Particulate matter pollution, polygenic risk score and mosaic loss of chromosome Y in middle-aged and older men from the Dongfeng-Tongji cohort study.

Mosaic loss of chromosome Y (mLOY) is the most common somatic alteration as men aging and may reflect genome instability. PM exposure is a major health concern worldwide, but its effects with genetic factors on mLOY has never been investigated. Here we explored the associations of PM2.5 and PM10 exposure with mLOY of 10,158 males measured via signal intensity of 2186 probes in male-specific chromosome-Y region from Illumina array data. The interactive and joint effects of PM2.5 and PM10 with genetic factors and smoking on mLOY were further evaluated. Compared with the lowest tertiles of PM2.5 levels in each exposure window, the highest tertiles in the same day, 7-, 14-, 21-, and 28-day showed a 0.005, 0.006, 0.007, 0.007, and 0.006 decrease in mLRR-Y, respectively (all P < 0.05), with adjustment for age, BMI, smoking pack-years, alcohol drinking status, physical activity, education levels, season of blood draw, and experimental batch. Such adverse effects were also observed in PM10-mLOY associations. Moreover, the unweighted and weighted PRS presented significant negative associations with mLRR-Y (both P < 0.001). Participants with high PRS and high PM2.5 or PM10 exposure in the 28-day separately showed a 0.018 or 0.019 lower mLRR-Y level [ß (95 %CI) = -0.018 (-0.023, -0.012) and - 0.019 (-0.025, -0.014), respectively, both P < 0.001], when compared to those with low PRS and low PM2.5 or PM10 exposure. We also observed joint effects of PM with smoking on exacerbated mLOY. This large study is the first to elucidate the impacts of PM2.5 exposure on mLOY, and provides key evidence regarding the interactive and joint effects of PM with genetic factors on mLOY, which may promote understanding of mLOY development, further modifying and increasing healthy aging in males.

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 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.

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.

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.

Elevated Levels of Serum Alkaline Phosphatase are Associated with Increased Risk of Cardiovascular Disease: A Prospective Cohort Study.

AIM: We aimed to investigate the associations of serum alkaline phosphatase (ALP) levels with incident cardiovascular disease (CVD), coronary heart disease (CHD), and stroke, as well as their subtypes, among men and women in a prospective cohort study. METHODS: A total of 11,408 men and 14,981 women were included to evaluate the associations between ALP levels and incident CVD. Participants were divided into four groups according to the quartiles of serum ALP levels in men and women separately. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: During an average follow-up of 7.3 years, 7,015 incident CVDs (5,561 CHDs and 1,454 strokes) were documented. After adjustments for age, body mass index, smoking status, drinking status, diabetes, hyperlipidemia, hypertension, physical activity, aspirin usage, anticoagulants usage, menopausal status (women only), family history of CVD, estimated glomerular filtration rate, white blood cell counts, and admission batch and comparing the lowest quartile of ALP, the adjusted HRs (95% CIs) of participants in the highest quartile were 1.22 (1.11-1.34) for CVD, 1.14 (1.02-1.28) for CHD, 1.43 (1.18-1.73) for stroke, 1.31 (1.09-1.57) for acute coronary syndrome (ACS), 1.37 (1.11-1.70) for ischemic stroke, and 1.75 (1.10-2.79) for hemorrhagic stroke in men and 1.12 (1.01-1.23) for CVD, 1.10 (0.99-1.23) for CHD, 1.18 (0.92-1.51) for stroke, 1.23 (1.03-1.47) for ACS, 1.10 (0.83-1.45) for ischemic stroke, and 1.54 (0.90-2.65) for hemorrhagic stroke in women. The ALP-CVD associations remained significant even within the normal ranges of ALP levels (40-150 U/L). Moreover, linear dose-response relationships were found between ALP levels and incident CVD. CONCLUSIONS: Higher ALP levels, even within the normal range, were significantly associated with increased risks of CVD, in a dose-dependent manner. These findings suggested that regular monitoring of ALP levels may help in improving the early identification of the population at higher CVD risk.

PHF6 mutation is associated with poor outcome in acute myeloid leukaemia.

INTRODUCTION: Mutation of plant homeodomain finger protein 6 (PHF6) occurs in approximately 3% of acute myeloid leukaemia (AML) cases. Although it was reported to be associated with poor prognosis, it was not confirmed by other groups. Recently, propensity score matching has provided an effective way to minimise bias by creating two groups that are well balanced with respect to baseline characteristics, providing more convincing results, which has an advantage, especially for rare subtype studies. To provide further evidence on the role of PHF6 mutation, we performed a retrospective propensity score-matched cohort study to assess the therapeutic responses and survival outcomes of AML patients with PHF6 mutation compared with those without PHF6 mutation after balancing age, sex and risk categories. PATIENTS AND METHODS: A total of 22 patients with PHF6 mutation from 801 consecutive newly diagnosed AML cases in our center were identified, and 43 patients with the PHF6 wild-type genotype were successfully matched at a 1:2 ratio. RESULTS: AML harbouring PHF6 mutation was associated with a lower complete remission (CR) rate (41% vs. 69%; OR = 3.64, 95% CI 1.10, 12.10; p = 0.035) and shorter median overall survival (OS) (6.0 vs. 39.0 months; p < 0.001) and event-free survival (EFS) (2.0 vs. 11.0 months; p = 0.013) compared with PHF6 wild-type patients. Further multivariate analysis supported that PHF6 mutation was an independent risk factor for overall survival in AML (HR = 8.910, 95% CI 3.51, 22.63; p < 0.001). In addition, allogeneic haematopoietic stem cell transplantation (allo-HSCT) seemed to ameliorate the poor prognosis of AML with PHF6 mutation in this study. CONCLUSION: Our data revealed that PHF6 mutation was associated with a lower chemotherapy response and shorter survival, suggesting that PHF6 mutation is a predictor of poor prognosis in AML.

