midday napping were associated with elevated serum Hcy levels, independently and jointly, and amplified the genetic susceptibility to higher Hcy.

Circulating organochlorine pesticide levels, genetic predisposition and the risk of incident type 2 diabetes.

Persistent organochlorine pesticide (OCP) has been associated with type 2 diabetes (T2D), and genetic polymorphism might modify such an association. However, prospective evidence remains scarce. We conducted a nested case-control study comprising 1006 incident diabetic cases and 1006 matched non-diabetic controls [sex and age (±5 years)] from 2008 to 2013 (mean follow-up period: ∼4.6 years) based on the Dongfeng-Tongji cohort in Shiyan City of China, determined baseline levels of nineteen OCPs, and examined the associations of circulating OCPs, both individually and collectively, with incident T2D risk. We also constructed overall genetic risk score (GRS) based on 161 T2D-associated variants and five pathway-specific cluster GRSs based on established variants derived from the Asian population. Compared with the first quartile of serum ß-BHC levels, the multivariable-adjusted ORs (95% CIs) of incident T2D risk in the second, third, and fourth quartiles were 0.98 (0.70-1.39), 1.43 (0.99-2.07), and 1.75 (1.14-2.68), respectively (FDR-adjusted Ptrend = 0.03). A positive association was observed between serum OCP mixture and incident T2D risk and can be largely attributed to ß-BHC. Furthermore, serum ß-BHC and p,p'-DDE showed significant interactions with the GRS for lipodystrophy, a T2D-related pathway representing fat redistribution to viscera, on T2D risk (Pinteraction < 0.05). In conclusion, higher circulating OCP levels were independently associated with an increased risk of T2D, with ß-BHC possibly being the major contributor. Genetic predisposition to T2D-related morbidity, such as visceral adiposity, should be considered when assessing the risk of T2D conferred by OCPs.

Lipid metabolic links between serum pyrethroid levels and the risk of incident type 2 diabetes: A mediation study in the prospective design.

Emerging evidence revealed that pyrethroids and circulating lipid metabolites are involved in incident type 2 diabetes (T2D). However, the pyrethroid-associated lipid profile and its potential role in the association of pyrethroids with T2D remain unknown. Metabolome-wide association or mediation analyses were performed among 1006 pairs of T2D cases and matched controls nested within the prospective Dongfeng-Tongji cohort. We identified 59 lipid metabolites significantly associated with serum deltamethrin levels, of which eight were also significantly associated with serum fenvalerate (false discovery rate [FDR] < 0.05). Pathway enrichment analysis showed that deltamethrin-associated lipid metabolites were significantly enriched in the glycerophospholipid metabolism pathway (FDR = 0.02). Furthermore, we also found that several deltamethrin-associated lipid metabolites (i.e., phosphatidylcholine [PC] 32:0, PC 34:4, cholesterol ester 20:0, triacylglycerol 52:5 [18:2]), and glycerophosphoethanolamine-enriched latent variable mediated the association between serum deltamethrin levels and T2D risk, with the mediated proportions being 44.81%, 15.92%, 16.85%, 16.66%, and 22.86%, respectively. Serum pyrethroids, particularly deltamethrin, may lead to an altered circulating lipid profile primarily in the glycerophospholipid metabolism pathway represented by PCs and lysophosphatidylcholines, potentially mediating the association between serum deltamethrin and T2D. The study provides a new perspective in elucidating the potential mechanisms through which pyrethroid exposure might induce T2D.

