The interaction effect of metals exposure and dietary habit on cognitive function in Chinese older adult cohort.

BACKGROUND: As the important factors in cognitive function, dietary habits and metal exposures are interactive with each other. However, fewer studies have investigated the interaction effect of them on cognitive dysfunction in older adults. METHODS: 2,445 registered citizens aged 60-85 years from 51 community health centers in Luohu District, Shenzhen, were recruited in this study based on the Chinese older adult cohort. All subjects underwent physical examination and Mini-cognitive assessment scale. A semi quantitative food frequency questionnaire was used to obtain their food intake frequency, and 21 metal concentrations in their urine were measured. RESULTS: Elastic-net regression model, a machine learning technique, identified six variables that were significantly associated with cognitive dysfunction in older adults. These variables included education level, gender, urinary concentration of arsenic (As) and cadmium (Cd), and the frequency of monthly intake of egg and bean products. After adjusting for multiple factors, As and Cd concentrations were positively associated with increased risk of mild cognitive impairment (MCI) in the older people, with OR values of 1.19 (95% CI: 1.05-1.42) and 1.32 (95% CI: 1.01-1.74), respectively. In addition, older adults with high frequency of egg intake (≥30 times/month) and bean products intake (≥8 times/month) had a reduced risk of MCI than those with low protein egg intake (<30 times/month) and low bean products intake (<8 times/month), respectively. Furthermore, additive interaction were observed between the As exposure and egg products intake, as well as bean products. Cd exposure also showed additive interactions with egg and bean products intake. CONCLUSIONS: The consumption of eggs and bean products, as well as the levels of exposure to the heavy metals Cd and As, have been shown to have a substantial influence on cognitive impairment in the elderly population.

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

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

Arsenic exposure at environmentally relevant levels induced metabolic toxicity in development mice: Mechanistic insights from integrated transcriptome and metabolome.

Emerging evidence has linked arsenic exposure and metabolic homeostasis, but the mechanism is incompletely understood, especially at relatively low concentrations. In this study, we used a mouse model to evaluate the health impacts and metabolic toxicity of arsenic exposure in drinking water at environmentally relevant levels (0.25 and 1.0 ppm). Our results indicated that arsenic damaged intestinal barrier and induced arsenic accumulation, oxidative stress, and pathological changes in the liver and illum. Interestingly, arsenic increased the hepatic triglyceride (TG) and total cholesterol (TC), while reduced serum TG and TC levels. The liver transcriptome found that arsenic exposure caused transcriptome perturbation and promoted hepatic lipid accumulation by regulating the exogenous fatty acids degradation and apolipoproteins related genes. The serum metabolomics identified 74 and 88 differential metabolites in 0.25 and 1.0 ppm, respectively. The KEGG disease and subcellular location analysis indicated that arsenic induced liver and intestinal diseases, and the mitochondrion might be the target organelle for arsenic-induced toxicity. Co-enrichment of transcriptome and metabolome identified 24 metabolites and 9 genes as metabolic toxicity biomarkers. Moreover, 40 male (20 nonalcoholic fatty liver disease (NAFLD) cases and 20 healthy controls) was further selected to validate our findings. Importantly, the significantly changed L-palmitoylcarnitine, 3-hydroxybutyric acid, 2-hydroxycaproic acid and 6 genes of Hadha, Acadl, Aldh3a2, Cpt1a, Cpt2, and Acox1 were found in the NAFLD cases. The results from integrated multi-omics and chemical-protein network analysis indicated that L-palmitoylcarnitine played a critical role in metabolic toxicity by regulating mitochondrial fatty acids ß-oxidation genes (Cpt1a, Cpt2). In conclusion, these findings provided new clues for the metabolic toxicity of arsenic exposure at environmentally relevant levels, which involved in the late-life NAFLD development. Our results also contribute to understanding the human responses and phenotypic changes to this hazardous material exposure in the environment.

Plasma metals, genetic risk, and rapid kidney function decline among type 2 diabetes.

