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.

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 its joint effects with cigarette smoking and physical exercise on lung function impairment: Evidence from an occupational cohort study.

BACKGROUND: Arsenic (As) is an established toxic metal, but its effect on longitudinal lung function change among occupational workers is less conclusive. METHODS: 1243 participants were recruited in a coke-oven plant and followed up from 2010 to 2014. Each individual provided 20 mL morning urine sample at baseline, which was then used for urinary levels of As (U-As) and polycyclic aromatic hydrocarbon (PAH) metabolites detecting. Lung function levels at both baseline and the end of follow-up were determined. Multiple linear regression models were used to analyze the associations between U-As with annual lung function changes, and to evaluate the joint effects of U-As with cigarette smoking and regular physical exercise. RESULTS: Among all participants, each 2-fold increase in U-As was associated with -12.09 (95%CI: -19.37, -4.81) mL, -0.32% (95%CI: -0.54%, -0.10%), -15.04 (95%CI: -24.62, -5.46) mL, and -0.36% (95%CI: -0.64%, -0.08%) annual changes in reduced forced expiratory volume in 1 second (FEV1), percent predicted FEV1 (ppFEV1), forced vital capacity (FVC), and percent predicted FVC (ppFVC), respectively. These effects were more pronounced among coke-oven workers with smoking (especially heavy smoking with pack-years≥15) and without regular physical exercise. Compared to low-As-exposed (≤4.70 µg/mmol creatinine) non-smokers with regular physical exercise, the high-As-exposed (>4.70 µg/mmol creatinine) smokers without regular physical exercise had the worst annual declines in FEV1 [ß (95%CI) = -69.01 (-106.67, -31.34) mL], ppFEV1 [ß (95%CI) = -1.94% (-3.02%, -0.87%)], FVC [ß (95%CI) = -78.66 (95%CI: -129.46, -27.86) mL], and ppFVC [ß (95%CI) = -1.80% (-3.23%, -0.37%)]. CONCLUSIONS: The findings in our prospective cohort study suggested the positively linear dose-response relationship of U-As with annual lung function decline. The adverse effects of As could be enhanced by cigarette smoking and attenuated by regular physical exercise. Specific emphasizes on tobacco control and physical exercise were suggested to prevent As exposure induced pulmonary impairment.

Lead exposure and its interactions with oxidative stress polymorphisms on lung function impairment: Results from a longitudinal population-based study.

Exposure to lead (Pb) and cadmium (Cd) were related to lung function impairment, and this association may be modified by genetic variants in oxidative stress response. Here we enrolled 1243 coke-oven workers in a prospective cohort who were followed up from 2010 to 2014, assessed the associations of Pb and Cd exposure with 4-year lung function impairment, and further explored the interaction effects of Pb with 2664 single nucleotide polymorphisms (SNPs) in 345 oxidative stress related genes. Urinary levels of Pb, Cd, and two oxidative stress biomarkers [8-iso-prostaglandin F2α (8-iso-PGF2α) for lipid peroxidation and 8-hydroxy-2'-deoxyguanosine (8-OHdG) for oxidative DNA damage] were measured at baseline only and their lung function levels were measured both at baseline and at the end of follow-up. Each 10-fold increase in urinary Pb was associated with -159 (95%CI: -254, -64.2) mL and -3.63% (95%CI: -6.48%, -0.78%) changes in FEV1 and percent predicted FEV1 (ppFEV1), respectively. But none significant associations were observed for Cd. NQO1 rs2917670 showed significant interaction with Pb on elevated FEV1 decline after multiple comparison (Pint=1.54 × 10-5). In addition, urinary Pb increased with 8-iso-PGF2α and the rs2917670-C could significantly decrease NQO1 expression in normal lung tissues. These findings suggested the gene-environmental interaction of NQO1 rs2917670 and Pb exposure on the reduction of FEV1. The effect of Pb exposure on elevated oxidative stress and the decreased expression of antioxidant enzyme NQO1 caused by rs2917670-C allele may partly explain the underlying biological mechanism.

Genome-Wide Analysis of DNA Methylation and Acute Coronary Syndrome.

