Person:

Su, Li

Background: Long-term occupational exposure to cotton dust that contains endotoxin is associated with chronic respiratory symptoms and excessive decline in forced expiratory volume in 1 sec (FEV1), but the mechanisms of endotoxin-related chronic airflow obstruction remain unclear. Objective: In the current study, we examined temporal aspects of the exposure–response relationship between airborne endotoxin exposure, longitudinal change in FEV1, and respiratory symptoms in a cohort of Chinese cotton textile workers. Methods: This prospective cohort study followed 447 cotton textile workers from 1981 to 2006.at approximately 5-year intervals. We used a generalized estimating equations approach to model FEV1 level and respiratory symptoms as a function of past exposure (cumulative exposure up to the start of the most recent 5-year survey interval) and cumulative exposure (within the most recent interval) to endotoxins, after adjusting for other covariates. Models were stratified by active versus retired work status and by years employed before the baseline survey (< 5 and ≥ 5 years). Results and conclusions: Past exposure to endotoxin was associated with reduced FEV1 level among retired cotton workers. Among all cotton workers, past exposure was more strongly associated with reduced FEV1 for those hired < 5 years before baseline than for those who were hired ≥ 5 years after baseline. Recent endotoxin exposure was significantly associated with byssinosis, chronic bronchitis, and chronic cough.

Background: Although recent research evidence suggests an association between household air pollution from solid fuel use, such as coal or biomass, and cardiovascular events such as hypertension, little epidemiologic data are available concerning such exposure effects on cardiovascular endpoints other than hypertension. We explored the association between in-home solid fuel use and self-reported diagnoses of cardiovascular endpoints, such as hypertension, coronary heart disease (CHD), stroke, and diabetes. Methods: We analyzed 14,068 Chinese adults, aged 18 years and older. Odds ratios (OR) and the corresponding 95% confidence intervals (CI) were estimated using logistic regression models for the risk of each outcome after adjusting for potential confounders. Results: The use of solid fuel in home was significantly associated with an increased risk for hypertension (OR 1.70, 95% CI 1.40 to 2.07), CHD (OR 2.58, 95% CI 1.53 to 4.32), and diabetes (OR 2.48, 95% CI 1.59 to 3.86), after adjusting for potential confounders. Compared with individuals in the lowest tertile of the duration of solid fuel exposure, those in the highest tertile of the duration of solid fuel exposure had an increased odds of hypertension (OR 1.73, 95% CI 1.45 to 2.06), stroke (OR 1.87, 95% CI 1.03 to 3.38), and diabetes (OR 3.18, 95% CI 2.11 to 4.78). Conclusions: Our data suggest that in-home solid fuel exposure maybe associated with increased risk for hypertension, CHD, stroke, and diabetes in the Chinese adult population. Further large-scale longitudinal studies are warranted to confirm these findings.

Background: Occupational exposure to endotoxin is associated with decrements in pulmonary function, but how much variation in this association is explained by genetic variants is not well understood. Objective: We aimed to identify single nucleotide polymorphisms (SNPs) that are associated with the rate of forced expiratory volume in one second (FEV1) decline by a large scale genetic association study in newly-hired healthy young female cotton textile workers. Methods: DNA samples were genotyped using the Illumina Human CVD BeadChip. Change rate in FEV1 was modeled as a function of each SNP genotype in linear regression model with covariate adjustment. We controlled the type 1 error in study-wide level by permutation method. The false discovery rate (FDR) and the family-wise error rate (FWER) were set to be 0.10 and 0.15 respectively. Results: Two SNPs were found to be significant (P<6.29×(10^{−5})), including rs1910047 (P = 3.07×(10^{−5}), FDR = 0.0778) and rs9469089 (P = 6.19×(10^{−5}), FDR = 0.0967), as well as other eight suggestive (P<5×(10^{−4})) associated SNPs. Gene-gene and gene-environment interactions were also observed, such as rs1910047 and rs1049970 (P = 0.0418, FDR = 0.0895); rs9469089 and age (P = 0.0161, FDR = 0.0264). Genetic risk score analysis showed that the more risk loci the subjects carried, the larger the rate of FEV1 decline occurred (Ptrend = 3.01×(10^{−18})). However, the association was different among age subgroups (P = 7.11×(10^{−6})) and endotoxin subgroups (P = 1.08×(10^{−2})). Functional network analysis illustrates potential biological connections of all interacted genes. Conclusions: Genetic variants together with environmental factors interact to affect the rate of FEV1 decline in cotton textile workers.