Polycyclic aromatic hydrocarbons exposure and plasma lncRNA signature: A profile and functional analysis.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants that pose detrimental effects on human health, and the exploration of the associations of PAHs exposure with long non-coding RNA (lncRNA) may provide novel clues to the underlying mechanisms. In the present study, we detected 10 urinary PAHs metabolites by GC-MS and plasma lncRNAs levels by Human LncRNA Array v4 among 230 participants from two panels (160 in the Shiyan panel and 70 in the Wuhan-Zhuhai panel). We applied linear regression models to assess the associations between PAHs metabolites and lncRNAs separately in each panel and combined the results using fixed-effect meta-analysis. To explore the potential origin of PAHs-related lncRNAs in plasma, we estimated their tissue-specificity and associations between lncRNAs levels in plasma and leukocytes. Leukocytes mRNA sequencing data and RNA binding proteins were utilized to explore implicated pathways of identified lncRNAs. We found that urinary 1-hydroxyphenanthrene (1-OH-Phe) was inversely associated with 8 lncRNAs and positively associated with 1 lncRNA, as well as 9-hydroxyphenanthrene (9-OH-Phe) was inversely associated with 11 lncRNAs (FDR < 0.1). Tissue specificity analysis using Genome Tissue Expression database suggested that several identified lncRNAs might specifically express in organs targeted by PAHs exposure (lung, liver, heart, kidney, and brain). Besides, plasma levels of 1-OH-Phe related ENSG00000260616 and 9-OH-Phe related STARD4-AS1 were inversely associated with their intra-leukocytes levels (P value < 0.05). Notably, STARD4-AS1 was positively associated with the expression levels of its neighboring protein-coding gene (CAMK4 and STARD4) in leukocytes and were involved in pathways related to cellular response to DNA damage, which we further confirmed using DNA damage biomarker, 8-hydroxydeoxyguanosine. Functional analysis also revealed vital pathways related to cytokine-mediated signaling and glucose homeostasis. Our findings provided novel insights into plausible biological mechanisms underlying the adverse effects of PAHs exposure.

Nontargeted Metabolomics Revealed Novel Association Between Serum Metabolites and Incident Acute Coronary Syndrome: A Mendelian Randomization Study.

Background This study was performed to identify metabolites associated with incident acute coronary syndrome (ACS) and explore causality of the associations. Methods and Results We performed nontargeted metabolomics in a nested case-control study in the Dongfeng-Tongji cohort, including 500 incident ACS cases and 500 age- and sex-matched controls. Three metabolites, including a novel one (aspartylphenylalanine), and 1,5-anhydro-d-glucitol (1,5-AG) and tetracosanoic acid, were identified as associated with ACS risk, among which aspartylphenylalanine is a degradation product of the gut-brain peptide cholecystokinin-8 rather than angiotensin by the angiotensin-converting enzyme (odds ratio [OR] per SD increase [95% CI], 1.29 [1.13-1.48]; false discovery rate-adjusted P=0.025), 1,5-AG is a marker of short-term glycemic excursions (OR per SD increase [95% CI], 0.75 [0.64-to 0.87]; false discovery rate-adjusted P=0.025), and tetracosanoic acid is a very-long-chain saturated fatty acid (OR per SD increase [95% CI], 1.26 [1.10-1.45]; false discovery rate-adjusted P=0.091). Similar associations of 1,5-AG (OR per SD increase [95% CI], 0.77 [0.61-0.97]) and tetracosanoic acid (OR per SD increase [95% CI], 1.32 [1.06-1.67]) with coronary artery disease risk were observed in a subsample from an independent cohort (152 and 96 incident cases, respectively). Associations of aspartylphenylalanine and tetracosanoic acid were independent of traditional cardiovascular risk factors (P-trend=0.015 and 0.034, respectively). Furthermore, the association of aspartylphenylalanine was mediated by 13.92% from hypertension and 27.39% from dyslipidemia (P<0.05), supported by its causal links with hypertension (P<0.05) and hypertriglyceridemia (P=0.077) in Mendelian randomization analysis. The association of 1,5-AG with ACS risk was 37.99% mediated from fasting glucose, and genetically predicted 1,5-AG level was negatively associated with ACS risk (OR per SD increase [95% CI], 0.57 [0.33-0.96], P=0.036), yet the association was nonsignificant when further adjusting for fasting glucose. Conclusions These findings highlighted novel angiotensin-independent involvement of the angiotensin-converting enzyme in ACS cause, and the importance of glycemic excursions and very-long-chain saturated fatty acid metabolism.

Individual and mixtures of metal exposures in associations with biomarkers of oxidative stress and global DNA methylation among pregnant women.