RATIONALE: Acute coronary syndrome (ACS) is a leading cause of death worldwide. Immune functions play a vital role in ACS development; however, whether epigenetic modulation contributes to the regulation of blood immune cells in this disease has not been investigated. OBJECTIVE: We conducted an epigenome-wide analysis with circulating immune cells to identify differentially methylated genes in ACS. METHODS AND RESULTS: We examined genome-wide methylation of whole blood in 102 ACS patients and 101 controls using HumanMethylation450 array, and externally replicated significant discoveries in 100 patients and 102 controls. For the replicated loci, we further analyzed their association with ACS in 6 purified leukocyte subsets, their correlation with the expressions of annotated genes, and their association with cardiovascular traits/risk factors. We found novel and reproducible association of ACS with blood methylation at 47 cytosine-phosphoguanine sites (discovery: false discovery rate <0.005; replication: Bonferroni corrected P<0.05). The association of methylation levels at these cytosine-phosphoguanine sites with ACS was further validated in at least 1 of the 6 leukocyte subsets, with predominant contributions from CD8+ T cells, CD4+ T cells, and B cells. Blood methylation of 26 replicated cytosine-phosphoguanine sites showed significant correlation with expressions of annotated genes (including IL6R, FASLG, and CCL18; P<5.9×10-4), and differential gene expression in case versus controls corroborated the observed differential methylation. The replicated loci suggested a role in ACS-relevant functions including chemotaxis, coronary thrombosis, and T-cell-mediated cytotoxicity. Functional analysis using the top ACS-associated methylation loci in purified T and B cells revealed vital pathways related to atherogenic signaling and adaptive immune response. Furthermore, we observed a significant enrichment of the replicated cytosine-phosphoguanine sites associated with smoking and low-density lipoprotein cholesterol (Penrichment≤1×10-5). CONCLUSIONS: Our study identified novel blood methylation alterations associated with ACS and provided potential clinical biomarkers and therapeutic targets. Our results may suggest that immune signaling and cellular functions might be regulated at an epigenetic level in ACS.

Daily cooking duration and its joint effects with genetic polymorphisms on lung cancer incidence: Results from a Chinese prospective cohort study.

OBJECTIVES: In this study, we conducted a prospective cohort study to investigate the joint effects of daily cooking duration with single nucleotide polymorphisms (SNPs) on lung cancer incidence. MATERIALS AND METHODS: A total of 33,868 individuals recruited in 2013 from Dongfeng-Tongji cohort study were included in our research, in which 5178 participants were genotyped. Daily cooking duration was accessed by questionnaire, and the incident lung cancer cases were confirmed. Fifteen lung cancer related SNPs were selected according to the previous reports. We used the multiple Cox regression models to evaluate the separate and joint effects of daily cooking duration and SNPs on lung cancer incidence. RESULTS: Each 1-h increase in daily cooking duration was associated with a 17% elevated risk of lung cancer incidence [hazard ratio (HR) (95%CI) = 1.17(1.03, 1.33)]. Specifically, subjects with daily cooking duration >2 h/day had a 2.05-fold increased incident risk of lung cancer than those without cooking [HR(95%CI) = 2.05(1.20, 3.53)] (Ptrend = 0.011). The rs2395185 and rs3817963, both located at 6p21.32, were significantly associated with lung cancer incidence. Compared with no cooking subjects with rs2395185GG or rs3817963TT genotype, subjects with daily cooking >2 h/day and carrying rs2395185GT + TT genotypes had a 2.48-fold increased risk of lung cancer [HR(95%CI) = 2.48(1.03, 5.97)], and there were significant joint effects of rs3817963TC + CC with daily cooking 1-2 and >2 h/day [HR(95%CI) = 2.23(1.07, 4.64) and 2.22(1.05, 4.68), respectively]. CONCLUSIONS: Longer daily cooking duration, especially daily cooking >2 h/day, was associated with increased risk of lung cancer. There were significant joint effects of rs2395185 and rs3817963 with daily cooking duration on lung cancer incidence. This study offered a new indicator of cooking related pollution exposure and added new evidence for the joint effects of environment and genetic factors on lung cancer incidence.

A genetic variant in long non-coding RNA MALAT1 associated with survival outcome among patients with advanced lung adenocarcinoma: a survival cohort analysis.

