Genome-wide association study identifies TPH2 variant as a novel locus for severe CV-A6-associated hand, foot, and mouth disease in Han Chinese.

BACKGROUND: Little is known about the association between genetic susceptibility and the severity of hand, foot, and mouth disease (HFMD) infected with coxsackievirus A6 (CV-A6). METHODS: Three hundred and sixty-four CV-A6 HFMD patients were enrolled, including 115 severe and 249 mild patients. A genome-wide association study (GWAS) was performed involving eight DNA pools of 115 severe and 115 mild CV-A6 HFMD patients pair-matched by age and gender. Differences in relative allele signal scores of SNPs in Illumina Human OmniZhongHua-8 BeadChips were compared between the two groups. The tag SNPS for potentially functional SNPs or their high linked SNPs were selected for individual genotyping in all 364 patients and assessed for their associations with severe CV-A6 HFMD using multivariable logistic regression analyses. RESULTS: The top 30 significant SNPs obtained from pooled DNA GWAS analysis were checked for biological functions and their high linkage disequilibrium (LD) SNPs. Four tag SNPs (rs1558206, rs6927647, rs9375728 and rs10879355) were selected for further individual genotyping in 364 CV-A6 patients. Only SNP rs10879355 was associated with severe CV-A6 HFMD, with CC genotype having a greater risk of severe illness than TT+TC genotypes (OR=2.48, 95%CI: 1.34, 4.56). SNP rs4290270 is in complete LD with rs10879355 in Chinese Han children. CONCLUSIONS: This is the first report that one potentially functional SNP rs4290270 in the TPH2 gene may be associated with the risk of severe CV-A6 HFMD.

Mediation of the association between polycyclic aromatic hydrocarbons exposure and telomere attrition by oxidative stress: A prospective cohort study.

Previous studies have reported associations between polycyclic aromatic hydrocarbons (PAHs) exposure and telomere attrition, but the underlying mechanisms remain to be elucidated. This study aimed to explore the mediation role of oxidative stress on the effects of PAHs exposure on telomere attrition in a cohort study of 1180 coke-oven workers. We determined baseline urinary concentrations of ten urinary PAH metabolites, two oxidative stress biomarkers [8-hydroxydeoxyguanosine (8-OHdG) and 8-iso-prostaglandin-F2α (8-isoPGF2α)] and peripheral leukocytes telomere length (TL) in both baseline and follow-up visits. Mediation analysis was applied to assess effects of oxidative stress biomarkers on the PAHs-TL attrition associations. The baseline 8-OHdG had a significant dose-response relationship with TL decline [ß(95 %CI) = 0.07(0.03-0.12), P = 0.001] and TL ratio [ß(95 %CI)]=0.07 (0.02-0.12), P = 0.003]. Mediation analyses indicated that 8-OHdG mediated a separate 39.1 %, 47.0 %, 43.3 %, and 58.0 % of the associations between 1-hydroxynaphthalene (1-OHNa), 2-OHNa, ΣOHNa, 1-hydroxypyrene (1-OHP) and TL decline (P = 0.016, 0.008, 0.012, and 0.014, respectively). Additionally, 8-OHdG mediated a separate 44.8 %, 49.4 %, 49.2 %, and 35.5 % of the associations between 1-OHNa, 2-OHNa, ΣOHNa, 1-OHP and TL ratio (P = 0.012, 0.008, 0.012, and 0.046, respectively). Our study proposed the positive association of 8-OHdG with TL attrition and revealed the mediation roles of 8-OHdG in PAHs-TL attrition associations.

Co-exposure to multiple metals, TERT-CLPTM1L variants, and their joint influence on leukocyte telomere length.