BACKGROUND: Rapid kidney function decline (RKFD) is a main clinical feature of early chronic kidney disease (CKD) in type 2 diabetes (T2D). Environmental and genetic factors influencing RKFD remain inadequately elucidated. OBJECTIVES: This study aimed to examine the associations of metals with RKFD among T2D and to further investigate the effect of metal mixtures on RKFD with the modifying effect of genetic susceptibility. METHODS: This study included 2209 people with T2D (1942 had genotyping data) free of CKD at baseline from the Dongfeng-Tongji cohort. We used inductively coupled plasma-mass spectrometry (ICP-MS) to measure 23 metals in baseline plasma. Using elastic net (ENET), multivariate logistic regression, and Bayesian kernel machine regression (BKMR) model, we examined independent associations of multiple metals with RKFD. We calculated the environmental risk score (ERS) to assess the effects of metal mixtures on RKFD and the genetic risk score (GRS) to assess genetic susceptibility. RKFD was defined as estimated glomerular filtration rate (eGFR) loss > 3 mL/min/1.73 m2/year. RESULTS: During a median of 9.8 years follow-up, 262 participants developed RKFD. Aluminum, vanadium, zinc, selenium, rubidium, tin, barium, and tungsten were screened from ENET. In multivariate logistic models, vanadium, selenium, and tungsten were negatively associated with RKFD, while zinc, tin, and rubidium were positively associated. The BKMR showed a nonlinear association of vanadium and rubidium with RKFD and interactions between metals (barium­vanadium, barium­rubidium). The ERS was positive associated with RKFD (per SD increase in ERS, OR = 1.94, 95% CI: 1.66, 2.27). No significant interaction between ERS and GRS was observed on RKFD, however, participants in the highest ERS and GRS group had the highest RKFD risk. CONCLUSION: Vanadium and rubidium were associated with RKFD in T2D. Metal mixtures was associated with an increased risk of RKFD in T2D, particularly in those at high genetic risk.

Mitochondrial DNA copy number mediated the associations between perfluoroalkyl substances and breast cancer incidence: A prospective case-cohort study.

Epidemiologic studies have reported the relationships between perfluoroalkyl substances (PFASs) and breast cancer incidence, yet the underlying mechanisms are not well understood. This study aimed to elucidate the mediation role of mitochondrial DNA copy number (mtDNAcn) in the relationships between PFASs exposure and breast cancer risk. We conducted a case-cohort study within the Dongfeng-Tongji cohort, involving 226 incident breast cancer cases and a random sub-cohort (n = 990). Their plasma concentrations of six PFASs [including perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluoroheptanoic acid (PFHpA), perfluorooctane sulfonic acid (PFOS) and perfluorohexane sulfonic acid (PFHxS)], and peripheral blood levels of mtDNAcn, were detected at baseline by using ultraperformance liquid chromatography-tandem mass spectrometry and quantitative real-time PCR, respectively. Linear regression and Barlow-weighted Cox models were employed separately to assess the relationships of mtDNAcn with PFASs and breast cancer risk. Mediation analysis was further conducted to quantify the mediating effects of mtDNAcn on PFAS-breast cancer relationships. We observed increased blood mtDNAcn levels among participants with the highest PFNA and PFHpA exposure [Q4 vs. Q1, ß(95%CI) = 0.092(0.022, 0.162) and 0.091(0.022, 0.160), respectively], while no significant associations were observed of PFOA, PFDA, PFOS, or PFHxS with mtDNAcn. Compared to participants within the lowest quartile subgroup of mtDNAcn, those with the highest mtDNAcn levels exhibited a significantly increased risk of breast cancer and postmenopausal breast cancer [Q4 vs. Q1, HR(95%CI) = 3.34(1.80, 6.20) and 3.71(1.89, 7.31)]. Furthermore, mtDNAcn could mediate 14.6 % of the PFHpA-breast cancer relationship [Indirect effect, HR(95%CI) = 1.02(1.00, 1.05)]. Our study unveiled the relationships of PFNA and the short-chain PFHpA with mtDNAcn and the mediation role of mtDNAcn in the PFHpA-breast cancer association. These findings provided insights into the potential biological mechanisms linking PFASs to breast cancer risk.

Polygenic Risk Score Modifies the Association of HbA1c With Hearing Loss in Middle-Aged and Older Chinese Individuals: The Dongfeng-Tongji Cohort.

OBJECTIVE: Evidence regarding the modifying effect of the polygenic risk score (PRS) on the associations between glycemic traits and hearing loss (HL) was lacking. We aimed to examine whether these associations can be influenced by genetic susceptibility. RESEARCH DESIGN AND METHODS: This cross-sectional study included 13,275 participants aged 64.9 years from the Dongfeng-Tongji cohort. HL was defined according to a pure tone average >25 dB in the better ear and further classified by severity. Prediabetes and type 2 diabetes (T2D) were defined based on the 2013 criteria from the American Diabetes Association. A PRS was derived from 37 single nucleotide polymorphisms associated with HL. Multivariable logistic regression models were fitted to estimate the associations of PRS and glycemic traits with HL and its severity. RESULTS: Elevated fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), and T2D were positively associated with higher HL risks and its severity, with odds ratios (ORs) ranging from 1.04 (95% CI 1.00, 1.08) to 1.25 (95% CI 1.06, 1.46). We also found significant interaction between HbA1c and PRS on risks of overall HL and its severity (P for multiplicative interaction <0.05), and the effects of HbA1c on HL risks were significant only in the group with high PRS. Additionally, compared with normoglycemia in the group with low PRS, T2D was associated with an OR of up to 2.00 and 2.40 for overall HL and moderate to severe HL, respectively, in the group with high PRS (P for additive interaction <0.05). CONCLUSIONS: PRS modifies the association of HbA1c with HL prevalence among middle-aged and older Chinese individuals.