BACKGROUND: Recently studies have demonstrated that the long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) may participate in the development and progression of lung cancer. In this study, we hypothesized that genetic variant of this lncRNA may affect the prognosis of lung cancer patients. METHODS: We conducted a follow-up study for 538 patients with non-small cell lung carcinoma (NSCLC), including 140 early-staged (stage I and II) and 398 advanced staged (stage III and IV) patients. The genetic variant rs3200401 in MALAT1 was then genotyped among this population by using TaqMan assay. The association of this variant with overall survival of these patients was further analyzed. RESULTS: It was shown that among the advanced lung adenoma patients, subjects carrying rs3200401 CT and CT + TT genotypes had significantly longer median survival time (MST = 29.9, 28.9 vs. 19.3 month, Long-rank P = 0.019 and 0.024, respectively) and decreased death risks [crude HR (95% CI) = 0.65 (0.43-0.98) and 0.64 (0.44-0.95), P = 0.040 and 0.025, respectively], when compared to subjects wtih the MALAT1 rs3200401 CC genotype. However, the beneficial effect of rs3200401 was not seen among early NSCLC and advanced lung squamous cell carcinoma patients. We further tested the TCGA data, and found that a higher expression of MALAT1 was associated with metastatic of advanced lung adenocarcinoma but not with lung squamous cell carcinoma. CONCLUSIONS: The rs3200401 T allele located on the lncRNA MALAT1 was associated with a better survival for advanced lung adenocarcinoma patients, which may offer a novel prognostic biomarker for this patient subgroup. However, these results need to be validated in larger populations of lung cancer and the biological function of this variant still warrants further investigation.

Essential Metals Zinc, Selenium, and Strontium Protect against Chromosome Damage Caused by Polycyclic Aromatic Hydrocarbons Exposure.

Essential metals play important roles in maintaining cellular homeostasis, but the effects of their interaction with the environmental pollutants are still not very well-known in human subjects. The aim of this study was to evaluate the roles of essential metals and their interactions with polycyclic aromatic hydrocarbons (PAHs) on chromosome damage, an early carcinogenic event. A total of 1245 male workers were included in this study and the levels of 11 urinary essential metals, 12 urinary PAH metabolites, plasma concentrations of benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydotetrol-albumin (BPDE-Alb) adducts, and lymphocyte micronucleus (MN) frequencies were monitored. We found that zinc (Zn), selenium (Se), and strontium (Sr) have significant inverse dose-response relationships with MN frequencies (all P < 0.05). Furthermore, the protective roles of Zn, Se, and Sr were mainly shown among subjects with high levels of BPDE-Alb adducts. Significant effect modification of BPDE-Alb adducts on the associations of Zn, Se, and Sr with MN frequencies was observed (all Pinteraction < 0.05). Our study showed evidence that Zn, Se, and Sr play protective roles in reducing chromosome damage, and these effects can be modified by PAH exposure levels. These findings add potential evidence for the preventive effects of Zn, Se, and Sr against carcinogenesis in human subjects.

Polycyclic aromatic hydrocarbons exposure and lung function decline among coke-oven workers: A four-year follow-up study.

OBJECTIVES: This study aimed to investigate quantitative relationships of urinary PAH metabolites with lung function declines among coke-oven workers. METHODS: We performed a prospective investigation involving 1243 workers with follow-up periods from 2010 to 2014. Their lung function measurements, including forced vital capacity (FVC), forced expiratory volume in one second (FEV1), the percentage of predicted FVC (FVC%) and FEV1 (FEV1%), FEV1/FVC ratio, and forced expiratory flow between 25% and 75% of vital capacity (FEF25-75), were detected in both baseline (2010) and follow-up study (2014). We also detected the urinary concentrations of 12 PAH metabolites in the baseline study. The relationships between the baseline urinary PAH metabolites and 4-year lung function declines were analyzed by multivariate linear regressions, with adjustment for potential confounders. RESULTS: We found that the baseline concentrations of urinary 1-hydroxynaphthalene (1-OHNa), 2-OHNa, 2-hydroxyfluorene (2-OHFlu), 9-OHFlu, 1-hydroxyphenanthrene (1-OHPh), 2-OHPh, and ΣOH-PAHs were significantly associated with accelerated decline in FEV1/FVC [all ß>0 and false discovery rate (FDR) P<0.05]. Additionally, the baseline levels of urinary 1-OHNa, 1-OHPh, 2-OHPh, 9-OHPh, 1-hydroxypyrene (1-OHP), and ΣOH-PAHs were associated with significantly deeper decline in FEF25-75 (all ß>0 and FDR P<0.10). When using backward selection to adjustment for 10 urinary PAH metabolites, the most significant determiner for FEV1/FVC decline was 1-OHNa among nonsmokers and 9-OHFlu among smokers, and the significant determiner for FEF25-75 decline was 9-OHPh among nonsmokers and 1-OHP among smokers. CONCLUSIONS: This longitudinal study revealed that higher baseline exposure levels of PAHs could lead to greater decline in lung function over a 4-year follow-up.

