A solute carrier family 22 member 3 variant rs3088442 G→A associated with coronary heart disease inhibits lipopolysaccharide-induced inflammatory response.

Recent genome-wide association studies have identified single-nucleotide polymorphism (SNPs) within the SLC22A3 (solute carrier family 22 member 3) gene associated with coronary heart disease (CHD) in the Caucasian population. We performed molecular analysis to investigate the potential role of SLC22A3 variants in CHD. Our study showed that the common polymorphism rs3088442 G→A, which is localized in the 3' UTR of the SLC22A3 gene, was associated with a decreased risk of CHD in the Chinese population by a case control study. In silico analysis indicated that G→A substitution of SNP rs3088442 created a putative binding site for miR-147 in the SLC22A3 mRNA. By overexpressing miR-147 or inhibiting endogenous miR-147, we demonstrated that SNP rs3088442 G→A recruited miR-147 to inhibit SLC22A3 expression. Moreover, SLC22A3 deficiency significantly decreased LPS-induced monocytic inflammatory response by interrupting NF-κB and MAPK signaling cascades in a histamine-dependent manner. Notably, the expression of SLC22A3(A) was also suppressed by LPS stimulus. Our findings might indicate a negative feedback mechanism against inflammatory response by which SLC22A3 polymorphisms decreased the risk of CHD.

Associations of the uric acid related genetic variants in SLC2A9 and ABCG2 loci with coronary heart disease risk.

BACKGROUND: Multiple studies investigated the associations between serum uric acid and coronary heart disease (CHD) risk. However, further investigations still remain to be carried out to determine whether there exists a causal relationship between them. We aim to explore the associations between genetic variants in uric acid related loci of SLC2A9 and ABCG2 and CHD risk in a Chinese population. RESULTS: A case-control study including 1,146 CHD cases and 1,146 controls was conducted. Association analysis between two uric acid related variants (SNP rs11722228 in SLC2A9 and rs4148152 in ABCG2) and CHD risk was performed by logistic regression model. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Compared with subjects with A allele of rs4148152, those with G allele had a decreased CHD risk and the association remained significant in a multivariate model. However, it altered to null when BMI was added into the model. No significant association was observed between rs11722228 and CHD risk. The distribution of CHD risk factors was not significantly different among different genotypes of both SNPs. Among subjects who did not consume alcohol, the G allele of rs4148152 showed a moderate protective effect. However, no significant interactions were observed between SNP by CHD risk factors on CHD risk. CONCLUSIONS: There might be no association between the two uric acid related SNPs with CHD risk. Further studies were warranted to validate these results.

A genome wide association study of genetic loci that influence tumour biomarkers cancer antigen 19-9, carcinoembryonic antigen and α fetoprotein and their associations with cancer risk.

OBJECTIVE: Tumour biomarkers are used as indicators for cancer screening and as predictors for therapeutic responses and prognoses in cancer patients. We aimed to identify genetic loci that influence concentrations of cancer antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA) and α fetoprotein (AFP), and investigated the associations between the significant single nucleotide polymorphisms (SNPs) with risks of oesophageal squamous cell (OSCC), pancreatic and hepatocellular cancers. DESIGN: We carried out a genome wide association study on plasma CA19-9, CEA and AFP concentrations in 3451 healthy Han Chinese and validated the results in 10 326 individuals. Significant SNPs were further investigated in three case control studies (2031 OSCC cases and 2044 controls; 981 pancreatic cancer cases and 1991 controls; and 348 hepatocellular cancer cases and 359 controls). RESULTS: The analyses showed association peaks on three genetic loci for CA19-9 (FUT6-FUT3 at 19p13.3, FUT2-CA11 at 19q13.3 and B3GNT3 at 19p13.1; p=1.16×10(-13)-3.30×10(-290)); four for CEA (ABO at 9q34.2, FUT6 at 19p13.3, FUT2 at 19q13.3 and FAM3B at 21q22.3; p=3.33×10(-22)-5.81×10(-209)); and two for AFP (AFP at 4q11-q13 and HISPPD2A at 15q15.3; p=3.27×10(-18) and 1.28×10(-14)). These explained 17.14% of the variations in CA19-9, 8.95% in CEA and 0.57% in AFP concentrations. Significant ABO variants were also associated with risk of OSCC and pancreatic cancers, and AFP variants with risk of hepatocellular cancer (p<0.05). CONCLUSIONS: This study identified several loci associated with CA19-9, CEA and AFP concentrations. The ABO variants were associated with risk of OSCC and pancreatic cancers and AFP variants with risk of hepatocellular cancer.

