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.

Associations between plasma metal/metalloid mixtures and the risk of central obesity: A prospective cohort study of Chinese adults.

Central obesity has increased rapidly over the past decade and posed a substantial disease burden worldwide. Exposure to metals/metalloids has been acknowledged to be involved in the development of central obesity through regulation of cortisol, insulin resistance, and glucocorticoid receptor reduction. Despite the importance, it is lack of prospective study which comprehensively evaluate the relations between multiple metals exposure and central obesity. We explored the prospective associations of plasma metal concentrations with central obesity in a prospective study of the Dongfeng-Tongji cohort. The present study included 2127 participants with a 6.87-year mean follow-up duration. We measured 23 plasma metal/metalloid concentrations at baseline. The associations between metals and incident central obesity were examined utilizing the Cox proportional hazard regression in single and multiple metals models. Additionally, we applied elastic net (ENET), Bayesian kernel machine regression (BKMR), plasma metal score (PMS), and quantile-based g-computation (Qgcomp) models to explore the joint associations of metal mixtures with central obesity. After adjusting potential confounders, we found significant associations of plasma manganese (Mn) and thallium (Tl) concentrations with a higher risk of central obesity, whereas plasma rubidium (Rb) concentration was associated with a lower risk of central obesity both in single and multiple metals models (all FDR <0.05). The ENET and Qqcomp models verified similar metals (Mn, Rb, and Tl) as important predictors for central obesity. The results of both BKMR model and PMS suggested cumulative exposure to metal mixtures was associated with a higher risk of central obesity. Our findings suggested that co-exposure to metals was associated with a higher risk of central obesity. This study expands our knowledge that the management of metals/metalloids exposure may be beneficial for the prevention of new-onset central obesity, which may subsequently alleviate the disease burden of late-life health outcomes.

Associations of multiple plasma metals with osteoporosis: findings from the Dongfeng-Tongji cohort.

With the aging population, osteoporosis has become a more prevalent public health issue. Existing researches have indicated significant relations of single metal exposure with osteoporosis (e.g., lead, copper, and zinc), whereas the evidence regarding the joint association of metal mixtures with osteoporosis remain limited and inconclusive. A total of 4924 participants from the Dongfeng-Tongji cohort were included in the present study. Plasma levels of 23 metals were determined by inductively coupled plasma mass spectrometry, and the presence of osteoporosis was defined as a bone mineral density T-score ≤ - 2.5. We applied stepwise regression, plasma metal score, and quantile g-computation model to evaluate the association between plasma metal mixtures and osteoporosis risk. Of the 4924 participants, the prevalence of osteoporosis was 10.9% (N = 265) in males and 27.5% (N = 684) in females. In the multiple-metals model, arsenic was positively associated with osteoporosis in males, while zinc was positively associated with osteoporosis in females. Comparing extreme quartiles, the multivariate-adjusted ORs of osteoporosis were 2.20 (95% CI, 1.29, 3.79; P-trend = 0.006) for arsenic in males and 2.16 (95% CI, 1.44, 3.23; P-trend < 0.001) for zinc in females. The plasma metal score was significantly and positively associated with a higher risk of osteoporosis, with ORs (95% CI) comparing extreme quartiles were 5.00 (95% CI, 3.36, 7.65; P-trend < 0.001) in males and 1.76 (95% CI, 1.35, 2.29; P-trend < 0.001) in females. Furthermore, the results of quantile g-computation revealed a consistent positive trend of metal mixtures with risk of osteoporosis and suggested the dominant role of arsenic in males and zinc in females, respectively. Our findings highlighted the importance of controlling metal mixtures exposure for the prevention of osteoporosis in the middle-aged and elder population. Further prospective studies in larger populations are warranted to confirm our findings.

Bedtime, sleep duration, and sleep quality and all-cause mortality in middle-aged and older Chinese adults: The Dongfeng-Tongji cohort study.