Healthy lifestyle and essential metals attenuated association of polycyclic aromatic hydrocarbons with heart rate variability in coke oven workers.

Whether adopting healthy lifestyles and maintaining moderate levels of essential metals could attenuate the reduction of heart rate variability (HRV) related to polycyclic aromatic hydrocarbons (PAHs) exposure are largely unknown. In this study, we measured urinary metals and PAHs as well as HRV, and constructed a healthy lifestyle score in 1267 coke oven workers. Linear regression models were used to explore the association of healthy lifestyle score and essential metals with HRV, and interaction analysis was performed to investigate the potential interaction between healthy lifestyle score, essential metals, and PAHs on HRV. Mean age of the participants was 41.9 years (84.5% male). Per one point higher healthy lifestyle score was associated with a 2.5% (95% CI, 1.0%-3.9%) higher standard deviation of all normal to normal intervals (SDNN), 2.1% (95% CI, 0.5%-3.6%) higher root mean square of successive differences in adjacent NN intervals (r-MSSD), 4.3% (95% CI, 0.4%-8.2%) higher low frequency, 4.4% (95% CI, 0.2%-8.5%) higher high frequency, and 4.4% (95% CI, 1.2%-7.6%) higher total power, respectively. Urinary level of chromium was positively associated with HRV indices, with the corresponding ß (95% CI) (%) was 5.17 (2.84, 7.50) for SDNN, 4.29 (1.74, 6.84) for r-MSSD, 12.26 (6.08, 18.45) for low frequency, 12.61 (5.87, 19.36) for high frequency, and 11.31 (6.19, 16.43) for total power. Additionally, a significant interaction was found between healthy lifestyle score and urinary total hydroxynaphthalene on SDNN (Pinteraction = 0.04), and higher level of urinary chromium could attenuate the adverse effect of total hydroxynaphthalene level on HRV (all Pinteraction <0.05). Findings of our study suggest adopting healthy lifestyle and maintaining a relatively high level of chromium might attenuate the reduction of HRV related to total hydroxynaphthalene exposure.

The effects and potential mechanisms of essential metals on the associations of polycyclic aromatic hydrocarbons with blood cell-based inflammation markers.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) are well-acknowledged pro-inflammatory chemicals, but their associations with blood cell-based inflammatory biomarkers need further investigation. Moreover, the effects and mechanisms of essential metals on PAH-related inflammation remain poorly understood. OBJECTS: To elucidate the associations of PAHs on inflammatory biomarkers, as well as the effects and mechanisms of essential metals on these associations. METHODS: A cross-sectional study was conducted on 1388 coke oven workers. We analyzed the modification effects of key essential metal(s) on PAHs-inflammatory biomarkers associations. To explore the possible mechanisms from an inflammation perspective, we performed a bioinformatic analysis on the genes of PAHs and essential metals obtained from the Comparative Toxicogenomics Database (CTD) and performed a mediation analysis. RESULTS: We observed associations of PAHs and essential metals with lymphocyte-to-monocyte ratio (LMR) (P < 0.05). PAH mixtures were inversely associated with LMR (ßQGC-index = -0.18, P < 0.001), with 1-hydroxypyrene (1-OH-Pyr) being the most prominent contributor (weight = 63.37%), whereas a positive association between essential metal mixtures and LMR was observed (ßQGC-index = 0.14, P < 0.001), with tin being the most significant contributor (weight = 51.61%). An inverse association of 1-OH-Pyr with LMR was weakened by increased tin exposure (P < 0.05). The CTD database showed that PAHs and tin compounds co-regulated 22 inflammation-associated genes, but they regulated most genes in opposite directions. Further identified the involvement of oxidative stress and mediation analysis showed that the mediation effect of 8-hydroxydeoxyguanosine (8-OHdG) on 1-OH-Pyr-LMR association presented heterogeneity between low and high tin tertile groups (I2 = 37.84%). CONCLUSION: 1-OH-Pyr and tin were significantly associated with LMR. Modification effects indicated that the inverse association of 1-OH-Pyr with LMR was mitigated with an increase in tin. The mediation effect of 8-OHdG on the inverse association of 1-OH-Pyr with LMR may be partially dependent on tin.