A genome-wide association study for serum bilirubin levels and gene-environment interaction in a Chinese population.

Bilirubin is an effective antioxidant and is influenced by both genetic and environmental factors. Recent genome-wide association studies (GWAS) have identified multiple loci affecting serum total bilirubin levels. However, most of the studies were conducted in European populations and little attention has been devoted either to genetic variants associated with direct and indirect bilirubin levels or to the gene-environment interactions on bilirubin levels. In this study, a two-stage GWAS was performed to identify genetic variants associated with all types of bilirubin levels in 10,282 Han Chinese individuals. Gene-environment interactions were further examined. Briefly, two previously reported loci, UGT1A1 on 2q37 (rs6742078 and rs4148323, combined P = 1.44 × 10(-89) and P = 5.05 × 10(-69) , respectively) and SLCO1B3 on 12p12 (rs2417940, combined P = 6.93 × 10(-19) ) were successfully replicated. The two loci explained 9.2% and 0.9% of the total variations of total bilirubin levels, respectively. Ethnic genetic differences were observed between Chinese and European populations. More importantly, a significant interaction was found between rs2417940 in SLCO1B3 gene and smoking on total bilirubin levels (P = 1.99 × 10(-3) ). Single nucleotide polymorphism (SNP) rs2417940 had stronger effects on total bilirubin levels in nonsmokers than in smokers, suggesting that the effects of SLCO1B3 genotype on bilirubin levels were partly dependent on smoking status. Consistent associations and interactions were observed for serum direct and indirect bilirubin levels.

Polycyclic aromatic hydrocarbons-associated microRNAs and their interactions with the environment: influences on oxidative DNA damage and lipid peroxidation in coke oven workers.

We previously identified five polycyclic aromatic hydrocarbons (PAHs)-associated microRNAs (miRNAs) and found they were associated with chromosome damage. As oxidative damage is the common contributory cause of various PAHs-related diseases, we further investigated the influences of these miRNAs and their interactions with environmental factors on oxidative DNA damage and lipid peroxidation. We measured PAHs internal exposure biomarkers [urinary monohydroxy-PAHs (OH-PAHs) and plasma benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydotetrol-albumin (BPDE-Alb) adducts], the expression levels of PAHs-associated plasma miRNAs (miR-24-3p, miR-27a-3p, miR-142-5p, miR-28-5p, and miR-150-5p), and urinary biomarkers of oxidative DNA damage [8-hydroxydeoxyguanosine (8-OH-dG)] and lipid peroxidation [8-iso-prostaglandin-F2α (8-iso-PGF2α)] in 365 healthy male coke oven workers. These miRNAs were associated with a dose-response increase in 8-OH-dG (ß > 0), and with a dose-response decrease in 8-iso-PGF2α (ß < 0), especially in workers with lower PAHs exposure levels, in nonsmokers, and in nondrinkers. These miRNAs interacted antagonistically with ΣOH-PAHs and BPDE-Alb adducts (ßinteraction < 0) and synergistically with drinking status (ßinteraction > 0) to influence 8-OH-dG, while they interacted synergistically with BPDE-Alb adducts (ßinteraction > 0) and antagonistically with smoking status (ßinteraction < 0) to influence 8-iso-PGF2α. Our results suggested that miRNAs and their interactions with environmental factors might be novel mechanisms mediating the effects of PAHs exposure on oxidative DNA damage and lipid peroxidation.

[Analysis on the association of single nucleotide polymorphism in the promoter region of pre-miR-320b-2 with coronary heart disease risk and factors influencing circulating microRNA-320b level].

