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1.  Epigenome-wide DNA methylation changes with development of arsenic-induced skin lesions in Bangladesh: a case-control follow-up study 
Studies have found an association between aberrant DNA methylation and arsenic-induced skin lesions. Yet, little is known about DNA methylation changes over time in people who develop arsenic-induced skin lesions. We sought to investigate epigenome-wide changes of DNA methylation in people who developed arsenic-induced skin lesions in a ten year period. In 2009–2011, we conducted a follow-up study of 900 skin lesion cases and 900 controls and identified 10 people who developed skin lesions since a baseline survey in 2001–2003. The 10 cases (“New Cases”) were matched with 10 controls who did not have skin lesions at baseline or follow-up (“Persistent Controls”). Drinking water and blood samples were collected and skin lesion was diagnosed by the same physician at both time points. We measured DNA methylation in blood using Infinium HumanMethylation450K BeadChip, followed by quantitative validation using pyrosequencing. Two-sample t-tests were used to compare changes in percent methylation between New Cases and Persistent Controls. Six CpG sites with greatest changes of DNA methylation over time among New Cases were further validated with a correlation of 93% using pyrosequencing. One of the validated CpG site (cg03333116; change of %methylation was 13.2 in New Cases versus −0.09 in Persistent Controls; P <0.001) belonged to the RHBDF1 gene, which was previously reported to be hypermethylated in arsenic-exposed cases. We examined DNA methylation changes with the development of arsenic-induced skin lesions over time but nothing was statistically significant given the small sample size of this exploratory study and the high dimensionality of data.
doi:10.1002/em.21860
PMCID: PMC4082746  PMID: 24677489
Arsenic; DNA methylation; Illumina 450K; longitudinal; skin lesion
2.  Women and Lung Cancer: What’s New? 
Seminars in thoracic and cardiovascular surgery  2013;25(2):10.1053/j.semtcvs.2013.05.002.
In the last 20 years there has been increased focus on gender differences in health and disease. The earliest studies of lung cancer enrolled mainly men, as the incidence of lung cancer among women was exceedingly low. As social patterns changed around World War II and women began to smoke more, the epidemiology of lung cancer has changed. The higher percentage of lung cancer in non-smoking women as compared to non-smoking men suggests that lung cancer in women behaves differently. Studies of lung cancer in women indicate that there are differences in risk factors, histology, pathophysiology, treatment outcomes and prognosis as compared to men. The purpose of this review is to provide a concise summary of the literature on lung cancer as it pertains to women, with an emphasis on new areas of research and treatment options.
doi:10.1053/j.semtcvs.2013.05.002
PMCID: PMC3827695  PMID: 24216523
Lung cancer; women; risk factors; genetic mutations
3.  Environmental Arsenic Exposure and Diabetes 
doi:10.1001/jama.300.7.845
PMCID: PMC4048320  PMID: 18714068
4.  Role of Diabetes in the Development of Acute Respiratory Distress Syndrome 
Critical care medicine  2013;41(12):2720-2732.
Objectives
Diabetes has been associated with decreased development of acute respiratory distress syndrome in some, but not all, previous studies. Therefore, we examined the relationship between diabetes and development of acute respiratory distress syndrome and whether this association was modified by type of diabetes, etiology of acute respiratory distress syndrome, diabetes medications, or other potential confounders.
Design
Observational prospective multicenter study.
Setting
Four adult ICUs at two tertiary academic medical centers.
Patients
Three thousand eight hundred sixty critically ill patients at risk for acute respiratory distress syndrome from sepsis, pneumonia, trauma, aspiration, or massive transfusion.
Interventions
None.
Measurements and Main Results
Diabetes history was present in 25.8% of patients. Diabetes was associated with lower rates of developing acute respiratory distress syndrome on univariate (odds ratio, 0.79; 95% CI, 0.66–0.94) and multivariate analysis (adjusted odds ratio, 0.76; 95% CI, 0.61–0.95). After including diabetes medications into the model, diabetes remained protective (adjusted odds ratio, 0.75; 95% CI, 0.59–0.94). Diabetes was associated with decreased development of acute respiratory distress syndrome both in the subgroup of patients with sepsis (adjusted odds ratio, 0.77; 95% CI, 0.61–0.97) and patients with noninfectious etiologies (adjusted odds ratio, 0.30; 95% CI, 0.10–0.90). The protective effect of diabetes on acute respiratory distress syndrome development is not clearly restricted to either type 1 (adjusted odds ratio, 0.50; 95% CI, 0.26–0.99; p = 0.046) or type 2 (adjusted odds ratio, 0.77; 95% CI, 0.60–1.00; p = 0.050) diabetes. Among patients in whom acute respiratory distress syndrome developed, diabetes was not associated with 60-day mortality on univariate (odds ratio, 1.11; 95% CI, 0.80–1.52) or multivariate analysis (adjusted odds ratio, 0.81; 95% CI, 0.56–1.18).
