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.

The interaction effects of zinc and polygenic risk score with benzo[a]pyrene exposure on lung cancer risk: A prospective case-cohort study among Chinese populations.

The relationship of exposure to benzo[a]pyrene (BaP) with lung cancer risk has been firmly established, but whether this association could be modified by other environmental or genetic factors remains to be explored. To investigate whether and how zinc (Zn) and genetic predisposition modify the association between BaP and lung cancer, we performed a case-cohort study with a 5.4-year median follow-up duration, comprising a representative subcohort of 1399 participants and 359 incident lung cancer cases. The baseline concentrations of benzo[a]pyrene diol epoxide-albumin adduct (BPDE-Alb) and Zn were quantified. We also genotyped the participants and computed the polygenic risk score (PRS) for lung cancer. Our findings indicated that elevated BPDE-Alb and PRS were linked to increased lung cancer risk, with the HR (95%CI) of 1.54 (1.36, 1.74) per SD increment in ln-transformed BPDE-Alb and 1.27 (1.14, 1.41) per SD increment in PRS, but high plasma Zn level was linked to a lower lung cancer risk [HR (95%CI)=0.77 (0.66, 0.91) per SD increment in ln-transformed Zn]. There was evidence of effect modification by Zn on BaP-lung cancer association (P for multiplicative interaction = 0.008). As Zn concentrations increased from the lowest to the highest tertile, the lung cancer risk per SD increment in ln-transformed BPDE-Alb decreased from 2.07 (1.48, 2.89) to 1.33 (0.90, 1.95). Additionally, we observed a significant synergistic interaction of BPDE-Alb and PRS [RERI (95%CI) = 0.85 (0.03, 1.67)], with 42% of the incident lung cancer cases among individuals with high BPDE-Alb and high PRS attributable to their additive effect [AP (95%CI) = 0.42 (0.14, 0.69)]. This study provided the first prospective epidemiological evidence that Zn has protective effect against BaP-induced lung tumorigenesis, whereas high genetic risk can enhance the harmful effect of BaP. These findings may provide novel insight into the environment-environment and environment-gene interaction underlying lung cancer development, which may help to develop prevention and intervention strategies to manage BaP-induced lung cancer.

Circulating concentrations of bile acids and prevalent chronic kidney disease among newly diagnosed type 2 diabetes: a cross-sectional study.

BACKGROUND: The relationship between circulating bile acids (BAs) and kidney function among patients with type 2 diabetes is unclear. We aimed to investigate the associations of circulating concentrations of BAs, particularly individual BA subtypes, with chronic kidney disease (CKD) in patients of newly diagnosed type 2 diabetes. METHODS: In this cross-sectional study, we included 1234 newly diagnosed type 2 diabetes who participated in an ongoing prospective study, the Dongfeng-Tongji cohort. Circulating primary and secondary unconjugated BAs and their taurine- or glycine-conjugates were measured using ultraperformance liquid chromatography-tandem mass spectrometry. CKD was defined as eGFR < 60 ml/min per 1.73 m2. Logistic regression model was used to compute odds ratio (OR) and 95% confidence interval (CI). RESULTS: After adjusting for multiple testing, higher levels of total primary BAs (OR per standard deviation [SD] increment: 0.78; 95% CI: 0.65-0.92), cholate (OR per SD: 0.78; 95% CI: 0.66-0.92), chenodeoxycholate (OR per SD: 0.81; 95% CI: 0.69-0.96), glycocholate (OR per SD: 0.81; 95% CI: 0.68-0.96), and glycochenodeoxycholate (OR per SD: 0.82; 95% CI: 0.69-0.97) were associated with a lower likelihood of having CKD in patients with newly diagnosed type 2 diabetes. No significant relationships between secondary BAs and odds of CKD were observed. CONCLUSIONS: Our findings showed that higher concentrations of circulating unconjugated primary BAs and their glycine-conjugates, but not taurine-conjugates or secondary BAs, were associated with lower odds of having CKD in patients with type 2 diabetes.