OBJECTIVE: To investigate the effects of rs10916581, a common single nucleotide polymorphism (SNP) located in the promoter region of pre-miR-320b-2, on coronary heart disease (CHD) risk and circulating microRNA-320b (miR-320b) level. To explore potential factors influencing circulating miR-320b level. METHODS: Rs10916581 was genotyped in a case-control study with 1 507 CHD cases and 1 379 age- and sex-frequency-matched controls. The cases were consecutively recruited from 3 hospitals (Tongji Hospital, Union Hospital, and Wugang Hospital) in Wuhan city (Hubei, China) between May 2004 and October 2009 and all the controls resided in Wuhan communities. A subgroup of 174 CHD cases and 181 non-diabetes controls without acute infection were randomly selected and their circulating miR-320b levels were detected using quantitative reverse transcriptase polymerase chain reaction assays. The association of rs10916581 with CHD susceptibility was analyzed with multivariable logistic regression model. Generalized linear regression model was used to explore the associations of rs10916581 and some other factors with circulating miR-320b level. RESULTS: In single-factor logistic regression analysis, no association was found between rs10916581 and CHD risk. After adjustment for age, sex, BMI, smoking status, hypertension, diabetes, total triglyceride, total cholesterol/high density lipoprotein (TC/HDL-C), the result did not materially alter(compared with CC genotype, the OR (95%CI) of CHR in the subjects carried CT, TT, CT+TT genotypes were 0.94 (0.76-1.15), 0.99 (0.74-1.33) and 0.95 (0.78-1.16) ). No significant interactions were observed between the conventional risk factors of CHD (age, gender, smoking status, BMI, hypertension, diabetes, CHD family history) and rs10916581 on CHD risk (P > 0.05). Rs10916581 showed no significant association with circulating miR-320b level in cases, controls or total population (ß(95%CI) was -0.028 (-0.495-0.440), 0.250 (-0.226-0.727) and 0.134 (-0.218-0.486) respectively, P > 0.05). However, circulating miR-320b level was negatively associated with BMI (ß (95%CI) was -0.140 (-0.261--0.020), P = 0.022) while positively associated with TC/HDL(ß (95%CI) was 0.620 (0.261-0.979), P = 0.001) in cases, and in total population, its circulating level tended to be lower in diabetes or hypertension patients (ß(95%CI) was -1.025 (-1.696--0.354) and -0.594 (-1.138--0.049) respectively, P = 0.003, 0.033 respectively) and was positively associated with TC/HDL-C (ß(95%CI) was 0.108 (0.027-0.190), P = 0.009). CONCLUSION: The common SNP (rs10916581) in the promoter region of pre-miR-320b-2 might have little contribution to the CHD predisposition in Chinese Han population, and it might not affect circulating miR-320b level. Conventional CHD risk factors (BMI, TC/HDL-C, hypertension and diabetes) might have effects on its circulating level.

Lifestyle factors modified the mediation role of liver fibrosis in the association between occupational physical activity and blood pressure.

Objectives: The study aimed to estimate the role of liver fibrosis in the association between occupational physical activity (OPA) and blood pressure (BP), which is modified by lifestyle factors. Methods: The questionnaire survey and physical examination were completed among 992 construction workers in Wuhan, China. Associations between OPA or lifestyle factors and liver fibrosis indices and blood pressure were assessed using generalized additive models. The mediation analysis was used to evaluate the role of liver fibrosis in the association between OPA and lifestyle factors and BP. Results: Moderate/high OPA group workers had an increased risk of liver fibrosis [odds ratio (OR) = 1.69, 95% confidence intervals (CI): 1.16-2.47, P < 0.05] compared with low OPA group workers. Smoking or drinking alcohol was related to liver fibrosis (aspartate aminotransferase to platelet ratio index: OR = 2.22, 95% CI: 1.07-4.62 or OR = 2.04, 95% CI: 1.00-4.15; P < 0.05). Compared with non-drinkers, drinkers were related to a 2.35-mmHg increase in systolic blood pressure (95% CI: 0.09-4.61), and a 1.60-mmHg increase in diastolic blood pressure (95% CI: 0.08-3.13; P < 0.05). We found a significant pathway, "OPA → liver fibrosis → blood pressure elevation," and lifestyle factors played a regulatory role in the pathway. Conclusion: OPA or lifestyle factors were associated with liver fibrosis indices or BP in construction workers. Furthermore, the association between OPA and BP may be partially mediated by liver fibrosis; lifestyle factors strengthen the relationship between OPA and BP and the mediation role of liver fibrosis in the relationship.

Occupational noise and genetic variants in stress hormone biosynthesis-based genes and rates of blood lipid changes in China: A five-year longitudinal study.