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.

Metabolic linkages between zinc exposure and lung cancer risk: A nested case-control study.

Epidemiologic studies have suggested that elevated concentrations of zinc are associated with a decreased risk of lung cancer, but the underlying mechanisms remain to be investigated. The metabolites are highly sensitive to environmental stress, which will help to reveal the linkages between zinc exposure and lung cancer risk. We designed a nested case-control study including 101 incident lung cancer cases and 1:2 age- and sex-frequency-matched 202 healthy controls from the Dongfeng-Tongji (DFTJ) cohort. Their plasma level of zinc was determined by using inductively coupled plasma-mass spectrometry (ICP-MS) and plasma profiles of metabolites were detected by using an untargeted metabolomics approach. The generalized linear models (GLM) were applied to assess the associations of plasma zinc with metabolites, and the mediation effects of zinc-related metabolites on zinc-lung cancer association were further testified. The concentrations of 55 metabolites had linear dose-response relationships with plasma zinc at a false discovery rate (FDR) < 0.05, among which L-proline, phosphatidylcholine (PC, 34:2), phosphatidylethanolamine (PE, O-36:5), L-altrose, and sphingomyelin (SM, 40:3) showed different levels between lung cancer cases and healthy controls (fold change = 0.92, 0.95, 1.07, 0.90, and 1.08, respectively, and all P < 0.05). The plasma concentration of SM(40:3) was negatively associated with incident risk of lung cancer [OR(95%CI) = 0.71(0.55, 0.91), P = 0.007] and could mediate 41.7% of the association between zinc and lung cancer risk (P = 0.004). Moreover, compared to the traditional factors, addition of SM(40:3) exerted improved prediction performance for incident risk of lung cancer [AUC(95%CIs) = 0.714(0.654, 0.775) vs. 0.663(0.600, 0.727), P = 0.030]. Our findings revealed metabolic profiles with zinc exposure and provide new insight into the alternations of metabolites underpinning the links between zinc exposure and lung cancer development.

Epigenome-wide DNA methylation signature of plasma zinc and their mediation roles in the association of zinc with lung cancer risk.

Essential trace element zinc is associated with decreased lung cancer risk, but underlying mechanisms remain unclear. This study aimed to investigate role of DNA methylation in zinc-lung cancer association. We conducted a case-cohort study within prospective Dongfeng-Tongji cohort, including 359 incident lung cancer cases and a randomly selected sub-cohort of 1399 participants. Epigenome-wide association study (EWAS) was used to examine association of plasma zinc with DNA methylation in peripheral blood. For the zinc-related CpGs, their mediation effects on zinc-lung cancer association were assessed; their diagnostic performance for lung cancer was testified in the case-cohort study and further validated in another 126 pairs of lung cancer case-control study. We identified 28 CpGs associated with plasma zinc at P < 1.0 × 10-5 and seven of them (cg07077080, cg01077808, cg17749033, cg15554270, cg26125625, cg10669424, and cg15409013 annotated to GSR, CALR3, SLC16A3, PHLPP2, SLC12A8, VGLL4, and ADAMTS16, respectively) were associated with incident risk of lung cancer. Moreover, the above seven CpGs were differently methylated between 126 pairs of lung cancer and adjacent normal lung tissues and had the same directions with EWAS of zinc. They could mediate a separate 7.05%∼22.65% and a joint 29.42% of zinc-lung cancer association. Compared to using traditional factors, addition of methylation risk score exerted improved discriminations for lung cancer both in case-cohort study [area under the curve (AUC) = 0.818 vs. 0.738] and in case-control study (AUC = 0.816 vs. 0.646). Our results provide new insights for the biological role of DNA methylation in the inverse association of zinc with incident lung cancer.