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.

Effects of multiple metals exposure on abnormal liver function: The mediating role of low-density lipoprotein cholesterol.

Equilibration of metal metabolism is critical for normal liver function. Most epidemiological studies have only concentrated on the influence of limited metals. However, the single and synergistic impact of multiple-metal exposures on abnormal liver function (ALF) are still unknown. A cross-sectional study involving 1493 Chinese adults residing in Shenzhen was conducted. Plasma concentrations of 13 metals, including essential metals (calcium, copper, cobalt, iron, magnesium, manganese, molybdenum, zinc, and selenium) and toxic metals (aluminum, cadmium, arsenic, and thallium) were detected by the inductively coupled plasma spectrometry (ICP-MS). ALF was ascertained as any observed abnormality from albumin, alanine transaminase, aspartate transaminase, γ-glutamyl transpeptidase, and direct bilirubin. Diverse statistical methods were used to evaluate the single and mixture effect of metals, as well as the dose-response relationships with ALF risk, respectively. Mediation analysis was conducted to evaluate the role of blood lipids in the relation of metal exposure with ALF. The average age of subjects was 59.7 years, and 56.7 % were females. Logistic regression and the least absolute shrinkage and selection operator (LASSO) penalized regression model consistently suggested that increased levels of arsenic, aluminum, manganese, and cadmium were related to elevated risk of ALF; while magnesium and zinc showed protective effects on ALF (all p-trend < 0.05). The grouped weighted quantile sum (GWQS) regression revealed that the WQS index of essential metals and toxic metals showed significantly negative or positive relationship with ALF, respectively. Aluminum, arsenic, cadmium, and manganese showed linear whilst magnesium and zinc showed non-linear dose-response relationships with ALF risk. Mediation analysis showed that LDL-c mediated 4.41 % and 14.74 % of the relationship of plasma cadmium and manganese with ALF, respectively. In summary, plasma aluminum, arsenic, manganese, cadmium, magnesium, and zinc related with ALF, and LDL-c might underlie the pathogenesis of ALF associated with cadmium and manganese exposure. This study may provide critical public health significances in liver injury prevention and scientific evidence for the establishment of environmental standard.

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.

Associations of mitochondrial DNA copy number with incident risks of gastrointestinal cancers: A prospective case-cohort study.

Epidemiological investigations implied that mitochondrial DNA copy number (mtDNAcn) variations could trigger predisposition to multiple cancers, but evidence regarding gastrointestinal cancers (GICs) was still uncertain. We conducted a case-cohort study within the prospective Dongfeng-Tongji cohort, including incident cases of colorectal cancer (CRC, n = 278), gastric cancer (GC, n = 138), and esophageal cancer (EC, n = 72) as well as a random subcohort (n = 1173), who were followed up from baseline to the end of 2018. We determined baseline blood mtDNAcn and associations of mtDNAcn with the GICs risks were estimated by using weighted Cox proportional hazards models. Significant U-shaped associations were observed between mtDNAcn and GICs risks. Compared to subjects within the second quartile (Q2) mtDNAcn subgroup, those within the 1st (Q1), 3rd (Q3), and 4th (Q4) quartile subgroups showed increased risks of CRC (hazard ratio [HR] [95% confidence interval, CI] = 2.27 [1.47-3.52], 1.65 [1.04-2.62], and 2.81 [1.85-4.28], respectively) and total GICs (HR [95%CI] = 1.84 [1.30-2.60], 1.47 [1.03-2.10], and 2.51 [1.82-3.47], respectively], and those within Q4 subgroup presented elevated GC and EC risks (HR [95% CI] = 2.16 [1.31-3.54] and 2.38 [1.13-5.02], respectively). Similar associations of mtDNAcn with CRC and total GICs risks remained in stratified analyzes by age, gender, smoking, and drinking status. This prospective case-cohort study showed U-shaped associations between mtDNAcn and GICs risks, but further research works are needed to uncover underlying biological mechanisms.