Lipid profiles are influenced by both noise and genetic variants. However, little is known about the associations of occupational noise and genetic variants with age-related changes in blood lipids, a crucial event in the initiation and evolution of atherosclerotic cardiovascular diseases. We aimed to evaluate the associations of blood lipid change rates with occupational noise and genetic variants in stress hormone biosynthesis-based genes. This cohort was established in 2012 and 2013 and was followed up until 2017. A total of 952 participants were included in the final analysis and all of them were categorized to two groups, the exposed group and control group, according to the exposed noise levels in their working area. Single nucleotide polymorphisms (SNPs) in stress hormone biosynthesis-based genes were genotyped. Five physical examinations were conducted from 2012 to 2017 and lipid measurements were repeated five times. The estimated annual changes (EACs) of blood lipid were calculated as the difference in blood lipid levels between any 2 adjacent examinations divided by their time interval (year). The generalized estimating equations for repeated measures analyses with exchangeable correlation structures were used to evaluate the influence of exposing to noise (versus being a control) and the SNPs mentioned above on the EACs of blood lipids. We found that the participants experienced accelerated age-related decline in high-density lipoprotein cholesterol (HDL-C) levels as they were exposed to noise (ß = -0.38, 95% confidence interval (CI), -0.66 to -0.10, P = 0.007), after adjusting for work duration, gender, smoking, alcohol consumption, and pack-years. This trend was only found in participants with COMT-rs165815 TT genotype (ß = -1.19, 95% CI, -1.80 to -0.58, P < 0.001), but not in those with the CC or CT genotypes. The interaction of noise exposure and rs165815 was marginally significant (Pinteraction = 0.010) after multiple adjustments. Compared with DDC-rs11978267 AA genotype carriers, participants carrying rs11978267 GG genotype had decreased EAC of triglycerides (TG) (ß = -5.06, 95% CI, -9.07 to -1.05, P = 0.013). Participants carrying DBH-rs4740203 CC genotype had increased EAC of total cholesterol (TC) (ß = 1.19, 95% CI, 0.06 to 2.33, P = 0.039). However, these findings were not statistically significant after multiple adjustments. These results indicated that Occupational noise exposure was associated with accelerated age-related decreases in HDL-C levels, and the COMT-rs165815 genotype appeared to modify the effect of noise exposure on HDL-C changes among the occupational population.

Genome-wide association study on serum alkaline phosphatase levels in a Chinese population.

BACKGROUND: Serum alkaline phosphatase (ALP) is a complex phenotype influenced by both genetic and environmental factors. Recent Genome-Wide Association Studies (GWAS) have identified several loci affecting ALP levels; however, such studies in Chinese populations are limited. We performed a GWAS analyzing the association between 658,288 autosomal SNPs and serum ALP in 1,461 subjects, and replicated the top SNPs in an additional 8,830 healthy Chinese Han individuals. The interactions between significant locus and environmental factors on serum ALP levels were further investigated. RESULTS: The association between ABO locus and serum ALP levels was replicated (P = 2.50 × 10⁻²¹, 1.12 × 10⁻56 and 2.82 × 10⁻²7 for SNP rs8176720, rs651007 and rs7025162 on ABO locus, respectively). SNP rs651007 accounted for 2.15% of the total variance of serum ALP levels independently of the other 2 SNPs. When comparing our findings with previously published studies, ethnic differences were observed across populations. A significant interaction between ABO rs651007 and overweight and obesity was observed (FDR for interaction was 0.036); for individuals with GG genotype, those with normal weight and those who were overweight or obese have similar serum ALP concentrations; minor allele A of rs651007 remarkably reduced serum ALP levels, but this effect was attenuated in overweight and obese individuals. CONCLUSIONS: Our findings indicate that ABO locus is a major determinant for serum ALP levels in Chinese Han population. Overweight and obesity modifies the effect of ABO locus on serum ALP concentrations.

Association between serum uric acid and the metabolic syndrome among a middle- and old-age Chinese population.

Our aim was to study whether there is causal association between serum uric acid and metabolic syndrome (MetS). A cross-sectional study was performed, including a total of 27,009 subjects (23,345 subjects having uric acid data) from the Dongfeng-Tongji Cohort study. The MetS was defined by the International Diabetes Foundation criteria of 2005. Association analysis was performed by logistic regression. A genetic risk score was calculated by adding the uric acid increasing alleles in two SNPs (rs11722228 in SLC2A9 and rs2231142 in ABCG2) which were identified from our genome-wide association study on uric acid levels. The causal association was examined by mendelian randomization analysis. Among a middle- and old-age Chinese population, serum uric acid concentrations were strongly associated with the risk of MetS and its several components (P < 0.0001). The effects were stronger in women than in men. Despite the lack of statistical significance, both SNPs exhibited a trend with increased MetS risk (rs11722228, OR = 1.06, 95 % CI 0.99-1.14; rs2231142, OR = 1.02, 95 % CI 0.95-1.10), consistent with their increasing uric acid effects. Each additional uric acid increasing allele in the genetic risk score was associated with 3 % increased MetS risk (OR = 1.03, 95 % CI 0.98-1.09; P = 0.23). Further adjustment for serum uric acid attenuated the trend of individual SNP and genetic risk score with increased MetS risk (all OR < 1.0). These findings suggested that serum uric acid was associated with MetS risk in a middle- and old-age Chinese population. Whether this association was causal remained to be investigated in the future studies.