OBJECTIVE: This study aims to investigate the associations of bedtime and its combination with sleep duration and sleep quality with all-cause mortality. METHODS: We conducted a prospective cohort study using data collected from 2008 to 2018 in the Dongfeng-Tongji cohort. Among 40,097 participants aged 62.1 on average at baseline, we applied Cox regression models to assess hazard ratios and 95% confidence intervals for mortality risk. RESULTS: During a mean follow-up of 8.2years, 4345 deaths were documented. U-shaped associations of bedtime and sleep duration with all-cause mortality were observed. Compared with bedtime between 10:01 PM and 11:00 PM, the hazard ratio (95% confidence interval) for all-cause mortality was 1.34 (1.20-1.49) for ≤9:00 PM, 1.18 (1.09-1.27) for 9:01-10:00 PM, and 1.50 (1.13-2.00) for >12:00 AM, respectively. Participants with sleep duration of <6, 6-<7, 8-<9, and ≥9 h/night had a respective 39%, 21%, 11%, and 25% higher all-cause mortality risk than those sleeping 7-<8 h/night. Additionally, participants with a healthy sleep score of 3, characterized as proper bedtime (10:01 PM-12:00 AM), moderate sleep duration (7-<8h/night), and good/fair sleep quality, had a significantly 36% (hazard ratio, 0.64; 95% confidence interval, 0.56-0.74) lower all-cause mortality risk than those with a score of 0. CONCLUSIONS: Individuals with early or late bedtimes and short or long sleep duration were at higher all-cause mortality risks. Having healthy sleep habits may significantly reduce death risk.

Associations of circulating multiple metals with the risk of incident hyperuricemia and the average annual change in uric acid levels.

BACKGROUND: Hyperuricemia has been linked to exposure to certain metals in cross-sectional studies. However, prospective studies evaluating the associations of multiple metal exposures with incident hyperuricemia are scarce. OBJECTIVES: To prospectively investigate the associations of multiple metal/metalloid concentrations with incident hyperuricemia as well as average annual change in uric acid levels in a longitudinal cohort. METHODS: A longitudinal cohort study included 3957 subjects who were free of cardiovascular disease with certain risk factors for cardiovascular disease at baseline. Incident hyperuricemia was ascertained if serum uric acid level was ≥ 420 µmol/L for men and ≥ 360 µmol/L for women during the follow-up visit in 2013. The relationships between 17 single plasma metals/metalloids and incident hyperuricemia were assessed using unconditional logistic regression models. For metals/metalloids significantly related to incident hyperuricemia, we further utilized generalized linear regression models to evaluate their associations with the average annual change in uric acid levels. Finally, we applied the weighted quantile sum (WQS) regression to investigate the joint effects of metals/metalloids on hyperuricemia risk and uric acid changes, and to identify the most significant metals. RESULTS: After adjusting for potential confounders, plasma aluminum, arsenic, barium, lead, strontium, vanadium, and zinc concentrations were positively associated with incident hyperuricemia in both main analyses and sensitivity analyzes. Compared to the lowest quartiles, participants in the highest quartiles had 63 %-125 % higher risks of incident hyperuricemia (all FDR < 0.05). Furthermore, the positive associations of these seven metals with an average annual uric acid increase reinforced the findings. Finally, the WQS analyses showed that plasma metals mixtures were positively associated with the risk of incident hyperuricemia (OR: 1.47; 95 % CI: 1.23, 1.76) and the average annual change in uric acid levels (ß: 3.17; 95 % CI: 2.42, 3.93), and strontium and vanadium were the most heavily weighted metals, respectively. CONCLUSION: Our findings identify aluminum, arsenic, barium, lead, strontium, vanadium, and zinc exposures as independent risk factors for hyperuricemia and provide new insights into the prevention of hyperuricemia.

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.

Neutralization against SARS-CoV-2 Delta/Omicron variants and B cell response after inactivated vaccination among COVID-19 convalescents.

Emerging SARS-CoV-2 variants have made COVID-19 convalescents susceptible to re-infection and have raised concern about the efficacy of inactivated vaccination in neutralization against emerging variants and antigen-specific B cell response. To this end, a study on a long-term cohort of 208 participants who have recovered from COVID-19 was conducted, and the participants were followed up at 3.3 (Visit 1), 9.2 (Visit 2), and 18.5 (Visit 3) months after SARS-CoV-2 infection. They were classified into three groups (no-vaccination (n = 54), one-dose (n = 62), and two-dose (n = 92) groups) on the basis of the administration of inactivated vaccination. The neutralizing antibody (NAb) titers against the wild-type virus continued to decrease in the no-vaccination group, but they rose significantly in the one-dose and two-dose groups, with the highest NAb titers being observed in the two-dose group at Visit 3. The NAb titers against the Delta variant for the no-vaccination, one-dose, and two-dose groups decreased by 3.3, 1.9, and 2.3 folds relative to the wild-type virus, respectively, and those against the Omicron variant decreased by 7.0, 4.0, and 3.8 folds, respectively. Similarly, the responses of SARS-CoV-2 RBD-specific B cells and memory B cells were boosted by the second vaccine dose. Results showed that the convalescents benefited from the administration of the inactivated vaccine (one or two doses), which enhanced neutralization against highly mutated SARS-CoV-2 variants and memory B cell responses. Two doses of inactivated vaccine among COVID-19 convalescents are therefore recommended for the prevention of the COVID-19 pandemic, and vaccination guidelines and policies need to be updated.