Arsenic exposure and pruritus: Evidence from observational, interventional, and mendelian randomization studies.

BACKGROUND: Pruritus is identified as an adverse drug reaction to arsenic trioxide, but the association of arsenic exposure with pruritus has not been investigated. METHODS: A cross-sectional study was conducted in Shimen, China. A Mendelian randomization analysis was conducted to confirm the causal relationship between genetically predicted percentages of monomethylated arsenic (MMA%) and dimethylated arsenic (DMA%) in urine with chronic pruritus in UK Biobank. A case-control study was then conducted to determine the biomarker for pruritus. Arsenite-treated mice were used to confirm the biomarker, and von Frey test was used to induce scratching bouts. Last, a randomized, double-blind, placebo-controlled trial was conducted to test the efficacy of naloxone in arsenic-exposed patients with pruritus in Shimen. RESULTS: Hair arsenic (µg/g) showed a dose-response relationship with the intensity of itch in 1079 participants, with odds ratios (OR) of 1.11 for moderate-to-severe itch (p = 0.012). The Mendelian randomization analysis confirmed the causal relationship, with ORs of 1.043 for MMA% (p = 0.029) and 0.904 for DMA% (p = 0.077) above versus under median. Serum ß-endorphin was identified as a significant biomarker for the intensity of itch (p < 0.001). Consistently, treatment with arsenite upregulated the level of ß-endorphin (p = 0.002) and induced scratching bouts (p < 0.001) in mice. The randomized controlled trial in 126 participants showed that treatment with sublingual naloxone significantly relieved the intensity of itch in arsenic-exposed participants in 2 weeks (ß = -0.98, p = 0.04). CONCLUSION: Arsenic exposure is associated with pruritus, and ß-endorphin serves as a biomarker of pruritus. Naloxone relieves pruritus in patients with arseniasis.

Association of urinary arsenic metabolism with type 2 diabetes and glucose homeostasis: Cross-sectional and longitudinal associations.

BACKGROUND: Previous researches have assessed the relationships of urinary arsenic metabolism with type 2 diabetes (T2D) and glucose-insulin homeostasis, but the results were controversial, and potential mechanisms remain largely unclear. OBJECTIVES: This study aimed to investigate the cross-sectional and longitudinal associations of urinary arsenic metabolism with T2D prevalence and glucose changes in relatively higher arsenic exposure, and further to evaluate the underlying roles of oxidative damage in these relationships. METHODS: We included 796 participants at baseline, among them 509 participants were followed up after 2 years. Logistic regression model and leave-one-out approach were applied to evaluate the associations of arsenic metabolism with T2D prevalence. Linear mixed model was conducted to estimate the relationship of arsenic metabolism with glycemic changes over two years. The associations between arsenic metabolism and indicators of oxidative stress were assessed with a linear regression model. We further performed mediation analysis to investigate the role of oxidative stress in the associations of arsenic metabolism with 2-year change of glucose levels. RESULTS: Higher urinary MMA% increased T2D prevalence and baseline glucose levels. MMA% was positively associated with 2-year change of glucose levels. Moreover, we observed significant dose-response relationship between MMA% and 8-hydroxy-2-deoxyguanosine (8-OHdG). However, the mediating role of 8-OHdG in the association of MMA% and 2-year change of glucose levels was not observed in this population. CONCLUSIONS: In this population exposure to relatively higher arsenic levels, higher MMA% contributed to increased T2D prevalence and glucose homeostasis disorder. Arsenic metabolism also affected oxidative stress levels, especially 8-OHdG. Further studies are required to investigate the potential mechanisms.

Prenatal ambient air pollutants exposure and the risk of stillbirth in Wuhan, central of China.