[Association between genetic polymorphisms in pre-miR-146a and pre-miR-196a2 and genetic damage levels among coke oven workers].

OBJECTIVE: To investigate the association of rs2910164 G > C polymorphism and rs11614913 T > C polymorphism in pre-miR-146a and pre-miR-196a2 with genetic damage levels in coke oven workers. METHODS: A total of 575 nonsmoking workers who have worked for more than one year in a coke-oven plant at Wuhan, Hubei Province were enrolled in this study in September to October, 2010. The general characteristics as well as blood and urine samples were collected. The genetic damage levels were detected by cytokinesis-block micronucleus cytom assay and represented as micronucleus (MN) frequencies of binucleate cells in peripheral blood lymphocytes. The rs2910164 G > C polymorphisms in pre-miR-146a and rs11614913 T > C polymorphisms in pre-miR-196a2 were genotyped by using TaqMan assay. The plasma concentrations of benzo[a]pyrene-diolepoxide (BPDE)-albumin adducts were determined by using ELISA. All data were analyzed, the frequency ratio (FR) and 95%CI were calculated. RESULTS: Totally, 575 workers were taken into consideration. The rs2910164 C allele was associated with increased MN frequencies in the coke oven workers (P trend = 0.025), and the MN frequencies were higher in rs2910164 CC genotype carriers (4.38 ± 3.46) than in wild-type rs2910164 GG genotype carriers (4.02 ± 3.09) (FR = 1.18, 95%CI:1.04-1.34). The further stratified analyses by working years, gender, alcohol consumption, and the levels of BPDE-albumin adducts showed that the effects of rs2910164 C allele in increasing MN frequencies were robust in subjects who were males (FR = 1.11, 95%CI:1.02-1.20), nondrinkers (FR = 1.07, 95%CI:1.00-1.14), working years less than 20 (FR = 1.12, 95%CI:1.03-1.22), and workers with lower BPDE-albumin adducts levels (FR = 1.11, 95%CI:1.02-1.21) (P trend = 0.011, 0.044, 0.006 and 0.020, respectively). In addition, the MN frequencies were higher in workers with rs11614913 TC genotype (4.27 ± 2.91) than workers with rs11614913 TT genotype (3.90 ± 3.32) (FR = 1.12, 95%CI:1.02-1.23).Workers carried both rs2910164 GG and rs11614913 TT genotypes were set as a control, and the MN frequencies of workers with both rs2910164 CC and rs11614913 CC genotypes (5.32 ± 4.94) were 1.51 (1.21-1.89) times higher than the control (3.75 ± 3.01). CONCLUSION: The rs2910164 C allele in pre-miR-146a and rs11614913 C allele in pre-miR-196a2 were associated with increased genetic damage levels in coke oven workers.

[Using the stable HSPA1A promoter-driven luciferase reporter HepG2 cells to assess the overall toxicity of coke oven emissions].

OBJECTIVE: Using the stable HSPA1A (HSP70-1) promoter-driven luciferase reporter HepG2 cells (HepG2/HSPA1A cells) to assess the overall toxicity of coke oven emissions. METHODS: The stable HepG2/HSPA1A cells were treated with different concentrations of coke oven emissions (COEs) collected from the top, side, and bottom of a coke oven battery for 24 h. After the treatments, luciferase activity, cell viability, malondialdehyde (MDA) concentration, Olive tail moment, and micronuclei frequency were determined, respectively. RESULTS: The bottom COEs induced significant increases (P < 0.01) in relative luciferase activity up to 1.4 times the control level at 0.15 µg/L. The low dose of side COEs (0.02 µg/L) led to a significant increase (P < 0.01) in relative luciferase activity that progressively increased to 2.1 times the control level at 65.4 µg/L. The top COEs produced a strong dose-dependent induction of relative luciferase activity up to over 5 times the control level at the highest concentration tested (202 µg/L). In HepG2/HSPA1A cells treated with the bottom COEs, relative luciferase activity was positively correlated with MDA concentration (r = 0.404, P < 0.05). For the three COEs samples, positive correlations were observed between relative luciferase activity and Olive tail moment and micronuclei frequency. CONCLUSION: The relative luciferase activity in HepG2/HSPA1A cells can sensitively reflect the overall toxicity of COEs. The stable HepG2/HSPA1A cells can be used for rapid screening of the overall toxicity of complex air pollutants in the workplace.