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.

Association of Complement C3 With Incident Type 2 Diabetes and the Mediating Role of BMI: A 10-Year Follow-Up Study.

CONTEXT: Impairment of immune and inflammatory homeostasis is reported to be one of the causal factors of diabetes. However, the association of complement C3 levels with incident diabetes in humans remains unclear. OBJECTIVE: This study aimed to examine the association between C3 levels and incident type 2 diabetes mellitus (T2DM), and further explore the potential mediating role of body mass index (BMI) in C3-T2DM associations. METHODS: We determined serum C3 levels of 2662 nondiabetic middle-aged and elderly (64.62 ± 7.25 years) individuals from the Dongfeng-Tongji cohort at baseline. Cox regression was employed to examine the incidence of T2DM in relationship to C3 levels during 10 years of follow-up. Mediation analysis was further applied to assess potential effect of BMI on the C3-T2DM associations. RESULTS: Overall, 711 (26.7%) participants developed T2DM during 23 067 person-years of follow-up. Higher serum C3 was significantly associated with higher risk of incident T2DM after full adjustment (HR [95% CI] = 1.16 [1.05, 1.27]; per SD higher). Compared with the first quartile of C3 levels, the HR in the fourth quartile was 1.52 (95% CI = [1.14, 2.02]; Ptrend = 0.029). Robust significant linear dose-response relationship was observed between C3 levels and BMI (Poverall < 0.001, Pnonlinear = 0.96). Mediation analyses indicated that BMI might mediate 41.0% of the associations between C3 and T2DM. CONCLUSION: The present prospective study revealed that C3 could be an early biomarker for incident T2DM, and that BMI might play a potential mediating role in the C3-T2DM associations, which provided clues for the pathogenesis of diabetes.

Humoral and cellular immunity of two-dose inactivated COVID-19 vaccination in Chinese children: A prospective cohort study.

Children are the high-risk group for COVID-19, and in need of vaccination. However, humoral and cellular immune responses of COVID-19 vaccine remain unclear in vaccinated children. To establish the rational immunization strategy of inactivated COVID-19 vaccine for children, the immunogenicity of either one dose or two doses of the vaccine in children was evaluated. A prospective cohort study of 322 children receiving inactivated COVID-19 vaccine was established in China. The baseline was conducted after 28 days of the first dose, and the follow-up was conducted after 28 days of the second dose. The median titers of receptor binding domain (RBD)-IgG, and neutralizing antibody (NAb) against prototype strain and Omicron variant after the second dose increased significantly compared to those after the first dose (first dose: 70.0, [interquartile range, 30.0-151.0] vs. second dose: 1261.0 [636.0-2060.0] for RBD-IgG; 2.5 [2.5-18.6] vs. 252.0 [138.6-462.1] for NAb against prototype strain; 2.5 [2.5-2.5] vs. 15.0 [7.8-26.5] for NAb against Omicron variant, all p < 0.05). The flow cytometry results showed that the first dose elicited SARS-CoV-2 specific cellular immunity, while the second dose strengthened SARS-CoV-2 specific IL-2+ or TNF-α+  monofunctional, IFN-γ+ TNF-α+  bifunctional, and IFN-γ- IL-2+ TNF-α+ multifunctional CD4+ T cell responses (p < 0.05). Moreover, SARS-CoV-2 specific memory T cells were generated after the first vaccination, including the central memory T cells and effector memory T cells. The present findings provide scientific evidence for the vaccination strategy of the inactive vaccines among children against COVID-19 pandemic.

Long-term outcomes of COVID-19 convalescents: An 18.5-month longitudinal study in Wuhan.