BACKGROUND: The existing studies on the relationships of prenatal ambient air pollutants exposure with stillbirth in the Chinese population are very limited and the results are inconsistent, and the susceptible windows and potential modifiers for air pollutants exposure on stillbirth remain unanswered. OBJECTIVE: We aimed to determine the relationships between exposure to ambient air pollutants and stillbirth, and explored the susceptible windows and potential modifiers for air pollutants exposure on stillbirth. METHODS: A population-based cohort was established through the Wuhan Maternal and Child Health Management Information System involving 509,057 mother-infant pairs in Wuhan from January 1, 2011 through September 30, 2017. Personal exposure concentrations of fine particles (PM2.5), inhalable particles (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and ozone (O3) for mothers were estimated based on their residential address during pregnancy using the inverse distance weighted (IDW) method. We used the logistic regression models to determine the associations at different stages of pregnancy with adjustment for confounding factors. RESULTS: There were 3218 stillbirths and 505,839 live births among the participants. For each 100 µg/m3 of CO and 10 µg/m3 of O3 increase in the first trimester (conception to 13+6 weeks), the risk of stillbirth increased by 1.0% (OR = 1.01, 95%CI: 1.00-1.03) and 7.0% (OR = 1.07, 95%CI: 1.05-1.09). In the second trimester (14 weeks-27+6 weeks), PM2.5, PM10, CO, and O3 exposure were closely related to the risk of stillbirth (P＜0.05). In the third trimester (28 weeks to delivery), for each 10 µg/m3 increase in exposure concentrations of PM2.5, SO2, and O3, the risk of stillbirth increased by 3.4%, 5.9%, and 4.0%, respectively. O3 exposure was positively relevant to the risk of stillbirth (OR = 1.11, 95%CI: 1.08-1.14) in the whole pregnancy. Exposure to NO2 was not significantly associated with the risk of stillbirth. Stratified analyses also presented a stronger association among mothers with boy infant, living in rural areas, delivering between 2011 and 2013, and those without gestational hypertension and history of stillbirth. CONCLUSION: This study provides evidence that maternal exposure to PM2.5, PM10, SO2, CO, and O3 were related to the increased risk of stillbirth. Both the second and third trimesters might be vital susceptible windows for stillbirth. Our findings expand the evidence base for the important impacts of air pollution on fetal growth.

Association between polychlorinated biphenyls exposure and incident type 2 diabetes mellitus: A nested case-control study.

BACKGROUND: Previous epidemiological studies indicated that the association between polychlorinated biphenyls (PCB) and type 2 diabetes mellitus (T2DM) was inconclusive. OBJECTIVE: We investigated the association between PCBs exposure and incident T2DM in a nested case-control study, and further explored the relationship between PCBs and 5-year fasting blood glucose (FBG) changes. METHODS: Baseline concentrations of seven indicator-PCB (PCB-28, 52, 101, 118, 138, 153, 180) were measured in 1006 pairs of incident T2DM cases and matched controls nested within the Dongfeng-Tongji cohort. Conditional logistic regression models and pre-adjusted residuals method were used to assess the associations between PCBs and incident T2DM. We further computed beta coefficients (ßs) of 5-year FBG changes using multivariable generalized linear regression. RESULTS: Non-dioxin-like PCBs (NDL-PCBs) were significantly associated with higher T2DM incidence after adjustment for all covariates. Significant differences were observed for extreme quartiles comparisons (Q4 vs. Q1) of PCBs except PCB-138, and the incidence of T2DM were 1- to 3-fold higher among those in the highest versus lowest PCBs quartiles. Serum NDL-PCBs were positively associated with changes in FBG (P for overall association ≤0.01). Additionally, triglycerides mediated the associations between PCBs and T2DM incidence. CONCLUSION: Our findings showed positive associations of NDL-PCBs with incident T2DM and 5-year FBG changes. PCBs increased incident T2DM via lipid metabolic pathways.

Multiple metals exposure and blood mitochondrial DNA copy number: A cross-sectional study from the Dongfeng-Tongji cohort.