Conclusions
Diabetes is associated with a lower rate of acute respiratory distress syndrome development, and this relationship remained after adjusting for clinical differences between diabetics and nondiabetics, such as obesity, acute hyperglycemia, and diabetes-associated medications. In addition, this association was present for type 1 and 2 diabetics and in all subgroups of at-risk patients.
doi:10.1097/CCM.0b013e318298a2eb
PMCID: PMC4007199  PMID: 23963123
acute lung injury; acute respiratory distress syndrome; diabetes mellitus; hyperglycemia; risk factors
5.  Single nucleotide polymorphisms in the matrix metalloproteinase gene family and the frequency and duration of gastroesophageal reflux disease influence the risk of esophageal adenocarcinoma 
The matrix metalloproteinase (MMP) family of proteins mediates various cellular pathways, including apoptosis and angiogenesis. Polymorphisms of MMP genes are associated with increased esophageal adenocarcinoma (EAC) risk. Gastroesophageal reflux disease (GERD) is an established EAC risk factor. We examined whether MMP polymorphism-EAC risk is modified by GERD. In total, 309 EAC patients and 279 frequency-matched healthy controls underwent MMP1 1G/2G, MMP3 6A/5A, MMP12 −82A/G and MMP12 1082A/G genotyping. Questionnaires collected GERD history. EAC risk was analyzed using logistic regression, adjusted for key covariates and stratified by GERD. Joint effects models explored GERD severity and duration, whereas additional models explored genotype–GERD interactions in EAC risk. We determined that each MMP1 and MMP3 minor (variant) allele was independently associated with increased EAC risk (adjusted odds ratio (AOR) 3.2, 95% confidence interval (CI) 2.0–5.1, p < 0.001 and AOR 1.8, 95% CI 1.1–2.7, p = 0.01, respectively) only among those with GERD but not in GERD-free individuals (all p = nonsignificant). There were significant interactions between the MMP1 variants and the presence of GERD (p = 0.002) and between MMP3 variants and GERD (p = 0.04). There was an equally strong interaction between cumulative GERD severity and MMP1 (p = 0.002). The AOR of each variant allele was 14.9 (95% CI 1.6–136) for individuals with severe GERD, 1.7 (95% CI 1.0–2.7) for mild-moderate GERD and 0.98 (95% CI 0.7–1.4) for those without GERD. This was further reflected in separate analyses of frequency and duration of GERD. In conclusion, MMP1 1G/2G (and possibly MMP3 6A/5A) polymorphisms alter EAC risk differentially for GERD and GERD-free individuals.
doi:10.1002/ijc.27541
PMCID: PMC3908453  PMID: 22422400
matrix metalloproteinase; gene polymorphism; gastroesophageal reflux disease; esophageal cancer
6.  A prospective cohort study of the association between drinking water arsenic exposure and self-reported maternal health symptoms during pregnancy in Bangladesh 
Environmental Health  2014;13:29.
Background
Arsenic, a common groundwater pollutant, is associated with adverse reproductive health but few studies have examined its effect on maternal health.
Methods
A prospective cohort was recruited in Bangladesh from 2008–2011 (N = 1,458). At enrollment (<16 weeks gestational age [WGA]), arsenic was measured in personal drinking water using inductively-coupled plasma mass spectrometry. Questionnaires collected health data at enrollment, at 28 WGA, and within one month of delivery. Adjusted odds ratios (aORs) and 95% confidence intervals (95% CI) for self-reported health symptoms were estimated for each arsenic quartile using logistic regression.
Results
Overall, the mean concentration of arsenic was 38 μg/L (Standard deviation, 92.7 μg/L). A total of 795 women reported one or more of the following symptoms during pregnancy (cold/flu/infection, nausea/vomiting, abdominal cramping, headache, vaginal bleeding, or swollen ankles). Compared to participants exposed to the lowest quartile of arsenic (≤0.9 μg/L), the aOR for reporting any symptom during pregnancy was 0.62 (95% CI = 0.44-0.88) in the second quartile, 1.83 (95% CI = 1.25-2.69) in the third quartile, and 2.11 (95% CI = 1.42-3.13) in the fourth quartile where the mean arsenic concentration in each quartile was 1.5 μg/L, 12.0 μg/L and 144.7 μg/L, respectively. Upon examining individual symptoms, only nausea/vomiting and abdominal cramping showed consistent associations with arsenic exposure. The odds of self-reported nausea/vomiting was 0.98 (95% CI: 0.68, 1.41), 1.52 (95% CI: 1.05, 2.18), and 1.81 (95% CI: 1.26, 2.60) in the second, third and fourth quartile of arsenic relative to the lowest quartile after adjusting for age, body mass index, second-hand tobacco smoke exposure, educational status, parity, anemia, ferritin, medication usage, type of sanitation at home, and household income. A positive trend was also observed for abdominal cramping (P for trend <0.0001). A marginal negative association was observed between arsenic quartiles and odds of self-reported cold/flu/infection (P for trend = 0.08). No association was observed between arsenic and self-reported headache (P for trend = 0.19).