OBJECTIVES: This study aimed to describe the full scope of long-term outcomes and the ongoing pathophysiological alterations among COVID-19 survivors. METHODS: We established a longitudinal cohort of 208 COVID-19 convalescents and followed them at 3.3 (interquartile range [IQR]: 1.3, 4.4, visit 1), 9.2 (IQR: 9.0, 9.6, visit 2), and 18.5 (IQR: 18.2, 19.1, visit 3) months after infection, respectively. Serial changes in multiple physical and psychological outcomes were comprehensively characterized. We, in addition, explored the potential risk factors of SARS-CoV-2 antibody response and sequelae symptoms. RESULTS: We observed continuous improvement of sequelae symptoms, lung function, chest computed tomography (CT), 6-minute walk test, and the Borg dyspnea scale, whereas sequelae symptoms (at least one) and abnormal chest CT patterns still existed in 45.2% and about 30% of participants at 18.5 months, respectively. Anxiety and depression disorders were alleviated for the convalescents, although depression status was sustained for a longer duration. CONCLUSIONS: Most COVID-19 convalescents had an overall improved physical and psychological health status, whereas sequelae symptoms, residual lesions on lung function, exercise impairment, and mental health disorders were still observed in a small proportion of participants at 18.5 months after infection. Implementing appropriate preventive and management strategies for the ever-growing COVID-19 population is warranted.

Genetic susceptibility, homocysteine levels, and risk of all-cause and cause-specific mortality: A prospective cohort study.

BACKGROUND: The associations of homocysteine (Hcy) and gene-Hcy interactions with the risk of all-cause and cause-specific mortality remain unclear. METHODS: A total of 19,826 middle-aged and elderly Chinese adults were included from the Dongfeng-Tongji cohort in 2013-2014 and were followed-up to 31 December 2018. Cox regression was used to examine the association between Hcy and mortality. We selected 18 well-established Hcy-associated genetic variants to constructed the weighted genetic risk score (GRS) among 15,434 participants with genetic data, and interactions between genetic susceptibility and Hcy on mortality were assessed. RESULTS: After multivariate adjustment, elevated serum Hcy levels were associated with higher risk of mortality from all-cause, CVD, coronary heart disease (CHD), stroke, and cancer. We also observed a significant interaction between GRS and Hcy on CHD mortality. Moreover, the rs7130284 and rs957140 on NOX4 modified the association between Hcy and mortality from CVD and CHD, and rs154657 on DPEP1 modified the association between Hcy and CHD mortality. CONCLUSIONS: Elevated Hcy levels were associated with increased risk of all-cause and cause-specific mortality among middle-aged and elderly Chinese. Hcy-related genetic variants on NOX4 and DPEP1 might modify the associations of Hcy with CVD mortality or CHD mortality.

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.

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.

Alternations in the gut microbiota and metabolome with newly diagnosed unstable angina.

Gut microbiota plays an important role in coronary heart disease, but its compositional and functional changes in unstable angina (UA) remain unexplored. We performed metagenomic sequencing of 133 newly diagnosed UA patients and 133 sex- and age-matched controls, and profiled the fecal and plasma metabolomes in 30 case-control pairs. The alpha diversity of gut microbiota was increased in UA patients: the adjusted odds ratios (ORs) per standard deviation increase in Shannon and Simpson indices were 1.30 (95% confidence interval, 1.01-1.70) and 1.36 (1.05-1.81), respectively. Two common species (depleted Klebsiella pneumoniae and enriched Streptococcus parasanguinis; P ≤ 0.002) and three rare species (depleted Weissella confusa, enriched Granulicatella adiacens and Erysipelotrichaceae bacterium 6_1_45; P ≤ 0.005) were associated with UA. The UA-associated gut microbiota was depleted in the pathway of L-phenylalanine degradation (P = 0.001), primarily contributed by Klebsiella pneumoniae. Consistently, we found increased circulating phenylalanine in UA patients (OR = 2.76 [1.17-8.16]). Moreover, Streptococcusparasanguinis was negatively correlated with fecal citrulline (Spearman's rs = -0.470, P = 0.009), a metabolite depleted in UA patients (OR = 0.26 [0.08-0.63]). These findings are informative to help understand the metabolic connection between gut microbiota and UA.

Multiple plasma metals, genetic risk and serum complement C3, C4: A gene-metal interaction study.