BACKGROUND: Prenatal exposure to metals has been linked with adverse pregnancy outcomes. Oxidative stress and epigenetic changes are potential mechanisms of action. OBJECTIVES: We aimed to examine the associations of individual and mixtures of metal exposures with oxidative stress and DNA methylation among pregnant women. METHODS: We measured a panel of 16 metals and 3 oxidative stress biomarkers including 8-hydroxydeoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal-mercapturic acid (HNE-MA) and 8-isoprostaglandin F2α (8-isoPGF2α) in urine from 113 pregnant women in a Chinese cohort. Biomarkers of global DNA methylation including Alu and long interspersed nucleotide element-1 (LINE-1) in cord blood were measured. Multivariable linear regression and Bayesian kernel machine regression (BKMR) models were separately applied to estimate the associations between individual and mixtures of metal exposures and biomarkers of oxidative stress and global DNA methylation. RESULTS: In single-metal analyses, we observed positive associations between 11 metals [arsenic (As), cadmium (Cd), thallium (Tl), barium (Ba), nickel (Ni), vanadium (V), cobalt (Co), zinc (Zn), copper (Cu), selenium (Se) and molybdenum (Mo)] and at least one of oxidative stress biomarkers (all FDR-adjusted P-values < 0.05). In mixture analyses, we found positive overall associations of metal mixtures with 8-OHdG and 8-isoPGF2α, and Se was the most important predictor. There was no evidence on associations of urinary metals as individual chemicals and mixtures with Alu and LINE-1 methylation. CONCLUSION: Urinary metals as individual chemicals and mixtures were associated with increased oxidative stress, especially Se.

Associations of Baseline and Changes in Leukocyte Counts with Incident Cardiovascular Events: The Dongfeng-Tongji Cohort Study.

AIM: The aim of the present study was to investigate the associations of baseline and longitudinal changes in leukocyte counts with incident cardiovascular disease (CVD). METHODS: We conducted a prospective study to investigate the associations of baseline and 5-year changes in leukocyte counts with incident CVD and its subtypes in middle-aged and elderly Chinese. We estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD using the Cox proportional-hazards models. RESULTS: In the analyses of baseline total leukocyte count of 26,655 participants, compared with the lowest quartile (＜4.71×109/L), participants in the fourth quartile (＞6.70×109/L) had 11% higher risk for CVD. Consistent with total leukocyte count, neutrophil count also exhibited a significant positive association with the risk of CVD. In the analyses of 5-year changes in total leukocyte count of 11,594 participants, the changes in leukocyte count were categorized into three groups, i.e., the decreased group (＜25%), stable group (25%-75%), and increased group (＞75%). Compared with participants in the stable group (-1.18 to 0.44×109/L), participants in the increased group (＞0.44×109/L) had 14% higher risk for CVD. We also observed significant positive associations of the changes in neutrophil and monocyte counts with the risk of CVD. Furthermore, the total leukocyte count in the second or third tertile at the first follow-up with a 5-year increase was related to higher CVD risk. CONCLUSION: High baseline total leukocyte count and a 5-year increase in total leukocyte count were related to higher CVD risk.

Circulating metals, leukocyte microRNAs and microRNA networks: A profiling and functional analysis in Chinese adults.