Conclusion
Moderate exposure to arsenic contaminated drinking water early in pregnancy was associated with increased odds of experiencing nausea/vomiting and abdominal cramping. Preventing exposure to arsenic contaminated drinking water during pregnancy could improve maternal health.
doi:10.1186/1476-069X-13-29
PMCID: PMC4021291  PMID: 24735908
Arsenic; Maternal health; Nausea; Vomiting; Cramping; Environmental health; Reproductive health
7.  Thrombocytopenia Is Associated with Acute Respiratory Distress Syndrome Mortality: An International Study 
PLoS ONE  2014;9(4):e94124.
Background
Early detection of the Acute Respiratory Distress Syndrome (ARDS) has the potential to improvethe prognosis of critically ill patients admitted to the intensive care unit (ICU). However, no reliable biomarkers are currently available for accurate early detection of ARDS in patients with predisposing conditions.
Objectives
This study examined risk factors and biomarkers for ARDS development and mortality in two prospective cohort studies.
Methods
We examined clinical risk factors for ARDS in a cohort of 178 patients in Beijing, China who were admitted to the ICU and were at high risk for ARDS. Identified biomarkers were then replicated in a second cohort of1,878 patients in Boston, USA.
Results
Of 178 patients recruited from participating hospitals in Beijing, 75 developed ARDS. After multivariate adjustment, sepsis (odds ratio [OR]:5.58, 95% CI: 1.70–18.3), pulmonary injury (OR: 3.22; 95% CI: 1.60–6.47), and thrombocytopenia, defined as platelet count <80×103/µL, (OR: 2.67; 95% CI: 1.27–5.62)were significantly associated with increased risk of developing ARDS. Thrombocytopenia was also associated with increased mortality in patients who developed ARDS (adjusted hazard ratio [AHR]: 1.38, 95% CI: 1.07–1.57) but not in those who did not develop ARDS(AHR: 1.25, 95% CI: 0.96–1.62). The presence of both thrombocytopenia and ARDS substantially increased 60-daymortality. Sensitivity analyses showed that a platelet count of <100×103/µLin combination with ARDS provide the highest prognostic value for mortality. These associations were replicated in the cohort of US patients.
Conclusions
This study of ICU patients in both China and US showed that thrombocytopenia is associated with an increased risk of ARDS and platelet count in combination with ARDS had a high predictive value for patient mortality.
doi:10.1371/journal.pone.0094124
PMCID: PMC3986053  PMID: 24732309
8.  Clinical Presentation, Recurrence, and Survival in Patients with Neuroendocrine Tumors: Results from a Prospective Institutional Database 
Endocrine-related cancer  2013;20(2):187-196.
The rarity of neuroendocrine tumors (NET) has contributed to a paucity of large epidemiologic studies of patients with this condition. We characterized presenting symptoms and clinical outcomes in a prospective database of over 900 patients with NET. We used data from patient questionnaires and the medical record to characterize presenting symptoms, disease-free survival (DFS) and overall survival (OS). The majority of patients in this database had gastroenteropancreatic NET. The median duration of patient-reported symptoms prior to diagnosis was 3.4 months; 19.5% reported durations from 1 to 5 years, 2.5% from 5 to 10 years and 2% greater than 10 years. The median DFS among patients with resected small bowel NET or pancreatic NET was 5.8 yrs and 4.1 years, respectively. After correcting for left truncation bias, the median OS was 7.9 yrs for advanced small bowel NET and 3.9 yrs for advanced pancreatic NET. Chromogranin A (CGA) above twice the upper limit of normal was associated with shorter survival times (HR 2.8 (1.9, 4.0) p<0.001) patients with metastatic disease, regardless of tumor subtype. Our data suggest that while most NET patients are diagnosed soon after symptom onset, prolonged symptom duration prior to diagnosis is a prominent feature of this disease. Though limited to observations from a large referral center, our observations confirm the prognostic value of CGA, and suggest that median survival durations may be shorter than reported in other institutional databases.
doi:10.1530/ERC-12-0340
PMCID: PMC3739696  PMID: 23319495
neuroendocrine tumors; disease-free survival; overall survival; chromogranin A
9.  Pleiotropic Associations of Risk Variants Identified for Other Cancers With Lung Cancer Risk: The PAGE and TRICL Consortia 
Background
Genome-wide association studies have identified hundreds of genetic variants associated with specific cancers. A few of these risk regions have been associated with more than one cancer site; however, a systematic evaluation of the associations between risk variants for other cancers and lung cancer risk has yet to be performed.