Risk for lung-related diseases associated with welding fumes in an occupational population: Evidence from a Cox model.

Background: Welding fumes are a risk factor for welder pneumoconiosis. However, there is a lack of population information on the occurrence of welding fume-induced lung cancer, and little is known about the welding fume pathogenesis. Methods: Welding fume and metal ion concentrations were assessed in a vehicle factory in Wuhan. A Cox regression model estimated lung-related disease risk in workers by independent and combined factors. Results: Workers' exposures were divided into four grades; the highest exposure was among the welders in the maintenance workshop, the highest Mn and Fe exposure was 4 grades, and the highest Cr exposure was 3 grades. Subgroup analysis found that the risk of lung-related disease was 2.17 (95% CI: 1.31-3.57, p < 0.05) in welders compared with non-welders, and the risk of pulmonary disease in male welders was 2.24 (95% CI: 1.34-3.73, p < 0.05) compared to non-welders. Smoking welders had a 2.44 (95% CI: 1.32-4.51, p < 0.01) higher incidence of lung-related diseases than non-welders. Total years of work as an independent protective factor for lung-related disease risk was 0.72 (95% CI: 0.66-0.78, p < 0.01). As an independent risk factor, high-high and high-low exposure had a 5.39 (95% CI: 2.52-11.52, p < 0.001) and 2.17 (95% CI: 1.07-4.41, p < 0.05) higher risk for lung-related diseases, respectively. Conclusions: High welding fume exposure is a significant risk factor for lung-related disease in workers.

Stress hormone biosynthesis-based genes and lifestyle moderated the association of noise exposure with blood pressure in a cohort of Chinese tobacco factory workers: A cross-sectional analysis.

When evaluating noise-related cardiovascular risk, noise is generally solely assessed as the major stressor. However, cardiovascular effect of other simultaneous exposure events, such as unhealthy lifestyle and genetic variation, is easily neglected. The aim of this study is to estimate the combined effect of noise and lifestyle on blood pressure alteration, particularly under different genetic background. This study included 536 workers from a tobacco factory in Wuhan, China, who were divided into high exposure group and low exposure group according to noise measurement in their working area. All participants took annual physical examination and questionnaire survey to provide information on individual systolic and diastolic blood pressure (SBP and DBP) and lifestyle (smoking, drinking and physical activity). Single nucleotide polymorphism at genes related to stress hormone production were determined. Moderated moderation models were constructed to investigate the interaction effect of noise exposure and lifestyle factors on blood pressure with regard to different genetic background. We identified an expected trend in association between noise exposure and SBP among active smokers (P = 0.086). The moderated moderation analysis showed significant three-way interaction effect (COMT rs4680 × smoking status × noise exposure levels) on SBP or DBP (both P < 0.05). For COMT rs4680 GA+AA genotype carriers, active smoking significantly moderated the association between noise exposure and SBP or DBP (both P < 0.05). The results indicated that for COMT rs4680 A allele carriers, tobacco and noise exposure contribute collectively to blood pressure alteration, supporting that stress hormone production may play a certain role in the smoke-and-noise-induced cardiovascular effect.

Is job strain associated with a higher risk of type 2 diabetes mellitus? A systematic review and meta-analysis of prospective cohort studies.

OBJECTIVES: Epidemiological studies have explored the relationship between work-related stress and the risk of type 2 diabetes mellitus (T2DM), but it remains unclear on whether work-related stress could increase the risk of T2DM. We aimed to evaluate the association between job strain and the risk of T2DM. METHODS: We searched PubMed and Web of Science up to April 2019. Summary risk estimates were calculated by random-effect models. And the analysis was also conducted stratifying by gender, study location, smoking, drinking, body mass index, physical activity, family history of T2DM, education and T2DM ascertainment. Studies with binary job strain and quadrants based on the job strain model were analyzed separately. RESULTS: A total of nine studies with 210 939 participants free of T2DM were included in this analysis. High job strain (high job demands and low control) was associated with the overall risk of T2DM compared with no job strain (all other combinations) [relative risk (RR) 1.16, 95% confidence interval (CI) 1.03-1.31], and the association was more evident in women (RR 1.48, 95% CI 1.02-2.14). A statistically significant association was also observed when using high strain as a category (job strain quadrants) rather than binary variable (RR 1.62, 95% CI 1.04-2.55) in women but not men. CONCLUSIONS: Our study suggests that job strain is an important risk factor for T2DM, especially among women. Appropriate preventive interventions in populations with high job strain would contribute to a reduction in T2DM risk.