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.

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.

Gut microbiota deficiency aggravates arsenic-induced toxicity by affecting bioaccumulation and biotransformation in C57BL/6J mice.

Gut microbiome can influence the arsenic metabolism in mammals. Confusingly, gut microbiome was found to both mitigate and exacerbate arsenic toxicity. In this study, the role of gut microbiota in arsenic bioaccumulation, biotransformation, and organ toxicity in C57BL/6J mice was investigated. Gut microbiota deficiency model was established by antibiotics (Ab) cocktail AVNM. Conventional and gut microbiota deficiency mice were exposed to NaAsO2 for 4 weeks. Comparing with Ab-treated mice, the total arsenic (tAs) in the tissues was significantly reduced in conventional mice, which was opposed to the results of those in feces. Interestingly, dimethyl arsenite (DMA) was the most abundant metabolite in the feces of Ab-treated mice, while arsenic acid (AsV) had the highest proportion in the feces of conventional mice with approximately 16-fold than that in Ab-treated mice, indicating the critical role of gut microbiota in metabolizing arsenious acid (AsIII) to AsV. Additionally, the liver and kidney in Ab-treated mice showed more severe pathological changes and apoptosis. The significant increased level of ionized calcium-binding adapter molecule 1 (IBA-1) was also found in the brains of Ab-treated mice. Our results indicated that gut microbiota protected the host from arsenic-induced toxicity in liver, kidney, and brain by reducing the arsenic accumulation.

Gut microbiota-derived secondary bile acids, bile acids receptor polymorphisms, and risk of cardiovascular disease in individuals with newly diagnosed type 2 diabetes: a cohort study.

BACKGROUND: Secondary bile acids (SBAs), the products of bacterial metabolism, are ligands of the nuclear farnesoid X receptor (FXR) and have been implicated in cardiovascular health. Diet can modulate gut microbiota composition and bile acid metabolism. OBJECTIVES: We aimed to examine the associations of circulating SBAs and their receptor polymorphisms with the risk of incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D). METHODS: A total of 1234 participants with newly diagnosed T2D without CVD or cancer were included from the Dongfeng-Tongji Cohort study in China. Circulating SBAs and their conjugated forms were quantified using liquid chromatography-tandem mass spectrometry. Fifteen single-nucleotide polymorphisms in genes encoding bile acid receptors were genotyped. RESULTS: During a median follow-up of 5.7 y, 259 incident CVD cases were documented. After multivariable adjustment, higher levels of unconjugated SBAs [sum of deoxycholic acid (DCA), lithocholic acid, and ursodeoxycholic acid] and DCA were significantly associated with a higher risk of CVD among people with T2D, with hazard ratios (HRs) and 95% confidence intervals (CIs) of 1.62 (1.12, 2.35) and 1.46 (1.04, 2.06) comparing the extreme quartile of SBAs and DCA, respectively. Restricted cubic spline regression suggested a linear relationship of unconjugated SBAs and DCA with an elevated risk of CVD, and per standard deviation, an increment in natural log-transformed unconjugated SBAs and DCA was associated with an 18% (95% CI: 4%, 34%) and 16% (95% CI: 2%, 33%) higher risk of CVD, respectively. Moreover, genetic variants in FXR (rs56163822 TT compared with GG, and rs17030295 TT compared with CC) were significantly associated with a 121%-129% higher risk of CVD among individuals with T2D. CONCLUSIONS: A higher proportion of unconjugated SBAs, especially DCA, is linearly associated with a higher risk of CVD among people with newly diagnosed T2D. Our findings support the potential role of gut microbiota-derived SBAs in cardiovascular health in individuals with T2D.

Associations of arsenic exposure and arsenic metabolism with the risk of non-alcoholic fatty liver disease.