Methods
We included 18023 patients with lung cancer and 60543 control subjects from two consortia, Population Architecture using Genomics and Epidemiology (PAGE) and Transdisciplinary Research in Cancer of the Lung (TRICL). We examined 165 single-nucleotide polymorphisms (SNPs) that were previously associated with at least one of 16 non–lung cancer sites. Study-specific logistic regression results underwent meta-analysis, and associations were also examined by race/ethnicity, histological cell type, sex, and smoking status. A Bonferroni-corrected P value of 2.5×10–5 was used to assign statistical significance.
Results
The breast cancer SNP LSP1 rs3817198 was associated with an increased risk of lung cancer (odds ratio [OR] = 1.10; 95% confidence interval [CI] = 1.05 to 1.14; P = 2.8×10–6). This association was strongest for women with adenocarcinoma (P = 1.2×10–4) and not statistically significant in men (P = .14) with this cell type (P het by sex = .10). Two glioma risk variants, TERT rs2853676 and CDKN2BAS1 rs4977756, which are located in regions previously associated with lung cancer, were associated with increased risk of adenocarcinoma (OR = 1.16; 95% CI = 1.10 to 1.22; P = 1.1×10–8) and squamous cell carcinoma (OR = 1.13; CI = 1.07 to 1.19; P = 2.5×10–5), respectively.
Conclusions
Our findings demonstrate a novel pleiotropic association between the breast cancer LSP1 risk region marked by variant rs3817198 and lung cancer risk.
doi:10.1093/jnci/dju061
PMCID: PMC3982896  PMID: 24681604
10.  Statin therapy as prevention against development of acute respiratory distress syndrome: An observational study* 
Critical care medicine  2012;40(5):1470-1477.
Objectives
The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (“statins”) have anti-inflammatory properties and are associated with improved outcomes in critically ill patients. We investigated whether previous statin therapy affects outcomes in patients at risk for acute respiratory distress syndrome.
Design
Patients were followed-up for the primary outcome of acute respiratory distress syndrome and secondary outcomes of intensive care unit and 60-day mortality, organ dysfunction, and ventilator-free days in a secondary analysis of a prospective cohort study. Receipt of statin therapy was recorded. Propensity score matching was used to adjust for confounding by indication.
Setting
Intensive care units at a tertiary care academic medical center.
Patients
Critically ill patients (2,743) with acute respiratory distress syndrome risk factors.
Interventions
None.
Measurements and Main Results
Acute respiratory distress syndrome developed in 738 (26%) patients; 413 patients (15%) received a statin within 24 hrs of intensive care unit admission. Those who had received a statin within 24 hrs had a lower rate of development of acute respiratory distress syndrome (odds ratio 0.56; 95% confidence interval 0.43–0.73; p < .0001). After multivariate adjustment for potential confounders, this association remained significant (odds ratio 0.69; 95% confidence interval 0.51–0.92; p = .01). However, after propensity score matching, the association was not statistically significant (odds ratio 0.79; 95% confidence interval 0.57–1.10; p = .16). Statin use was not associated with reduced acute respiratory distress syndrome mortality, organ dysfunction, or ventilator-free days. Results of the study were presented in accordance with STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines.
Conclusions
Statin therapy at the time of intensive care unit admission was not associated with a lower rate of development of acute respiratory distress syndrome after matching for patient propensity to receive statins. Statin therapy was not associated with improvements in acute respiratory distress syndrome mortality, organ failure, or days free from mechanical ventilation.
doi:10.1097/CCM.0b013e3182416d7a
PMCID: PMC3939937  PMID: 22430234
ALI/ARDS; critical illness; statin
11.  Genetic susceptibility to lung cancer—light at the end of the tunnel? 
Carcinogenesis  2013;34(3):487-502.
Lung cancer is one of the most common and deadliest cancers in the world. The major socio-environmental risk factor involved in the development of lung cancer is cigarette smoking. Additionally, there are multiple genetic factors, which may also play a role in lung cancer risk. Early work focused on the presence of relatively prevalent but low-penetrance alterations in candidate genes leading to increased risk of lung cancer. Development of new technologies such as genomic profiling and genome-wide association studies has been helpful in the detection of new genetic variants likely involved in lung cancer risk. In this review, we discuss the role of multiple genetic variants and review their putative role in the risk of lung cancer. Identifying genetic biomarkers and patterns of genetic risk may be useful in the earlier detection and treatment of lung cancer patients.
doi:10.1093/carcin/bgt016
PMCID: PMC3581605  PMID: 23349013
12.  Long term respiratory health effects in textile workers 
Purpose of review
Over 60 million people worldwide work in the textile or clothing industry. Recent studies have recognized the contribution of workplace exposures to chronic lung diseases, in particular chronic obstructive pulmonary disease (COPD). Early studies in textile workers have focused on the relationship between hemp or cotton dust exposure and the development of a syndrome termed Byssinosis. The purpose of this review is to evaluate the effect of long term exposure to organic dust in textile workers on chronic respiratory disease in the broader context of disease classifications such as reversible or irreversible obstructive lung disease (i.e. asthma or COPD), and restrictive lung disease.