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.

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.

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.

Prospective Study on Plasma MicroRNA-4286 and Incident Acute Coronary Syndrome.

Background Mounting evidence suggests that circulating microRNAs (miRNAs) are critical indicators of cardiovascular disease. However, prospective studies linking circulating miRNAs to incident acute coronary syndrome (ACS) are limited, and the underlying effect of associated miRNA on incident ACS remains unknown. Methods and Results Based on a 2-stage prospective nested case-control design within the Dongfeng-Tongji cohort, we profiled plasma miRNAs from 23 pairs of incident ACS cases and controls by microarray and validated the candidate miRNAs in 572 incident ACS case-control pairs using quantitative real-time polymerase chain reaction. We observed that plasma miR-4286 was associated with higher risk of ACS (adjusted odds ratio according to an interquartile range increase, 1.26 [95% CI, 1.07-1.48]). Further association analysis revealed that triglyceride was positively associated with plasma miR-4286, and an interquartile range increase in triglyceride was associated with an 11.04% (95% CI, 3.77%-18.83%) increase in plasma miR-4286. In addition, the Mendelian randomization analysis suggested a potential causal effect of triglyceride on plasma miR-4286 (ß coefficients: 0.27 [95% CI, 0.01-0.53] and 0.27 [95% CI, 0.07-0.47] separately by inverse variance-weighted and Mendelian randomization-pleiotropy residual sum and outlier tests). Moreover, the causal mediation analysis indicated that plasma miR-4286 explained 5.5% (95% CI, 0.7%-17.0%) of the association of triglyceride with incident ACS. Conclusions Higher level of plasma miR-4286 was associated with an increased risk of ACS. The upregulated miR-4286 in plasma can be attributed to higher triglyceride level and may mediate the effect of triglyceride on incident ACS.

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.

Associations of multiple plasma metals with incident type 2 diabetes in Chinese adults: The Dongfeng-Tongji Cohort.

The long-term associations between multiple metals and incident diabetes are uncertain. We aimed to examine the relationship between plasma concentrations of 23 metals and the incidence of type 2 diabetes among Chinese senior adults. We quantified fasting plasma concentrations of 23 metals by inductively coupled plasma mass spectrometry among 1039 incident diabetes cases and 1039 controls (age and sex matched) nested in a prospective study, the Dongfeng-Tongji cohort. Both cases and controls were free of diabetes at baseline (2008-2010), incident diabetes were identified using the following criteria: fasting glucose ≥ 7.0 mmoL/l; or hemoglobin A1c (HbA1c) ≥ 6.5%; or self-reported physician diagnosis of diabetes or use of anti-diabetic medication during the follow-up visits in 2013. In the conditional logistic regression models, the multivariable adjusted ORs (95% CIs) of diabetes across quartiles (Q1-Q4) of metal concentrations were as follows: titanium, 1.00, 0.92, 1.31, 1.38 (1.00-1.91, Ptrend = 0.011); selenium, 1.00, 1.08, 1.45, 1.27 (0.93-1.74, Ptrend = 0.05); and antimony, 1.00, 0.79, 0.77, 0.60 (0.44-0.83, Ptrend = 0.002). Arsenic was significantly associated with diabetes in the crude model (ORs comparing extreme quartiles 1.30; 1.02-1.65; Ptrend = 0.006), but was not significant after adjustment for socio-demographic factors. No significant associations were found for other metals. In conclusion, titanium and selenium were positively while antimony was negatively associated with incident diabetes.

Tetra-kis(µ-3,4-dimethoxy-phenyl-acetato)bis-[(3,4-dimethoxy-phenyl-acetato)(1,10-phenanthroline)dysprosium(III)].

The title centrosymmetric dinuclear dysprosium(III) complex, [Dy(2)(C(10)H(11)O(4))(6)(C(12)H(8)N(2))(2)] or [Dy(L)(3)phen](2), is comprised of six 3,4-dimethoxy-phenylacetate (L) anions, two 1,10-phenanthroline (phen) mol-ecules and two Dy(III) ions. The Dy(III) atom is nine-coordinated by seven O atoms from five L ligands and two N atoms from the phen mol-ecules. The L ligands are coordinated to the Dy(III) ion in three coordination modes: chelating, bridging and bridging-tridentate. C-H⋯O hydrogen bonding interactions consolidate the crystal packing.