OBJECTIVE: Mitochondria are essential organelles that execute fundamental biological processes, while mitochondrial DNA is vulnerable to environmental insults. The aim of this study was to investigate the individual and mixture effect of plasma metals on blood mitochondria DNA copy number (mtDNAcn). METHODS: This study involved 1399 randomly selected subcohort participants from the Dongfeng-Tongji cohort. The blood mtDNAcn and plasma levels of 23 metals were determined by using quantitative real-time polymerase chain reaction (qPCR) and inductively coupled plasma mass spectrometer (ICP-MS), respectively. The multiple linear regression was used to explore the association between each metal and mtDNAcn, and the LASSO penalized regression was performed to select the most significant metals. We also used the quantile g-computation analysis to assess the mixture effect of multiple metals. RESULTS: Based on multiple linear regression models, each 1% increase in plasma concentration of copper (Cu), rubidium (Rb), and titanium (Ti) was associated with a separate 0.16% [ß(95% CI) = 0.158 (0.066, 0.249), P = 0.001], 0.20% [ß(95% CI) = 0.196 (0.073, 0.318), P = 0.002], and 0.25% [ß(95% CI) = 0.245 (0.081, 0.409), P = 0.003] increase in blood mtDNAcn. The LASSO regression also confirmed Cu, Rb, and Ti as significant predictors for mtDNAcn. There was a significant mixture effect of multiple metals on increasing mtDNAcn among the elder participants (aged ≥65), with an approximately 11% increase in mtDNAcn for each quartile increase in all metal concentrations [ß(95% CI) = 0.146 (0.048, 0.243), P = 0.004]. CONCLUSIONS: Our results show that plasma Cu, Rb and Ti were associated with increased blood mtDNA, and we further revealed a significant mixture effect of all metals on mtDNAcn among elder population. These findings may provide a novel perspective on the effect of metals on mitochondrial dysfunction.

Association of serum phthalates exposure with incident type 2 diabetes risk in Chinese population: A nested case-control study.

Prospective epidemiological evidence was lacking on the association of phthalates (PAEs) exposure with incident type 2 diabetes mellitus (T2DM) risk. In present nested case-control study, we identified 1006 T2DM cases and matched 1006 controls based on Dongfeng-Tongji cohort study, and 6 PAEs were detected in baseline serum. The conditional logistic regression model, Bayesian kernel machine regression (BKMR) model and Quantile-based g-computation were applied to evaluate the associations of determined PAEs, either as individuals or as a mixture, with incident T2DM risk. Subgroup analysis was conducted to identify the potential sensitive population of PAEs effects on T2DM. After multiple adjustment, no statistically significant association was observed between single or mixture of PAEs and incident T2DM risk in the whole population. However, serum levels of Di-n-butyl phthalate (DnBP) [OR= 2.06; 95% CI: (1.11-3.96)], Σdibutyl phthalate (ΣDBP) [OR= 1.96; 95% CI: (1.06-3.76)], and Σlow-molecular- weight phthalate (ΣLMW) [OR= 2.27; 95% CI: (1.17-4.57)] were significantly associated with T2DM in current drinker group. Moreover, significant potential interactions were observed among Di-iso-butyl phthalate (DiBP), DnBP, Butyl-benzyl phthalate (BBP), ΣDBP, and ΣLMW with drinking status on T2DM risk (P for interaction = 0.036, 0.005, 0.049. 0.010, and 0.005). We did not find significant associations between serum PAEs levels and T2DM in the whole population. However, current alcohol drinkers expose to higher levels of DnBP, ΣDBP, and ΣLMW had higher risk of T2DM.

Associations of combined healthy lifestyles with cancer morbidity and mortality among individuals with diabetes: results from five cohort studies in the USA, the UK and China.