OBJECTIVE: Telomere is required for maintaining chromosome stability and genome integrity, while telomere length is sensitive to environmental stressors. We aimed to identify the effects of multiple metals co-exposure as well as their joint effects with TERT-CLPTM1L variants on leukocyte telomere length (LTL). METHODS: This study included 842 workers from a coke-oven plant, of whom plasma concentrations of 23 metals and LTL were determined. Genetic variations in TERT-CLPTM1L were genotyped by using the Global Screening Array. Multipollutant-based statistical methods, including the Bonferroni-correction, backward elimination procedure, and LASSO penalized regression analysis, were used to select the LTL-associated metals. Generalized linear regression models were used to evaluate the joint effects of TERT-CLPTM1L variants with positive metal on LTL. RESULTS: Each 1% increase in plasma concentration of manganese (Mn) was significantly associated with a 0.153% increase in LTL [ß(95%CI) = 0.153(0.075, 0.230), P < 0.001] in single-metal models after Bonferroni-correction. The multiple-metal models and the LASSO penalized regression analysis both indicated Mn as the sole significant predictor for LTL. Furthermore, 5 tagSNPs (rs33954691, rs6554759, rs465498, rs2455393, and rs31489) in TERT-CLPTM1L with high plasma Mn (>4.21 µg/L) showed joint effects on increasing LTL. CONCLUSIONS: Our study revealed the independent and positive association between plasma Mn and LTL when accounting for co-exposure to other metals. This effect can be further enhanced by TERT-CLPTM1L variants. These results may advance our understanding of the complex interplay between genetic and environmental factors on telomere length. Further experimental studies are warranted to elucidate the underlying mechanisms.

Polycyclic aromatic hydrocarbons exposure and their joint effects with age, smoking, and TCL1A variants on mosaic loss of chromosome Y among coke-oven workers.

Mosaic loss of chromosome Y (mLOY) is the most common structure somatic event that related to increased risks of various diseases and mortality. Environmental pollution and genetic susceptibility were important contributors to mLOY. We aimed to explore the associations of polycyclic aromatic hydrocarbons (PAHs) exposure, as well as their joint effects with age, smoking, and genetic variants on peripheral blood mLOY. A total of 1005 male coke-oven workers were included in this study and their internal PAHs exposure levels of 10 urinary PAH metabolites and plasma benzo[a]pyrene-r-7,t-8,t-9,c-10-tetrahydotetrol-albumin (BPDE-Alb) adducts were measured. mLOY was defined by the median log R ratio(mLRR) of 1480 probes in male-specific region of chromosome-Y from genotyping array. We found that the PAHs exposure levels were linearly associated with mLOY. A 10-fold increase in urinary 1-hydroxynaphthalene (1-OHNa), 1-hydroxyphenanthrene (1-OHPh), 2-OHPh, 1-hydroxypyrene (1-OHP), ΣOH-PAHs, and plasma BPDE-Alb adducts could generate 0.0111, 0.0085, 0.0069, 0.0103, 0.0134, and 0.0152 decrease in mLRR-Y, respectively. Additionally, mLOY accelerated with age, smoking pack-years, and TCL1A rs1122138-C allele, and we observed the most severe mLOY among subjects carrying more than 3 of the above risk factors. Our results revealed the linear dose-effect associations between PAHs exposure and mLOY. Elder male smokers carrying rs1122138CC genotype were the most susceptible subpopulations to mLOY, who should be given protections for PAHs exposure induced chromosome-Y aberration.

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.

Circulating essential metals and lung cancer: Risk assessment and potential molecular effects.

OBJECTIVE: Essential metals play important roles in the carcinogenic process. However, seldom longitudinal investigations have evaluated their roles in lung cancer development. We aimed to investigate the associations between multiple essential metals and lung cancer incidence and to explore the potential mechanisms. METHODS: A nested case-control study of 440 incident lung cancer cases and 1:3 frequency matched 1320 healthy controls from the Dongfeng-Tongji Cohort was conducted. The baseline plasma concentrations of 11 essential metals (cobalt, copper, iron, manganese, molybdenum, rubidium, selenium, strontium, stannum, vanadium, and zinc) were measured, and their associations with lung cancer incidence were estimated. Effect of positive metal (zinc) on 4-year telomere attrition was then evaluated among an occupational cohort of 724 workers. We also assessed the transcriptional regulation effects of plasma zinc on mRNA expression profiles, and the expressions of zinc-related genes were further compared in pair-wised lung tumor and normal tissues. RESULTS: Elevated plasma level of zinc was associated with lower incident risk of lung cancer [OR (95% CI) = 0.89 (0.79, 0.99)] and decreased 4-year telomere attrition [ß (95% CI) = -0.73 (-1.27, -0.19)]. These effects were pronounced among males. In particularly, zinc could regulate the expressions of 8 cancer-related genes, including SOD1, APE, TP53BP1, WDR33, LAPTM4B, TRIT1, HUWE1, and ZNF813, which were over-expressed in lung tumor tissues. CONCLUSIONS: We propose that high plasma zinc could prevent incident lung cancer, probably by slowing down telomere attrition and regulating the expressions of cancer-related genes. These results provided a new insight into lung cancer prevention.