BACKGROUND: Metals in the human body represent both environmental exposure and nutritional status. Little is known about the miRNA signature in relation to circulating metals in humans. OBJECTIVES: To characterize metal-associated miRNAs in leukocytes, individually and collectively as networks. METHODS: In a panel of 160 Chinese adults, we measured 23 metals/metalloids in plasma, and sequenced miRNAs and mRNAs in leukocytes. We used linear regression to model the associations between ln-transformed metal concentrations and normalized miRNA levels adjusting for potential confounders. We inferred the enriched leukocyte subtypes for the identified miRNAs using an association approach. We utilized mRNA sequencing data to explore miRNA functions. We also constructed modules to identify metal-associated miRNA networks. RESULTS: We identified 55 metal-associated miRNAs at false discovery rate-adjusted P < 0.05. In particular, we found that lead, nickel, and vanadium were positively associated with potentially lymphocyte-enriched miR-142-3p, miR-150-3p, miR-28-5p, miR-361-3p, and miR-769-5p, and were inversely associated with potentially granulocyte-enriched let-7a/c/d-5p and miR-1294. Interestingly, the five lymphocyte-enriched miRNAs inhibited, whereas miR-1294 activated, ROS and DNA repair pathways. We further confirmed the findings using oxidative damage biomarkers. Next, we clustered co-expressed miRNAs into modules, and identified four miRNA modules that were associated with different metals. The identified modules represented miRNAs enriched in different leukocyte subtypes, and were involved in biological processes including hematopoiesis and immune response, mitochondrial functions, and response to the stimulus. CONCLUSIONS: At commonly exposed low levels, circulating metals were associated with distinct miRNA signatures in leukocytes. The identified miRNAs, individually or as regulatory networks, may provide a mechanistic link between metal exposure and pathophysiological changes in the immune system.

Road traffic and air pollution: Evidence from a nationwide traffic control during coronavirus disease 2019 outbreak.

Existing estimations of air pollution from automobile sources are based on either experiments or small-scale governmental interventions. China's nationwide traffic control during the coronavirus disease 2019 outbreak provided us a unique opportunity to assess the direct dose-effect relationship between vehicle density and air pollution. We found that, during the coronavirus disease 2019 outbreak, the nationwide reduced air pollution (except for O3) could be largely explained by traffic control measures. During the traffic control period, every doubling of vehicle density was associated with a decrease of 4.2 (2.0, 6.4) µg/m3 in PM2.5, 5.5 (2.9, 8.1) µg/m3 in PM10, 1.5 (0.9, 2.0) µg/m3 in NO2, and 0.04 (0.02, 0.07) mg/m3 in CO comparing cities with different vehicle densities. Similarly, for every 10% increase in the truck proportion, PM2.5 decreased by 12.3 (4.1, 20.6) µg/m3, PM10 decreased by 14.3 (4.6, 23.9) µg/m3, and CO decreased by 0.14 (0.05, 0.23) mg/m3. Moreover, the associations between vehicle density and reduction in PM2.5, PM10, and CO during the traffic control period were stronger and showed near-complete linearity in cities with low green coverage rate (All P < 0.05 for interaction). According to our estimation, PM2.5 emissions from every doubling of vehicle density can lead to over 8000 excess deaths per year, 66% of which were caused by cardiopulmonary diseases. This natural experiment study is the first to observe the dose-effect relationship between on-road traffic and traffic-generated air pollution, as well as the mitigating effect of urban greening. Findings provide key evidence to the assessment and control of traffic-generated air pollution and its public health impact.

Identification of infiltrating immune cell subsets and heterogeneous macrophages in the lesion microenvironment of hepatic cystic echinococcosis patients with different cyst viability.

Human cystic echinococcosis (CE) is characterized by lesion microenvironment formation through gathering various immune cells, including macrophages. However, immune cell subsets and heterogeneous macrophages in CE lesion microenvironment are poorly defined. Massive infiltrating immune cells formed lesion microenvironment, among which CD4+T cells and CD19+B cells were predominant and CD68+ macrophages were more evident in patients with active cysts. Different degrees of liver fibrosis was observed in Peri-Lesion (PL) liver samples, which was more evident in patients with active cysts. Expression of both M1 and M2 macrophage markers was significantly increased in PL liver samples. Importantly, elevation of M1 macrophage markers was more obvious in patients with inactive cysts, whereas M2 macrophage markers represented dominant macrophage phenotype in patients with active cysts. Additionally, macrophage-derived MIF, TGF-ß1 and ECM1 were also expressed at higher level in CE lesion microenvironment of patients with active cysts. Moreover, MIF was evidently enhanced in the serum of hepatic CE patients, which was also predominant in patients with active cysts. Correlation analysis demonstrated positive correlation between expression of macrophage-derived cytokines and liver fibrosis degree. Heterogeneous macrophages may play significant roles in liver fibrosis of CE lesion microenvironment through producing pro-fibrogenic cytokines.