Accumulating evidence demonstrates that particulate air pollutants can cause both pulmonary and airway inflammation. However, few data show that particulates can induce systemic inflammatory responses. We conducted an exploratory study using microarray techniques to analyze whole-blood total RNA in boilermakers before and after occupational exposure to metal fumes. A self-controlled study design was used to overcome the problems of larger between-individual variation interferences with observations of relatively smaller changes caused by environmental exposure. Moreover, we incorporated the dichotomous data of absolute gene expression status in the microarray analyses. Compared with nonexposed controls, we observed that genes with altered expression in response to particulate exposure were clustered in biologic processes related to inflammatory response, oxidative stress, intracellular signal transduction, cell cycle, and programmed cell death. In particular, the preinflammatory cytokine interleukin 8 and one of its receptors, chemokine receptor 4, seemed to play important roles in early-stage response to heavy metal exposure and were down-regulated. Furthermore, most observed expression variations were from nonsmoking exposed individuals, suggesting that smoking profoundly affects whole-blood expression profiles. Our study is the first to demonstrate that with a paired sampling study design of pre- and postexposed individuals, small changes in gene expression profiling can be measured in whole-blood total RNA from a population-based study. This technique can be applied to evaluate the host response to other forms of environmental exposures.

Background: Welding-associated air pollutants negatively affect the health of exposed workers; however, their molecular mechanisms in causing disease remain largely unclear. Few studies have systematically investigated the systemic toxic effects of welding fumes on humans. Objectives: To explore the effects of welding fumes on the plasma metabolome, and to identify biomarkers for risk assessment of welding fume exposure. Methods: The two-stage, self-controlled exploratory study included 11 boilermakers from a 2011 discovery panel and 8 boilermakers from a 2012 validation panel. Plasma samples were collected pre- and post-welding fume exposure and analyzed by chromatography/mass spectrometry. Results: Eicosapentaenoic or docosapentaenoic acid metabolic changes post-welding were significantly associated with particulate (PM2.5) exposure (p<0.05). The combined analysis by linear mixed-effects model showed that exposure was associated with a statistically significant decline in metabolite change of eicosapentaenoic acid [(95% CI) = −0.013(−0.022∼−0.004); p = 0.005], docosapentaenoic acid n3 [(95% CI) = −0.010(−0.018∼−0.002); p = 0.017], and docosapentaenoic acid n6 [(95% CI) = −0.007(−0.013∼−0.001); p = 0.021]. Pathway analysis identified an association of the unsaturated fatty acid pathway with exposure (pStudy−2011 = 0.025; pStudy−2012 = 0.021; pCombined = 0.009). The functional network built by these fatty acids and their interactive genes contained significant enrichment of genes associated with various diseases, including neoplasms, cardiovascular diseases, and lipid metabolism disorders. Conclusions: High-dose exposure of metal welding fumes decreases unsaturated fatty acids with an exposure-response relationship. This alteration in fatty acids is a potential biological mediator and biomarker for exposure-related health disorders.

We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 × 10−20) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10−13). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10−10) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data.

Background: In occupational settings, boilermakers are exposed to high levels of metallic fine particulate matter (PM2.5) generated during the welding process. The effect of welding PM2.5 on heart rate variability (HRV) has been described, but the relationship between PM2.5, DNA methylation, and HRV is not known. Methods: In this repeated-measures panel study, we recorded resting HRV and measured DNA methylation levels in transposable elements Alu and long interspersed nuclear element-1 (LINE-1) in peripheral blood leukocytes under ambient conditions (pre-shift) and right after a welding task (post-shift) among 66 welders. We also monitored personal PM2.5 level in the ambient environment and during the welding procedure. Results: The concentration of welding PM2.5 was significantly higher than background levels in the union hall (0.43 mg/m3 vs. 0.11 mg/m3, p < 0.0001). The natural log of transformed power in the high frequency range (ln HF) had a significantly negative association with PM2.5 exposure (β = -0.76, p = 0.035). pNN10 and pNN20 also had a negative association with PM2.5 exposure (β = -0.16%, p = 0.006 and β = -0.13%, p = 0.030, respectively). PM2.5 was positively associated with LINE-1 methylation [β = 0.79%, 5-methylcytosince (%mC), p = 0.013]; adjusted for covariates. LINE-1 methylation did not show an independent association with HRV. Conclusions: Acute decline of HRV was observed following exposure to welding PM2.5 and evidence for an epigenetic response of transposable elements to short-term exposure to high-level metal-rich particulates was reported. Electronic supplementary material The online version of this article (doi:10.1186/1471-2458-14-1279) contains supplementary material, which is available to authorized users.