Effect of thallium exposure and its interaction with smoking on lung function decline: A prospective cohort study.

BACKGROUND: Thallium (Tl) is a cumulative high toxicant in the environment, but few longitudinal studies have investigated the respiratory impairment of Tl exposure. OBJECTIVES: This study aimed to evaluate the effect of Tl and its interaction with smoking on lung function decline, and explore the potential mechanisms. METHODS: The baseline and follow-up lung functions were measured from a prospective cohort study of 1243 workers, who were followed from 2010 to 2014. Their baseline urinary levels of Tl were determined. We also measured the plasma C-reactive protein (CRP) and urinary 8-iso-prostaglandin-F2α (8-iso-PGF2α) in a randomly selected subcohort of 474 subjects. RESULTS: The results showed that a 2-fold increase in urinary Tl was associated with 29.81 mL (95%CI: 3.83-55.80) increased decline in forced expiratory volume in 1 s (FEV1). The effect was more pronounced among heavy-smokers (≥15 pack-years) [ß(95%CI) = 56.42 mL (9.66-103.19)]. In particular, compared to never-smokers with low Tl, heavy-smokers with high Tl had a separate 158.44 mL (95%CI: 54.88-262.00) and 4.58% (95%CI: 1.40-7.76) increased declines in FEV1 and percentage of predicted (ppFEV1), respectively. There was a significant interaction between Tl and smoking intensity on ppFEV1 decline (Pint = 0.034). More importantly, the increasing level of urinary Tl was correlated with elevated CRP and 8-iso-PGF2α. CONCLUSION: Our prospective cohort study identified that exposure to high Tl had a deleterious effect on lung function, and this effect may be enhanced by tobacco smoking. Increased inflammation may partly contribute to the joint effects of Tl and smoking on impaired lung function, but the biological mechanisms need further explorations.

Multiple metals exposure and chromosome damage: Exploring the mediation effects of microRNAs and their potentials in lung carcinogenesis.

OBJECTIVE: This study aimed to investigate the associations of multiple metals with chromosome damage, and further explore the mediation roles of microRNAs (miRNAs) and their potentials in lung cancer. METHODS: We determined the urinary levels of 23 metals, lymphocytic micronucleus (MN) frequency, and ten candidate miRNAs in plasma among 365 healthy workers. Poisson and linear regression models were conducted to analyze the associations of urinary metals with MN frequency and miRNAs, respectively. The mediation effects of miRNAs on the metal-MN frequency associations were assessed by causal mediation analysis. Additionally, the levels of effective metal and miRNAs were measured in 43 pair-wised tumor and normal lung tissues. RESULTS: The urinary level of titanium was inversely associated with MN frequency after Bonferroni correction [frequency ratio (FR) and 95% confidence interval (95%CI) = 0.88 (0.82, 0.94), p = 5.0 × 10-4]. A doubling in urinary titanium was associated with 14.72%-38.17% decrease in plasma miRNAs. After multiple comparison, miR-24-3p and miR-28-5p significantly mediated 24.8% (7.7%, 70.0%) and 20.4% (5.7%, 52.0%) of the association between titanium and MN frequency (pmediation = 0.002 and 0.004, respectively). Besides, a doubling in titanium was associated with a separate 53.4% and 47.2% decreased miR-24-3p and miR-28-5p expression in normal lung tissues. Lower titanium but higher levels of miR-24-3p and miR-28-5p were shown in tumor than normal tissues of lung squamous cell carcinoma patients (all p < 0.05). CONCLUSIONS: Our study proposed the negative associations of titanium with chromosome damage and lung cancer, and highlighted the mediating roles of miR-24-3p and miR-28-5p. Further investigations are warranted to validate these associations and uncover the underlying mechanisms.