Recent findings
Cessation of exposure to cotton dusts leads to improvement in lung function. Recent animal models have suggested a shift in the lung macrophage:dendritic cell population as a potential mechanistic explanation for persistent inflammation in the lung due to repeated cotton-dust related endotoxin exposure. Other types of textile dust, such as silk, may contribute to COPD in textile workers.
Summary
Textile dust related obstructive lung disease has characteristics of both asthma and COPD. Significant progress has been made in the understanding of chronic lung disease due to organic dust exposure in textile workers.
doi:10.1097/MCP.0b013e32835cee9a
PMCID: PMC3725301  PMID: 23361196
byssinosis; textile; lung; chronic obstructive pulmonary disease (COPD); endotoxin; vegetable dust
13.  Adiponectin Gene Polymorphisms and Acute Respiratory Distress Syndrome Susceptibility and Mortality 
PLoS ONE  2014;9(2):e89170.
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.
doi:10.1371/journal.pone.0089170
PMCID: PMC3929660  PMID: 24586568
14.  Distinct and replicable genetic risk factors for acute respiratory distress syndrome of pulmonary or extrapulmonary origin 
Journal of medical genetics  2012;49(11):671-680.
Background
The role of genetics in the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) from direct or indirect lung injury has not been investigated specifically. The aim of this study was to identify genetic variants contributing to ARDS from pulmonary or extrapulmonary causes.
Methods
We conducted a multi-stage genetic association study. We first performed a large-scale genotyping (50K IBC Chip) in 1,717 Caucasian critically ill patients with either pulmonary or extrapulmonary injury, to identify single nucleotide polymorphisms (SNPs) associated with the development of ARDS from direct or indirect insults to the lung. Identified SNPs (p ≤ 0.0005) were validated in two separated populations (Stage II), with trauma (Population I; n = 765) and pneumonia/pulmonary sepsis (Population II; n = 838), as causes for ARDS/ALI. Genetic variants replicating their association with trauma related-ALI in Stage II were validated in a second trauma-associated ALI population (n = 224, Stage III).
Results
In Stage I, non-overlapping SNPs were significantly associated with ARDS from direct/indirect lung injury, respectively. The association between rs1190286 (POPDC3) and reduced risk of ARDS from pulmonary injury was validated in Stage II (p < 0.003). SNP rs324420 (FAAH) was consistently associated with increased risk of ARDS from extrapulmonary causes in two independent ALI-trauma populations (p < 0.007, Stage II; p < 0.05, Stage III). Meta-analysis confirmed these associations.
Conclusions
Different genetic variants may influence ARDS susceptibility depending on direct vs indirect insults. Functional SNPs in POPDC3 and FAAH genes may be driving the association with direct and indirect ALI, respectively.
doi:10.1136/jmedgenet-2012-100972
PMCID: PMC3654537  PMID: 23048207
acute respiratory distress syndrome; acute lung injury; pulmonary/extrapulmonary injury; single-nucleotide polymorphism; genetic susceptibility profile; large scale genomic association study; replication
15.  Influence of GSTT1 Genetic Polymorphisms on Arsenic Metabolism 
SUMMARY
A repeated measures study was conducted in Pabna, Bangladesh to investigate factors that influence biomarkers of arsenic exposure. Drinking water arsenic concentrations were measured by inductively-coupled plasma mass spectrometry (ICP-MS) and urinary arsenic species [arsenite (As3), arsenate (As5), monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA)] were detected using High Performance Liquid Chromatography (HPLC) and Hydride Generated Atomic Absorption Spectrometry (HGAAS). Linear mixed effects models with random intercepts were used to evaluate the effects of arsenic contaminated drinking water, genetic polymorphisms in glutathione-S-transferase (GSTT1 and GSTM1) on total urinary arsenic, primary methylation index [MMA/(As3+As5)], secondary methylation index (DMA/MMA), and total methylation index [(MMA+DMA)/(As3+As5)]. Drinking water arsenic concentrations were positively associated with total urinary arsenic concentrations and total methylation index. A significant gene-environment interaction was observed between urinary arsenic exposure in drinking water GSTT1 but not GSTM1 where GSTT1 null individuals had a slightly higher excretion rate of arsenic compared to GSTT1 wildtypes after adjusting for other factors. Additionally, individuals with GSTT1 null genotypes had a higher primary methylation index and lower secondary methylation index compared to GSTT1 wildtype after adjusting for other factors. This data suggests that GSTT1 contributes to the observed variability in arsenic metabolism. Since individuals with a higher primary methylation index and lower secondary methylation index are more susceptible to arsenic related disease, these results suggest that GSTT1 null individuals may be more susceptible to arsenic-related toxicity. No significant associations were observed between GSTM1 and any of the arsenic methylation indices.