Exposure to metals and metalloids is widely related with human health, and could affect the function of immune system. The complement system links innate and adaptive immunity, and is critically involved in the pathogenesis of inflammatory and immune diseases. The third and fourth components of complement (C3, C4) play key roles in the complement system. However, few studies have examined the relations between multiple metals and complement levels. In this study, based on a total of 2977 participants from the Dongfeng-Tongji cohort, China, we investigated 17 plasma metals and serum C3, C4 levels, and calculated C3/C4-associated genetic risk scores (GRSs) using established single nucleotide polymorphisms. We further explored the potential gene-metal interactions on C3 and C4. After multivariable adjustment, an increment of 10-standard deviation increase in natural log-transformed exposure concentrations of plasma copper was associated with 0.549 (0.489, 0.608) (FDR <0.0001), and 1.146 (0.999, 1.294) (FDR <0.0001) higher natural log-transformed serum C3 and C4 levels, respectively. While each increment of 10-standard deviation of natural log-transformed zinc was associated with a difference of 0.083 (0.024, 0.143) (FDR = 0.049) and 0.007 (-0.138, 0.152) (FDR = 0.935) in log-transformed C3 and C4 levels, respectively. Participants with higher GRS had higher C3 and C4 levels. Furthermore, we found a significant interaction between arsenic exposure and C3-GRS in relation to C3 level (Pinteraction = 0.0096). Our results suggested that plasma arsenic would modify the association between C3 genetic predisposition and serum C3 level. We provide new insight into metals exposure on the human immune system. These findings require replication in future research.

Leisure-time physical activity and risk of incident cardiovascular disease in Chinese retired adults.

The optimum amounts and types of leisure-time physical activity (LTPA) for cardiovascular disease (CVD) prevention among Chinese retired adults are unclear. The prospective study enrolled 26,584 participants (mean age [SD]: 63.3 [8.4]) without baseline disease from the Dongfeng-Tongji cohort in 2013. Cox-proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During a mean 5.0 (1.5) years of follow-up, 5704 incident CVD cases were documented. Compared with less than 7.5 metabolic equivalent of task-hours per week (MET-hours/week) of LTPA, participating LTPA for 22.5-37.5 MET-hours/week, which was equivalent to 3 to 5 times the world health organization (WHO) recommended minimum, was associated with a 18% (95% CI 9 to 25%) lower CVD risk; however, no significant additional benefit was gained when exceeding 37.5 MET-hours/week. Each log10 increment of MET-hours/week in square dancing and cycling was associated with 11% (95% CI 2 to 20%) and 32% (95% CI 21 to 41%), respectively, lower risk of incident CVD. In Chinese retired adults, higher LTPA levels were associated with lower CVD risk, with a benefit threshold at 3 to 5 times the recommended physical activity minimum. Encouraging participation in square dancing and cycling might gain favourable cardiovascular benefits.

Trans-ethnic genome-wide association study of severe COVID-19.

COVID-19 has caused numerous infections with diverse clinical symptoms. To identify human genetic variants contributing to the clinical development of COVID-19, we genotyped 1457 (598/859 with severe/mild symptoms) and sequenced 1141 (severe/mild: 474/667) patients of Chinese ancestry. We further incorporated 1401 genotyped and 948 sequenced ancestry-matched population controls, and tested genome-wide association on 1072 severe cases versus 3875 mild or population controls, followed by trans-ethnic meta-analysis with summary statistics of 3199 hospitalized cases and 897,488 population controls from the COVID-19 Host Genetics Initiative. We identified three significant signals outside the well-established 3p21.31 locus: an intronic variant in FOXP4-AS1 (rs1853837, odds ratio OR = 1.28, P = 2.51 × 10-10, allele frequencies in Chinese/European AF = 0.345/0.105), a frameshift insertion in ABO (rs8176719, OR = 1.19, P = 8.98 × 10-9, AF = 0.422/0.395) and a Chinese-specific intronic variant in MEF2B (rs74490654, OR = 8.73, P = 1.22 × 10-8, AF = 0.004/0). These findings highlight an important role of the adaptive immunity and the ABO blood-group system in protection from developing severe COVID-19.

Associations of plasma metal concentrations with the risks of all-cause and cardiovascular disease mortality in Chinese adults.