The interaction effects of polycyclic aromatic hydrocarbons exposure and TERT- CLPTM1L variants on longitudinal telomere length shortening: A prospective cohort study.

Telomere length (TL) is an index of cellular aging and can predict the incidences of many age-related diseases. Change of TL might be affected by environmental pollution and individual's genetic background. In this cohort study, we aimed to evaluate the associations between polycyclic aromatic hydrocarbons (PAHs) exposure and longitudinal TL shortening, and investigate whether genetic variations in TERT-CLPTM1L can modify these associations. We measured the baseline concentrations of twelve urinary PAH metabolites and genotyped six variants at TERT-CLPTM1L among 1243 coke-oven workers. The relative leukocyte TL was detected in both baseline and follow-up (4 years later) visits. The TL shortening were estimated by TL decline and TL ratio. We found that the urinary level of 1-hydroxypyrene (1-OHP) had significant dose-response relationships with increased TL decline [ß(95%CI) = 0.078(0.023, 0.133), P = 0.005] and TL ratio [ß(95%CI) = 0.096(0.037, 0.155), P = 0.002]. Besides, urinary 1-hydroxynaphthalene (1-OHNa) was marginally dose-related with elevated TL decline [ß(95%CI) = 0.053(-0.001, 0.107), P = 0.055] and TL ratio [ß(95%CI) = 0.057(-0.002, 0.116), P = 0.058]. Analyses of TERT-CLPTM1L variants showed that the rs401681 and rs465498 could modify the effect of 1-OHP on increasing TL decline (Pinteraction = 0.012 and 0.035, respectively) and TL ratio (Pinteraction = 0.014 and 0.067, respectively), which were pronounced among rs401681TT and rs465498CC carriers, but not seen among rs401681TC + CC and rs465498CT + TT carriers. In conclusion, elevated exposure to PAHs can accelerate the TL shortening and this effect can be modified by TERT-CLPTM1L variants. These results may add potential evidence for gene-environment interactions on dynamic changes of telomere length. Further studies are warranted to validate these findings and uncover the underlying mechanisms.

Association of shift-work, daytime napping, and nighttime sleep with cancer incidence and cancer-caused mortality in Dongfeng-tongji cohort study.

BACKGROUND: Few studies investigated the combined effects of night-shift work, daytime napping, and nighttime sleep on cancer incidence and mortality. METHODS: A total of 25,377 participants were included in this study. Information on sleep habits, cancer incidences, and mortalities were collected. Cox proportional hazards models were used to calculate the adjusted hazard ratios and 95% confidence intervals (HRs, 95%CIs). RESULTS: Male subjects experienced ≥20 years of night-shift work, or without daytime napping had an increased risk of cancer, when compared with males who did not have night-shift work or napped for 1-30 min [HR (95%CI) = 1.27 (1.01-1.59) and 2.03 (1.01-4.13), respectively]. Nighttime sleep for ≥10 h was associated with a separate 40% and 59% increased risk of cancer [HR (95%CI) = 1.40 (1.04-1.88)] and cancer-caused mortality [HR (95%CI) = 1.59 (1.01-2.49)] than sleep for 7-8 h/night. Combined effects of three sleep habits were further identified. Male participants with at least two above risk sleep habits had a 43% increased risk of cancer [HR (95%CI) = 1.43 (1.07-2.01)] and a 2.07-fold increased cancer-caused mortality [HR (95%CI) = 2.07 (1.25-3.29)] than those who did not have any above risk sleep habits. However, no significant associations were observed among women. CONCLUSIONS: Long night-shift work history, without daytime napping, and long nighttime sleep duration were independently and jointly associated with higher cancer incidence among males. KEY MESSAGES Night-shift work of ≥20 years, without napping, and nighttime sleep of ≥10 h were associated with increased cancer incidence. Nighttime sleep ≥10 h was associated with a 2.07-fold increased cancer-caused mortality among males. Combined effects of night-shift work ≥20 years, without napping, and nighttime sleep ≥10 h on increasing cancer incidence were existed among males.