Growing evidences supported that arsenic exposure contributes to non-alcoholic fatty liver disease (NAFLD) risk, but findings were still inconsistent. Additionally, once absorbed, arsenic is methylated into monomethyl and dimethyl arsenicals. However, no studies investigated the association of arsenic metabolism with NAFLD. Our objectives were to evaluate the associations of arsenic exposure and arsenic metabolism with NAFLD prevalence. We conducted a case-control study with 1790 participants derived from Dongfeng-Tongji cohort and measured arsenic species (arsenite, arsenate, monomethylarsonate [MMA], dimethylarsinate [DMA], and arsenobetaine) in urine. Arsenic exposure (∑As) was defined as the sum of inorganic arsenic (iAs), MMA, and DMA. Arsenic metabolism was evaluated as the proportions of inorganic-related species (iAs%, MMA%, and DMA%) and methylation efficiency ratios (primary methylation index [PMI], secondary methylation index [SMI]). NAFLD was diagnosed by liver ultrasound. Logistic regression was used to evaluate the associations. The median of ∑As was 13.24 µg/g creatinine. The ∑As showed positive and nonlinear association with moderate/severe NAFLD (OR: per log-SD = 1.33, 95% CI: [1.03,1.71]; Pfor nonlinearity = 0.021). The iAs% (OR: per SD = 1.16, 95% CI: [1.03,1.30]) and SMI (OR: per log-SD = 1.16, 95% CI: [1.03,1.31]) showed positive while MMA% (OR: per SD = 0.80, 95% CI: [0.70,0.91]) and PMI (OR: per log-SD = 0.86, 95% CI: [0.77,0.96]) showed inverse associations with NAFLD. Moreover, the ORs (95% CI) of NAFLD for each 5% increase in iAs% was 1.36 (1.17,1.58) when MMA% decreased and 1.07 (1.01,1.13) when DMA% decreased; and for each 5% increase in MMA%, it was 0.74 (0.63,0.86) and 0.79 (0.69,0.91) when iAs% and DMA% decreased, respectively. The results suggest that inorganic arsenic exposure is positively associated with NAFLD risk and arsenic methylation efficiency plays a role in the NAFLD. The findings provide clues to explore potential interventions for the prevention of NAFLD. Prospective studies are needed to validate our findings.

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.

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

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

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

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

Epigenome-wide perspective of cadmium-associated DNA methylation and its mediation role in the associations of cadmium with lipid levels and dyslipidemia risk.

BACKGROUND: Studies demonstrated the associations of cadmium (Cd) with lipid levels and dyslipidemia risk, but the mechanisms involved need further exploration. OBJECTIVES: We aimed to explore the role of DNA methylation (DNAM) in the relationship of Cd with lipid levels and dyslipidemia risk. METHODS: Urinary cadmium levels (UCd) were measured by inductively coupled plasma mass spectrometry, serum high-density lipoprotein (HDL), total cholesterol, triglyceride, and low-density lipoprotein were measured with kits, and DNAM was measured using the Infinium MethylationEPIC BeadChip. Robust linear regressions were conducted for epigenome-wide association study. Multivariate linear and logistic regressions were performed to explore the associations of UCd with lipid levels and dyslipidemia risk, respectively. Mediation analyses were conducted to explore potential mediating role of DNAM in the associations of Cd with lipid levels and dyslipidemia risk. RESULTS: UCd was negatively associated with HDL levels (p = 0.01) and positively associated with dyslipidemia (p < 0.01). There were 92/11 DMPs/DMRs (FDR<0.05) associated with UCd. Cd-associated DNAM and pathways were connected with cardiometabolic diseases and immunity. Cg07829377 (LINC01060) mediated 42.05%/22.88% of the UCd-HDL/UCd-dyslipidemia associations (p = 0.02 and 0.01, respectively). CONCLUSIONS: Cadmium caused site-specific DNAM alterations and the associations of UCd with lipid levels and dyslipidemia risk may be partially mediated by DNAM.

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

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

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

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

Genotypic and Allelic Frequencies of GJB2 Variants and Features of Hearing Phenotypes in the Chinese Population of the Dongfeng-Tongji Cohort.

BACKGROUND: This study aimed to describe the distribution of the genotype and allele frequencies of GJB2 variants in the Chinese population of the Dongfeng Tongji cohort and to analyze the features of the hearing phenotype. METHODS: We used data from 9910 participants in the Dongfeng Tongji cohort in 2013 and selected nine GJB2 variants. Pure tone audiometry was employed to measure hearing. Differences in genotype and allele frequencies were analyzed via chi-squared test or Fisher's exact test. RESULTS: Of the 9910 participants, 5742 had hearing loss. The genotype frequency of the GJB2 variant c.109G>A was statistically significantly distributed between the normal and impaired hearing groups, but not for the variant c.235delC. A higher frequency of the c.109G>A homozygous genotype was found in the hearing loss group (0.5%) than in the normal hearing group (0.1%). Patients with c.109G>A and c.235delC homozygous mutations exhibited varying degrees of hearing loss, mainly presenting sloping and flat audiogram shapes. CONCLUSIONS: A significant difference was found in the genotype frequency of the GJB2 variant c.109G>A between the case and control groups, but not in that of the variant c.235delC. Different degrees of hearing loss and various audiogram shapes were observed in patients with c.109G>A and c.235delC homozygous mutations.

Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci.

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10-8) and suggestive (p < 1 × 10-6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.