AIMS/HYPOTHESIS: Cancer has contributed to an increasing proportion of diabetes-related deaths, while lifestyle management is the cornerstone of both diabetes care and cancer prevention. We aimed to evaluate the associations of combined healthy lifestyles with total and site-specific cancer risks among individuals with diabetes. METHODS: We included 92,239 individuals with diabetes but without cancer at baseline from five population-based cohorts in the USA (National Health and Nutrition Examination Survey and National Institutes of Health [NIH]-AARP Diet and Health Study), the UK (UK Biobank study) and China (Dongfeng-Tongji cohort and Kailuan study). Healthy lifestyle scores (range 0-5) were constructed based on current nonsmoking, low-to-moderate alcohol drinking, adequate physical activity, healthy diet and optimal bodyweight. Cox regressions were used to calculate HRs for cancer morbidity and mortality, adjusting for sociodemographic, medical and diabetes-related factors. RESULTS: During 376,354 person-years of follow-up from UK Biobank and the two Chinese cohorts, 3229 incident cancer cases were documented, and 6682 cancer deaths were documented during 1,089,987 person-years of follow-up in the five cohorts. The pooled multivariable-adjusted HRs (95% CIs) comparing participants with 4-5 vs 0-1 healthy lifestyle factors were 0.73 (0.61, 0.88) for incident cancer and 0.55 (0.46, 0.67) for cancer mortality, and ranged between 0.41 and 0.63 for oesophagus, lung, liver, colorectum, breast and kidney cancers. Findings remained consistent across different cohorts and subgroups. CONCLUSIONS/INTERPRETATION: This international cohort study found that adherence to combined healthy lifestyles was associated with lower risks of total cancer morbidity and mortality as well as several subtypes (oesophagus, lung, liver, colorectum, breast and kidney cancers) among individuals with diabetes.

Metabolomics study reveals systematic metabolic dysregulation and early detection markers associated with incident pancreatic cancer.

Biomarkers for early detection of pancreatic cancer are in urgent need. To explore systematic circulating metabolites unbalance and identify potential biomarkers for pancreatic cancer in prospective Chinese cohorts, we conducted an untargeted metabolomics study in subjects with incident pancreatic cancer and matched controls (n = 192) from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. We characterized 998 metabolites in baseline serum and calculated 156 product-to-precursor ratios based on the KEGG database. The identified metabolic profiling revealed systematic metabolic network disorders before pancreatic cancer diagnosis. Forty-Five metabolites or product-to-precursor ratios showed significant associations with pancreatic cancer (P < .05 and FDR < 0.1), revealing abnormal metabolism of amino acids (especially alanine, aspartate and glutamate), lipids (especially steroid hormones), vitamins, nucleotides and peptides. A novel metabolite panel containing aspartate/alanine (OR [95% CI]: 1.97 [1.31-2.94]), androstenediol monosulfate (0.69 [0.49-0.97]) and glycylvaline (1.68 [1.04-2.70]) was significantly associated with risk of pancreatic cancer. Area under the receiver operating characteristic curves (AUCs) was improved from 0.573 (reference model of CA 19-9) to 0.721. The novel metabolite panel was validated in an independent cohort with AUC improved from 0.529 to 0.661. These biomarkers may have a potential value in early detection of pancreatic cancer.

A Lipid Signature with Perturbed Triacylglycerol Co-Regulation, Identified from Targeted Lipidomics, Predicts Risk for Type 2 Diabetes and Mediates the Risk from Adiposity in Two Prospective Cohorts of Chinese Adults.

BACKGROUND: The roles of individual and co-regulated lipid molecular species in the development of type 2 diabetes (T2D) and mediation from metabolic risk factors remain unknown. METHODS: We conducted profiling of 166 plasma lipid species in 2 nested case-control studies within 2 independent cohorts of Chinese adults, the Dongfeng-Tongji and the Jiangsu non-communicable disease cohorts. After 4.61 (0.15) and 7.57 (1.13) years' follow-up, 1039 and 520 eligible participants developed T2D in these 2 cohorts, respectively, and controls were 1:1 matched to cases by age and sex. RESULTS: We found 27 lipid species, including 10 novel ones, consistently associated with T2D risk in the 2 cohorts. Differential correlation network analysis revealed significant correlations of triacylglycerol (TAG) 50:3, containing at least one oleyl chain, with 6 TAGs, at least 3 of which contain the palmitoyl chain, all downregulated within cases relative to controls among the 27 lipids in both cohorts, while the networks also both identified the oleyl chain-containing TAG 50:3 as the central hub. We further found that 13 of the 27 lipids consistently mediated the association between adiposity indicators (body mass index, waist circumference, and waist-to-height ratio) and diabetes risk in both cohorts (all P < 0.05; proportion mediated: 20.00%, 17.70%, and 17.71%, and 32.50%, 28.73%, and 33.86%, respectively). CONCLUSIONS: Our findings suggested notable perturbed co-regulation, inferred from differential correlation networks, between oleyl chain- and palmitoyl chain-containing TAGs before diabetes onset, with the oleyl chain-containing TAG 50:3 at the center, and provided novel etiological insight regarding lipid dysregulation in the progression from adiposity to overt T2D.