BACKGROUND: Exposure to metals/metalloids from both the natural environment and anthropogenic sources have a complex influence on human health. However, relatively few studies have explored the relations of exposure to multiple metals/metalloids with mortality. Therefore, this prospective study aims to examine the relations of multiple metal/metalloids exposures with all-cause and cardiovascular disease (CVD) mortality. METHODS: A total of 6155 participants within the Dongfeng-Tongji (DF-TJ) cohort were involved in this analysis, which were followed for mortality until December 31, 2018. We applied inductively coupled plasma mass spectrometry (ICP-MS) to measure baseline plasma concentrations of 23 metals. We utilized Cox regression models to calculate the hazard ratios (HRs) for all-cause and CVD mortality associated with metal concentrations. We proposed plasma metal score to assess the simultaneous exposure to multiple metals through summing each metal concentration weighted by the regression coefficients with all-cause mortality. RESULTS: During the follow-up (mean duration, 9.8 years), we ascertained 876 deaths, including 416 deaths of CVD (157 deaths of coronary heart disease and 259 deaths of stroke). In the multiple-metals model, after adjusting for potential confounders, plasma copper, molybdenum, and vanadium were positively associated with all-cause mortality, whereas manganese, selenium, and thallium were negatively associated with the risk of all-cause mortality, with adjusted HRs (95% Confidence Interval, CI) of the fourth quartiles were 1.73 (1.42-2.11, P-trend < 0.001) for copper, 1.33 (1.09-1.63, P-trend = 0.005) for molybdenum, 1.43 (1.16-1.77, P-trend < 0.001) for vanadium, 0.74 (0.58-0.94, P-trend = 0.005) for manganese, 0.68 (0.56-0.83, P-trend < 0.001) for selenium, and 0.74 (0.59-0.92, P-trend = 0.002) for thallium, respectively. Positive associations were observed between plasma copper, molybdenum, vanadium concentrations and CVD mortality, whereas negative associations were found for plasma selenium and thallium concentrations with CVD mortality in the multiple-metals model. Compared with the first quartiles, the HRs of fourth quartiles were 1.94 (1.45-2.58, P-trend < 0.001) for copper, 1.72 (1.26-2.35, P-trend < 0.001) for molybdenum, 1.81 (1.32-2.47, P-trend < 0.001) for vanadium, 0.67 (0.50-0.89, P-trend = 0.003) for selenium, and 0.58 (0.41-0.81, P-trend < 0.001) for thallium, respectively. The plasma metal score was significantly associated with higher risks of all-cause and CVD death in dose-response fashions. When compared with the first quartiles of plasma metal score, the HRs of fourth quartiles were 2.16 (1.76-2.64; P-trend < 0.001) for all-cause mortality and 3.00 (2.24-4.02; P-trend < 0.001) for CVD mortality. CONCLUSIONS: The study indicated that several plasma metals/metalloids were key determinants and predictors of all-cause and CVD death in the Chinese population. Our findings highlighted the importance to comprehensively assess and monitor multiple metals/metalloids exposures.

Exposure to polycyclic aromatic hydrocarbons, DNA methylation and heart rate variability among non-current smokers.

Polycyclic aromatic hydrocarbons (PAHs) exposure is associated with heart rate variability (HRV) reduction, a widely used marker of cardiovascular autonomic dysfunction. The role of DNA methylation in the relationship between PAHs exposure and decreased HRV is largely unknown. This study aims to explore epigenome-wide DNA methylation changes associated with PAHs exposure and further evaluate their associations with HRV alternations among non-current smokers. We measured 10 mono-hydroxylated PAHs (OH-PAHs) in urine and DNA methylation levels in blood leukocytes among participants from three panels of Chinese non-current smokers (152 in WHZH, 99 in SY, and 53 in COW). We conducted linear regression analyses between DNA methylation and OH-PAHs metabolites with adjustment for age, gender, body mass index, drinking, blood cell counts, and surrogate variables in each panel separately, and combined the results by using inverse-variance weighted fixed-effect meta-analysis to obtain estimates of effect size. The median value of total OH-PAHs ranged from 0.92 × 10-2 in SY panel (62.6% men) to 13.82 × 10-2 µmol/mmol creatinine in COW panel (43.4% men). The results showed that methylation levels of cg18223625 (COL20A1) and cg07805771 (SLC16A1) were significantly or marginally significantly associated with urinary 2-hydroxynaphthalene [ß(SE) = 0.431(0.074) and 0.354(0.068), FDR = 0.016 and 0.056, respectively], while methylation level of cg09235308 (PLEC1) was positively associated with urinary total OH-PAHs [ß(SE) = 0.478(0.079), FDR = 0.004]. Hypermethylations of cg18223625, cg07805771, and cg09235308 were inversely associated with HRV indices among the WHZH and COW non-current smokers. However, we did not observe significant epigenome-wide associations for the other 9 urinary OH-PAHs. These findings provide new evidence that PAHs exposure is linked to differential DNA methylation, which may help better understand the influences of PAHs exposure on HRV alternations.