PMCID: PMC3916182  PMID: 24511153
Arsenic; Methylation; Urinary arsenic; GSTT1; Gene environment interaction; Bangladesh; Environmental health
16.  Tuberculosis burden in China: a high prevalence of pulmonary tuberculosis in household contacts with and without symptoms 
Background
In the context of decreasing tuberculosis prevalence in China, we examined the effectiveness of screening household contacts of tuberculosis patients.
Methods
A tuberculosis survey was conducted in 2008. All 3,355 household contacts of notified tuberculosis cases were examined with a questionnaire interview, chest X-ray and three sputum smear tests. The effectiveness was examined by comparing the prevalence of pulmonary tuberculosis in household contacts with or without presenting clinical symptoms against the respective notification rates. Regression models were used to evaluate the factors associated with pulmonary tuberculosis.
Results
Of the 3,355 household contacts, 92 members (2.7%) had pulmonary tuberculosis, among which 46 cases were asymptomatic. The prevalence of pulmonary tuberculosis and smear positive cases in household contacts without symptoms were 20 and 7 times higher than the notification rates in 2008, while those in household contacts with symptoms were 247 and 108 times higher than notification rates, respectively. The patients detected were mainly Index Cases’ spouses, sisters/brothers and those who were in contact with female Index Cases.
Conclusions
The present study provides convincing evidence that household contacts of notified tuberculosis cases are at higher risk of developing tuberculosis. Routine screening for household contacts without any symptoms is recommended for sustained tuberculosis control in China as well as in the world.
doi:10.1186/1471-2334-14-64
PMCID: PMC3918223  PMID: 24502559
Tuberculosis; Household contact; Index cases
17.  The Relationship between Inflammatory Biomarkers and Telomere Length in an Occupational Prospective Cohort Study 
PLoS ONE  2014;9(1):e87348.
Background
Chronic inflammation from recurring trauma is an underlying pathophysiological basis of numerous diseases. Furthermore, it may result in cell death, scarring, fibrosis, and loss of tissue function. In states of inflammation, subsequent increases in oxidative stress and cellular division may lead to the accelerated erosion of telomeres, crucial genomic structures which protect chromosomes from decay. However, the association between plasma inflammatory marker concentrations and telomere length has been inconsistent in previous studies.
Objective
The purpose of this study was to determine the longitudinal association between telomere length and plasma inflammatory biomarker concentrations including: CRP, SAA, sICAM-1, sVCAM-1, VEGF, TNF-α, IL-1β, IL-2, IL-6, IL-8, and IL-10.
Methods
The longitudinal study population consisted of 87 subjects. The follow-up period was approximately 2 years. Plasma inflammatory biomarker concentrations were assessed using highly sensitive electrochemiluminescent assays. Leukocyte relative telomere length was assessed using Real-Time qPCR. Linear mixed effects regression models were used to analyze the association between repeated-measurements of relative telomere length as the outcome and each inflammatory biomarker concentration as continuous exposures separately. The analyses controlled for major potential confounders and white blood cell differentials.
Results
At any follow-up time, each incremental ng/mL increase in plasma CRP concentration was associated with a decrease in telomere length of −2.6×10−2 (95%CI: −4.3×10−2, −8.2×10−3, p = 0.004) units. Similarly, the estimate for the negative linear association between SAA and telomere length was −2.6×10−2 (95%CI:−4.5×10−2, −6.1×10−3, p = 0.011). No statistically significant associations were observed between telomere length and plasma concentrations of pro-inflammatory interleukins, TNF-α, and VEGF.
Conclusions
Findings from this study suggest that increased systemic inflammation, consistent with vascular injury, is associated with decreased leukocyte telomere length.