Association of occupational noise exposure, bilateral hearing loss with atherosclerotic cardiovascular disease risk in Chinese adults.

We aimed to explore the association of occupational noise exposure with atherosclerotic cardiovascular disease (ASCVD) risk in Chinese adults. We included 21,412 participants from the Dongfeng-tongji Cohort Study, occupational noise exposure was evaluated through workplace noise level and/or the job titles, hearing loss was defined as a pure-tone mean of 25 dB or higher at 0.5, 1, 2, and 4 kHz in any ear. Compared with participants without occupational noise exposure, the 10-year ASCVD risk was significantly higher for noise exposure duration ≥20 years (OR = 1.20, 95%CI = 1.05-1.32) after adjusting for potential confounders. In the subgroup analysis, the association was only statistically significant in males (OR = 1.86, 95%CI = 1.12-3.14) and participants aged equal to or over 60 years old (OR = 1.20, 95%CI = 1.05-1.33), but not in females (OR = 1.15, 95%CI = 0.71-1.92) and aged below 60 (OR = 1.51, 95%CI = 0.75-2.85). In the subsample analyses (N = 10,165), bilateral hearing loss was associated with a higher risk of 10-year ASCVD (OR = 1.72, 95%CI = 1.30-2.30), especially for participants who were males (OR = 2.40, 95%CI = 1.61-3.42) and aged equal to or over 60 (OR = 1.85, 95%CI = 1.40-2.44). The present study suggests that occupational noise exposure may be a potential risk factor for ASCVD, especially for males and older participants.

Association of urinary metal profiles with serum uric acid: a cross-sectional study of traffic policemen in Wuhan, China.

OBJECTIVES: Serum uric acid (SUA) is both a strong antioxidant and one of the key risk factors of cardiovascular diseases (CVDs). We aimed to investigate the associations of urinary metal profile with SUA in traffic policemen in Wuhan, China. DESIGN: A cross-sectional study was carried out in traffic policemen. SETTING: A seriously polluted Chinese city. PARTICIPANTS: A total of 186 traffic policemen were recruited in this study. About 56 of them worked in the logistics department and the other 130 maintained traffic order or dealt with traffic accidents on the roads. All these subjects had worked as a policeman for at least 1 year. MAIN OUTCOME MEASURES: SUA. RESULTS: The significantly negative association of lead with SUA was consistent between single-metal and multiple-metal models (p=0.004 and p=0.020, respectively). Vanadium, chromium and tin were reversely associated with SUA levels in the single-metal models after false discovery rate (FDR) adjustment (all P_FDR < 0.05). One IQR increase in vanadium, chromium, tin and lead was associated with 26.9 µmol/L (95% CI -44.6 to -9.2; p=0.003), 27.4 µmol/L (95% CI -46.1 to -8.8; p=0.004), 11.2 µmol/L (95% CI -18.9 to -3.4; p=0.005) and 16.4 µmol/L (95% CI -27.6 to -5.2; p=0.004) decrease in SUA, respectively. Significant interaction between smoking and vanadium on decreased SUV was found (pfor interaction = 0.007 and p_FDR = 0.028). CONCLUSIONS: Urinary vanadium, chromium, tin and lead were negatively associated with SUA. Vanadium and cigarette smoking jointly affected SUA levels. Further studies are needed to replicate these findings and to investigate the potential mechanisms.

Co-exposure to metals and polycyclic aromatic hydrocarbons, microRNA expression, and early health damage in coke oven workers.