Plasma perfluoroalkyl substance exposure and incidence risk of breast cancer: A case-cohort study in the Dongfeng-Tongji cohort.

Experimental studies have suggested perfluoroalkyl substances (PFASs) as mammary toxicants, but few studies evaluated the prospective associations of PFASs with breast cancer risk. We performed a case-cohort study within the Dongfeng-Tongji cohort, including incident breast cancer cases (n = 226) and a random sub-cohort (n = 990). Baseline plasma concentrations of four perfluorinated carboxylic acids (PFCAs) [perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroheptanoic acid (PFHpA)] and two perfluorinated sulfonic acids (PFSAs) [perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS)] were measured. Barlow-weighted Cox regression models revealed that each 1-unit increase in ln-transformed PFOA and PFHpA was associated with a separate 35% and 20% elevated incident risk of breast cancer [HR(95%CI) = 1.35(1.03, 1.78) and 1.20(1.02, 1.40), respectively], which were also significant among postmenopausal females [HR(95%CI) = 1.34(1.01, 1.77) and 1.23 (1.02, 1.48), respectively]. Quantile g-computation analysis observed a 19% increased incident risk of breast cancer along with each simultaneous quartile increase in all ln-transformed PFCA concentrations [HR(95%CI) = 1.19(1.01, 1.41)], with PFOA accounting for 56% of the positive effect. Our findings firstly revealed the impact of short-chain PFHpA on increased incident risk of breast cancer, suggested exposure to PFASs as a risk factor for breast cancer, and shed light on breast cancer prevention by regulating PFASs as a chemical class.

Age-related DNA methylation on Y chromosome and their associations with total mortality among Chinese males.

In view of the sex differences in aging-related diseases, sex chromosomes may play a critical role during aging process. This study aimed to identify age-related DNA methylation changes on Y chromosome (ChrY). A two-stage study design was conducted in this study. The discovery stage contained 419 Chinese males, including 205 from the Wuhan-Zhuhai cohort panel, 107 from the coke oven workers panel, and 107 from the Shiyan panel. The validation stage contained 587 Chinese males from the Dongfeng-Tongji sub-cohort. We used the Illumina HumanMethylation BeadChip to determine genome-wide DNA methylation in peripheral blood of the study participants. The associations between age and methylation levels of ChrY CpGs were investigated by using linear regression models with adjustment for potential confounders. Further, associations of age-related ChrY CpGs with all-cause mortality were tested in the validation stage. We identified the significant associations of 41 ChrY CpGs with age at false discovery rate (FDR) <0.05 in the discovery stage, and 18 of them were validated in the validation stage (p < 0.05). Meta-analysis of both stages confirmed the robust positive associations of 14 CpGs and negative associations of 4 CpGs with age (FDR<0.05). Among them, cg03441493 and cg17816615 were significantly associated with all-cause mortality risk [HR(95% CI) = 1.37 (1.04, 1.79) and 0.70 (0.54, 0.93), respectively]. Our results highlighted the importance of ChrY CpGs on male aging.

A machine learning-based biological aging prediction and its associations with healthy lifestyles: the Dongfeng-Tongji cohort.

This study aims to establish a biological age (BA) predictor and to investigate the roles of lifestyles on biological aging. The 14,848 participants with the available information of multisystem measurements from the Dongfeng-Tongji cohort were used to estimate BA. We developed a composite BA predictor showing a high correlation with chronological age (CA) (r = 0.82) by using an extreme gradient boosting (XGBoost) algorithm. The average frequency hearing threshold, forced expiratory volume in 1 second (FEV1 ), gender, systolic blood pressure, and homocysteine ranked as the top five important features for the BA predictor. Two aging indexes, recorded as the AgingAccel (the residual from regressing predicted age on CA) and aging rate (the ratio of predicted age to CA), showed positive associations with the risks of all-cause (HR (95% CI) = 1.12 (1.10-1.14) and 1.08 (1.07-1.10), respectively) and cause-specific (HRs ranged from 1.06 to ∼1.15) mortality. Each 1-point increase in healthy lifestyle score (including normal body mass index, never smoking, moderate alcohol drinking, physically active, and sleep 7-9 h/night) was associated with a 0.21-year decrease in the AgingAccel (95% CI: -0.27 to -0.15) and a 0.4% decrease in the aging rate (95% CI: -0.5% to -0.3%). This study developed a machine learning-based BA predictor in a prospective Chinese cohort. Adherence to healthy lifestyles showed associations with delayed biological aging, which highlights potential preventive interventions.