doi:10.1371/journal.pone.0087348
PMCID: PMC3903646  PMID: 24475279
19.  MTHFR Polymorphisms, Folate Intake, and Carcinogen DNA Adducts in the Lung 
The methylenetetrahydrofolate reductase (MTHFR) genes and folate in one-carbon metabolism are essential for DNA methylation and synthesis. However, their role in carcinogen DNA damage in target lung tissue, a dosimeter for cancer risk, is not known. Our study aimed to investigate the association between genetic and nutritional one-carbon metabolism factors and DNA adducts in target lung. Data on 135 lung cancer cases from the Massachusetts General Hospital were studied. Genotyping was completed for MTHFR C677T (rs1801133) and A1298C (rs1801131). Information on dietary intake for one-carbon related micronutrients, folate and other B vitamin, was derived from a validated food frequency questionnaire. DNA adducts in lung were measured by 32P-postlabeling. After adjusting for potential confounders, DNA adduct levels in lung significantly increased by 69.2% [95% confidence interval (CI), 5.5% to 171.5%] for the MTHFR 1298AC+CC genotype. The high risk group, combining the A1298C (AC+CC) plus C677T (CT+TT) genotypes, had significantly enhanced levels of lung adducts by 210.7% (95% CI, 21.4% to 695.2%) in contrast to the A1298C (AA) plus C677T (CC) genotypes. Elevation of DNA adduct was pronounced - 111.3% (95% CI, −3.0 to 360.5%) among 1298AC+CC patients who consumed the lowest level of folate intake as compared with 1298AA individuals with highest tertile of intake. These results indicate that DNA adducts levels are influenced by MTHFR polymorphisms and low folate consumption, suggesting an important role of genetic and nutritional factors in protecting DNA damage from lung carcinogen in at-risk populations.
doi:10.1002/ijc.27338
PMCID: PMC3293105  PMID: 22052259
MTHFR; folate; genetic polymorphisms; DNA adducts; one carbon metabolism
20.  Polymorphisms in XPD (Asp312Asn and Lys751Gln) genes, sunburn and arsenic-related skin lesions 
Carcinogenesis  2007;28(8):10.1093/carcin/bgm099.
Background
Single-nucleotide polymorphisms in genes related to DNA repair capacity and ultraviolet exposure have not been well investigated in relation to skin lesions associated with arsenic exposure. This population based case–control study, of 600 cases and 600 controls, frequency matched on age and gender in Pabna, Bangladesh, in 2001–2002, investigated the association and potential effect modification between polymorphisms in Xeroderma Pigmentosum complementation group D (XPD) (Lys751Gln and Asp312Asn) genes, tendency to sunburn and arsenic-related skin lesions.
Methods
Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).
Result
No significant association was observed between skin lesions and the XPD 312 Asp/Asn (adjusted OR = 0.87, 95% CI = 0.65–1.15) Asn/Asn (adjusted OR = 0.76, 95% CI = 0.50–1.15) (referent Asp/Asp); XPD 751 Lys/Gln (adjusted OR = 0.92, 95% CI = 0.69–1.23) Gln/Gln (adjusted OR = 0.98, 95% CI = 0.66–1.45) (referent Lys/Lys). While we did not observe any evidence of effect modification of these polymorphisms on the association between well arsenic concentration and skin lesions, we did observe effect modification between these polymorphisms and sunburn tendency and arsenic-related skin lesions. Individuals with the heterozygote or homozygote variant forms (Asp/Asn or Asn/Asn) had half the risk of skin lesions (OR = 0.45, 95% CI = 0.29–0.68) compared with those with the wild-type XPDAsp312Asn genotype (Asp/Asp) and individuals with heterozygote or homozygote variant forms (Lys/Gln or Gln/Gln) had half the risk of skin lesions (OR = 0.47, 95% CI = 0.31–0.72) compared with those with the wild-type XPDLys751Gln genotype (Lys/Lys), within the least sensitive strata of sunburn severity. We observed effect modification on the multiplicative scale for XPD 751 and XPD 312.
Conclusion
XPD polymorphisms modified the relationship between tendency to sunburn and skin lesions in an arsenic exposed population. Further study is necessary to explore the effect of XPD polymorphisms and sun exposure on risk of arsenic-related skin lesions.
doi:10.1093/carcin/bgm099
PMCID: PMC3879118  PMID: 17470448
21.  Acute health impacts of airborne particles estimated from satellite remote sensing✩ 
Environment international  2012;51:150-159.
Satellite-based remote sensing provides a unique opportunity to monitor air quality from space at global, continental, national and regional scales. Most current research focused on developing empirical models using ground measurements of the ambient particulate. However, the application of satellite-based exposure assessment in environmental health is still limited, especially for acute effects, because the development of satellite PM2.5 model depends on the availability of ground measurements. We tested the hypothesis that MODIS AOD (aerosol optical depth) exposure estimates, obtained from NASA satellites, are directly associated with daily health outcomes. Three independent healthcare databases were used: unscheduled outpatient visits, hospital admissions, and mortality collected in Beijing metropolitan area, China during 2006. We use generalized linear models to compare the short-term effects of air pollution assessed by ground monitoring (PM10) with adjustment of absolute humidity (AH) and AH-calibrated AOD. Across all databases we found that both AH-calibrated AOD and PM10 (adjusted by AH) were consistently associated with elevated daily events on the current day and/or lag days for cardiovascular diseases, ischemic heart diseases, and COPD. The relative risks estimated by AH-calibrated AOD and PM10 (adjusted by AH) were similar. Additionally, compared to ground PM10, we found that AH-calibrated AOD had narrower confidence intervals for all models and was more robust in estimating the current day and lag day effects. Our preliminary findings suggested that, with proper adjustment of meteorological factors, satellite AOD can be used directly to estimate the acute health impacts of ambient particles without prior calibrating to the sparse ground monitoring networks.