BACKGROUND: All humans are now co-exposed to multiple toxic chemicals, among which metals and polycyclic aromatic hydrocarbons (PAHs) are of special concern as they are often present at high levels in various human environments. They can also induce similar early health damage, such as genetic damage, oxidative stress, and heart rate variability (HRV). Exposure to metals, PAHs, and their combined pollutants can alter microRNA (miRNA) expression patterns. OBJECTIVES: To explore the associations of metal-PAH co-exposure with miRNA expression, and of the associated miRNAs with early health damage. METHODS: We enrolled 360 healthy male coke oven workers and quantified their exposure levels of metals and PAHs by urinary metals, urinary monohydroxy-PAHs (OH-PAHs), and plasma benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydotetrol-albumin (BPDE-Alb) adducts, respectively. We selected and measured ten miRNAs: let-7b-5p, miR-126-3p, miR-142-5p, miR-150-5p, miR-16-5p, miR-24-3p, miR-27a-3p, miR-28-5p, miR-320b, and miR-451a. For miRNAs influenced by the effect modification of metals or PAHs and/or metal-PAH interactions, we further evaluated their associations with biomarkers for genetic damage, oxidative stress, and HRV. RESULTS: After adjusting for PAHs and other metals, miRNA expression was found to be negatively associated with aluminum, antimony, lead, and titanium, and positively associated with molybdenum and tin (p < 0.05). Antimony showed modifying effects on the PAH-miRNA associations, while OH-PAHs and BPDE-Alb adducts modified the associations of metals with miRNAs (p for modifying effect < 0.05). Furthermore, miRNA expression was influenced by the antagonistic interactions between antimony and OH-PAHs, and by the synergistical interactions between metals and BPDE-Alb adducts (pinteraction < 0.05). Let-7b-5p, miR-126-3p, miR-16-5p, and miR-320b were additionally found to be associated with increased genetic damage in the present study [false discovery rate (FDR)-adjusted p < 0.05]. CONCLUSIONS: Associations of metal-PAH co-exposure with miRNA expression, and of associated miRNAs with early health damage, suggested potential mechanistic connections between the complex metal-PAH interactions and their deleterious effects that are worthy of further investigation.

Polycyclic Aromatic Hydrocarbons-Associated MicroRNAs and Heart Rate Variability in Coke Oven Workers.

OBJECTIVE: We aimed to evaluate the association between polycyclic aromatic hydrocarbons (PAHs)-related microRNAs (miRNAs) and heart rate variability indices in coke oven workers. METHODS: We recruited 365 male coke oven workers and measured urinary PAH metabolites by gas chromatography-mass spectrometry. Five heart rate variability indices were measured using three-channel Holter monitor. Six miRNAs were detected by TaqMan miRNA assays (Life Technologies, Foster City, CA). RESULTS: miR-24-3p, miR-27a-3p, miR-142-5p, and miR-320b were negatively associated with the root mean of square of successive differences between adjacent normal NN intervals (RMSSD) (P(trend) = 0.006, 0.047, 0.019, 0.011, respectively). miR-142-5p and miR-320b were also negatively associated with standard deviation of all normal to normal NN intervals (SDNN) (P(trend) = 0.01 and 0.035). miR-24-3p, miR-27a-3p, and miR-320b were significantly interacted with multiple PAH metabolites and influenced heart rate variability indices, whereas miR-24-3p also significantly interacted with smoking to influence low frequency (P(interaction) < 0.05 for all). CONCLUSIONS: Plasma miRNAs might act as potential biomarkers for the adverse effect of PAH exposure on the cardiovascular system.

Exposure to Polycyclic Aromatic Hydrocarbons, Plasma Cytokines, and Heart Rate Variability.

Epidemiological studies have suggested associations between polycyclic aromatic hydrocarbons (PAHs) and heart rate variability (HRV). However, the roles of plasma cytokines in these associations are limited. In discovery stage of this study, we used Human Cytokine Antibody Arrays to examine differences in the concentrations of 280 plasma cytokines between 8 coke-oven workers and 16 community residents. We identified 19 cytokines with significant different expression (fold change ≥2 or ≤-2, and q-value <5%) between exposed workers and controls. 4 cytokines were selected to validate in 489 coke-oven workers by enzyme-linked immunosorbent assays in validation stage. We found OH-PAHs were inversely associated with brain-derived neurotrophic factor (BDNF) (p < 0.05), and interquartile range (IQR) increases in OH-PAHs were associated with >16% BDNF decreases. Additionally, OH-PAHs were positively associated with activated leukocyte cell adhesion molecule (ALCAM) and C-reactive protein (CRP) (p < 0.05), and IQR increases in OH-PAHs were associated with >20% increases in CRP. We also found significant associations between these cytokines and HRV (p < 0.05), and IQR increases in BDNF and CRP were associated with >8% decreases in HRV. Our results indicated PAH exposure was associated with plasma cytokines, and higher cytokines were associated with decreased HRV, but additional human and potential mechanistic studies are needed.