Rationale: Adiponectin is an anti-inflammatory adipokine that is the most abundant gene product of adipose tissue. Lower levels have been observed in obesity, insulin resistance, and in critical illness. However, elevated levels early in acute respiratory failure have been associated with mortality. Polymorphisms in adiponectin-related genes (ADIPOQ, ADIPOR1, ADIPOR2) have been examined for relationships with obesity, insulin resistance and diabetes, cardiovascular disease, and to circulating adipokine levels, but many gaps in knowledge remain. The current study aims to assess the association between potentially functional polymorphisms in adiponectin-related genes with acute respiratory distress syndrome (ARDS) risk and mortality. Methods: Consecutive patients with risk factors for ARDS admitted to the ICU were enrolled and followed prospectively for development of ARDS. ARDS cases were followed through day 60 for all-cause mortality. 2067 patients were successfully genotyped using the Illumina CVD BeadChip high-density platform. Of these, 567 patients developed ARDS. Forty-four single nucleotide polymorphisms (SNPs) on ADIPOQ, ADIPOR1 and ADIPOR2 were successfully genotyped. Of these, 9 SNPs were hypothesized to be functional based on their location (promoter, exon, or 3′ untranslated region). These 9 SNPs were analyzed for association with ARDS case status and mortality among ARDS cases. Results: After multivariable analysis and adjustment for multiple comparisons, no SNPs were significantly associated with ARDS case status. Among ARDS cases, homozygotes for the minor allele of rs2082940 (ADIPOQ) had increased mortality (hazard ratio 2.61, 95% confidence interval 1.36–5.00, p = 0.0039) after adjustment for significant covariates. The significance of this association persisted after adjustment for multiple comparisons (FDR_q = 0.029). Conclusions: A common and potentially functional polymorphism in ADIPOQ may impact survival in ARDS. Further studies are required to replicate these results and to correlate genotype with circulating adiponectin levels.

mRNA splicing is an important mechanism to regulate mRNA expression. Abnormal regulation of this process may lead to lung cancer. Here, we investigated the associations of 11,966 single-nucleotide polymorphisms (SNPs) in 206 mRNA splicing-related genes with lung cancer risk by using the summary data from six published genome-wide association studies (GWASs) of Transdisciplinary Research in Cancer of the Lung (TRICL) (12,160 cases and 16,838 controls) and another two lung cancer GWASs of Harvard University (984 cases and 970 controls) and deCODE (1,319 cases and 26,380 controls). We found that a total of 12 significant SNPs with false discovery rate (FDR) ≤0.05 were mapped to one novel gene PRPF6 and two previously reported genes (DHX16 and LSM2) that were also confirmed in this study. The six novel SNPs in PRPF6 were in high linkage disequilibrium and associated with PRPF6 mRNA expression in lymphoblastoid cells from 373 Europeans in the 1000 Genomes Project. Taken together, our studies shed new light on the role of mRNA splicing genes in the development of lung cancer.

In a subset of lung adenocarcinomas the epidermal growth factor receptor (EGFR) is activated by kinase domain mutations and/or gene amplification, but the interaction between the two types of abnormalities is complex and unclear. We selected to study 99 consecutive never-smoking women of East Asian origin with lung adenocarcinomas that were characterized by histologic subtype. We analyzed EGFR mutations by PCR-capillary sequencing, EGFR copy number abnormalities by fluorescence and chromogenic in situ hybridization and quantitative PCR, and EGFR expression by immunohistochemistry with both specific antibodies against exon 19 deletion-mutated EGFR and total EGFR. We compared molecular and clinicopathologic features with disease-free survival. Lung adenocarcinomas with EGFR amplification had significantly more EGFR exon 19 deletion mutations than adenocarcinomas with disomy, low and high polysomy (100% v 54%, P=0.009). EGFR amplification occurred invariably on the mutated and not the wildtype allele (median mutated:wildtype ratios 14.0 v .33, P=0.003), was associated with solid histology (P=0.008), and advanced clinical stage (P=0.009). EGFR amplification was focally distributed in lung cancer specimens, mostly in regions with solid histology. Patients with EGFR amplification had a significantly worse outcome in univariate analysis (median disease-free survival 16 v 31 months, P=0.01) and when adjusted for stage (P=0.027). Lung adenocarcinomas with EGFR amplification have a unique association with exon 19 deletion mutations and demonstrate distinct clinicopathologic features associated with a significantly worsened prognosis. In these cases, EGFR amplification is heterogeneously distributed, mostly in areas with a solid histology.