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

Metabolome-Wide Association Study of Multiple Plasma Metals with Serum Metabolomic Profile among Middle-to-Older-Aged Chinese Adults.

Metal exposure has been associated with risk of various cardio-metabolic disorders, and investigation on the association between exposure to multiple metals and metabolic responses may reveal novel clues to the underlying mechanisms. Based on a metabolome-wide association study of 17 plasma metals with untargeted metabolomic profiling of 189 serum metabolites among 1992 participants within the Dongfeng-Tongji cohort, we replicated two metal-associated pathways, linoleic acid metabolism and aminoacyl-tRNA biosynthesis, with novel metal associations (false discovery rate, FDR < 0.05), and we also identified two novel pathways, including biosynthesis of unsaturated fatty acids and alpha-linolenic acid metabolism, as associated with metal exposure (FDR < 0.05). Moreover, two-way orthogonal partial least-squares analysis showed that five metabolites, including aspartylphenylalanine, free fatty acid 14:1, uridine, carnitine C14:2, and LPC 18:2, contributed most to the joint covariation between the two data matrices (12.3%, 8.3%, 8.0%, 7.4%, and 7.3%, respectively). Further BKMR analysis showed significant positive joint associations of plasma Al, As, Ba, and Zn with aspartylphenylalanine and of plasma Ba, Co, Mn, and Pb with carnitine C14:2, when all the metals were at the 55th percentiles or above, compared with the median. We also found significant interactions between As and Ba in the association with aspartylphenylalanine (P for interaction = 0.048) and between Ba and Pb in the association with carnitine C14:2 (P for interaction < 0.001). Together, these findings may provide new insights into the mechanisms underlying the adverse health effects induced by metal exposure.

Plasma PFOA and PFOS Levels, DNA Methylation, and Blood Lipid Levels: A Pilot Study.

Exposure to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) is associated with blood lipids in adults, but the underlying mechanisms remain unclear. This pilot study aimed to investigate the associations between PFOA or PFOS and epigenome-wide DNA methylation and assess the mediating effect of DNA methylation on the PFOA/PFOS-blood lipid association. We measured plasma PFOA/PFOS and leukocyte DNA methylation in 98 patients enrolled from the hospital between October 2018 and August 2019. The median plasma PFOA/PFOS levels were 0.85 and 2.29 ng/mL. Plasma PFOA and PFOS levels were significantly associated with elevated total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) levels. There were 63/87 CpG positions and 8/11 differentially methylated regions (DMRs) associated with plasma PFOA/PFOS levels, respectively. In addition, 5 CpG positions (annotated to AFF3, CREB5, NRG2, USF2, and intergenic region) and one DMR annotated to IRF6 may mediate the association between plasma PFOA/PFOS and LDL levels (mediated proportion from 7.29 to 46.77%); two CpG positions may mediate the association between plasma PFOA/PFOS and TC levels (annotated to CREB5 and USF2, mediated proportion is around 30%). The data suggest that PFOA/PFOS exposure alters DNA methylation. More importantly, the association of PFOA/PFOS with lipid indicators was partly mediated by DNA methylation changes in lipid metabolism-related genes.

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.