Physical activity attenuates the associations of systemic immune-inflammation index with total and cause-specific mortality among middle-aged and older populations.

Systemic immune-inflammation index (SII) emerged as a biomarker of chronic inflammation and an independent prognostic factor for many cancers. We aimed to investigate the associations of SII level with total and cause-specific mortality risks in the general populations, and the potential modification effects of lifestyle-related factors on the above associations. In this study, we included 30,521 subjects from the Dongfeng-Tongji (DFTJ) cohort and 25,761 subjects from the National Health and Nutrition Examination Survey (NHANES) 1999-2014. Cox proportional hazards regression models were used to estimate the associations of SII with mortality from all-cause, cardiovascular diseases (CVD), cancer and other causes. In the DFTJ cohort, compared to subjects in the low SII subgroup, those within the middle and high SII subgroups had increased risks of total mortality [hazard ratio, HR (95% confidence interval, CI) = 1.12 (1.03-1.22) and 1.26 (1.16-1.36), respectively) and CVD mortality [HR (95%CI) = 1.36 (1.19-1.55) and 1.50 (1.32-1.71), respectively]; those within the high SII subgroup had a higher risk of other causes mortality [HR (95%CI) = 1.28 (1.09-1.49)]. In the NHANES 1999-2014, subjects in the high SII subgroup had higher risks of total, CVD, cancer and other causes mortality [HR (95%CI) = 1.38 (1.27-1.49), 1.33 (1.11-1.59), 1.22 (1.04-1.45) and 1.47 (1.32-1.63), respectively]. For subjects with a high level of SII, physical activity could attenuate a separate 30% and 32% risk of total and CVD mortality in the DFTJ cohort, and a separate 41% and 59% risk of total and CVD mortality in the NHANES 1999-2014. Our study suggested high SII level may increase total and CVD mortality in the general populations and physical activity exerted a beneficial effect on the above associations.

Circulating white blood cells and lung function impairment: the observational studies and Mendelian randomization analysis.

BACKGROUND: Circulating white blood cell (WBC) counts have been related to lung function impairment, but causal relationship was not established. We aimed to evaluate independent effects and causal relationships of WBC subtypes with lung function. METHODS: The 19,159 participants from NHANES 2011-2012 (n = 3570), coke-oven workers (COW, n = 1762) and Dongfeng-Tongji (DFTJ, n = 13,827) cohorts were included in the observational studies. The associations between circulating counts of WBC subtypes and prebronchodilator lung function were evaluated by linear regression models and LASSO regression was used to select effective WBC subtypes. Summary statistics for WBC-associated SNPs were extracted from literature, and Mendelian randomization (MR) analysis with inverse-variance weighted (IVW) method was applied to estimate the causal effects of total WBC and subtypes on lung function among 4012 subjects from COW (n = 1126) and DFTJ cohorts (n = 2886). RESULTS: Total WBC counts were negatively associated with lung function among three populations and their pooled analysis indicated that per 1 × 109 cells/L increase in total WBC was associated with 36.13 (95% CI: 30.35, 41.91) mL and 25.23 (95% CI: 19.97, 30.50) mL decrease in FVC and FEV1, respectively. Independent associations with lung function were found for neutrophils, monocytes, eosinophils and basophils (all p < .05), except lymphocytes. Besides, IVW MR analysis showed that genetically predicted total WBC and neutrophil counts were associated with reduced FVC (p = .017 and .021, respectively) and FEV1 (p = .048 and .043, respectively). CONCLUSIONS: WBC subtypes were independently associated with lower lung function except lymphocytes. Our findings suggest that circulating neutrophils may be causal factors in lung function impairment.KEY MESSAGESWhite blood cell (WBC) subtypes were negatively associated with lung function level except lymphocytes in the observational studies.Associations of WBC subtypes with lung function may be modified by sex and smoking.Mendelian randomization analysis shows that neutrophils may be causal factors in lung function impairment.