doi:10.1016/j.envint.2012.10.011
PMCID: PMC3711510  PMID: 23220016
Absolute humidity; Aerosol optical depth; Environmental health; Particulate matter; Satellite remote sensing
22.  Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation 
PLoS Medicine  2013;10(12):e1001577.
In this paper, Choi and colleagues analyzed levels of mitochondrial DNA in two prospective observational cohort studies and found that increased mtDNA levels are associated with ICU mortality, and improve risk prediction in medical ICU patients. The data suggests that mtDNA could serve as a viable plasma biomarker in MICU patients.
Background
Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients.
Methods and Findings
Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6–15.8, p = 1×10−7) and ME ARDS (OR 8.4, 95% CI 2.9–24.2, p = 9×10−5) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10−4) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers.
Conclusions
Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Intensive care units (ICUs, also known as critical care units) are specialist hospital wards that provide care for people with life-threatening injuries and illnesses. In the US alone, more than 5 million people are admitted to ICUs every year. Different types of ICUs treat different types of problems. Medical ICUs treat patients who, for example, have been poisoned or who have a serious infection such as sepsis (blood poisoning) or severe pneumonia (inflammation of the lungs); trauma ICUs treat patients who have sustained a major injury; cardiac ICUs treat patients who have heart problems; and surgical ICUs treat complications arising from operations. Patients admitted to ICUs require constant medical attention and support from a team of specially trained nurses and physicians to prevent organ injury and to keep their bodies functioning. Monitors, intravenous tubes (to supply essential fluids, nutrients, and drugs), breathing machines, catheters (to drain urine), and other equipment also help to keep ICU patients alive.
Why Was This Study Done?
Although many patients admitted to ICUs recover, others do not. ICU specialists use scoring systems (algorithms) based on clinical signs and physiological measurements to predict their patients' likely outcomes. For example, the APACHE II scoring system uses information on heart and breathing rates, temperature, levels of salts in the blood, and other signs and physiological measurements collected during the first 24 hours in the ICU to predict the patient's risk of death. Existing scoring systems are not perfect, however, and “biomarkers” (molecules in bodily fluids that provide information about a disease state) are needed to improve risk prediction for ICU patients. Here, the researchers investigate whether levels of circulating cell-free mitochondrial DNA (mtDNA) are associated with ICU deaths and whether these levels can be used as a biomarker to improve risk prediction in ICU patients. Mitochondria are cellular structures that produce energy. Levels of mtDNA in the plasma (the liquid part of blood) increase in response to trauma and infection. Moreover, mtDNA activates molecular processes that lead to inflammation and organ injury.
What Did the Researchers Do and Find?
The researchers measured mtDNA levels in the plasma of patients enrolled in two prospective observational cohort studies that monitored the outcomes of ICU patients. In the Brigham and Women's Hospital Registry of Critical Illness study, blood was taken from 200 patients within 24 hours of admission into the hospital's medical ICU. In the Molecular Epidemiology of Acute Respiratory Distress Syndrome study (acute respiratory distress syndrome is a life-threatening inflammatory reaction to lung damage or infection), blood was taken from 243 patients within 48 hours of admission into medical and non-medical ICUs at two other US hospitals. Patients admitted to medical ICUs with a raised mtDNA level (3,200 or more copies of a specific mitochondrial gene per microliter of plasma) had a 7- to 8-fold increased risk of dying within 28 days of admission compared to patients with mtDNA levels of less than 3,200 copies/µl plasma. There was no evidence of an association between raised mtDNA levels and death among patients admitted to non-medical ICUs. The addition of an elevated mtDNA level to a clinical model for risk prediction that included the APACHE II score and biomarkers that are already used to predict ICU outcomes improved the net reclassification index (an indicator of the improvement in risk prediction algorithms offered by new biomarkers) of 28-day mortality among medical ICU patients in both studies.
What Do These Findings Mean?
These findings indicate that raised mtDNA plasma levels are associated with death in medical ICUs and show that, among patients in medical ICUs, measurement of mtDNA plasma levels can improve the prediction of the risk of death from the APACHE II scoring system, even when commonly measured biomarkers are taken into account. These findings do not indicate whether circulating cell-free mtDNA increased because of the underlying severity of illness or whether mtDNA actively contributes to the disease process in medical ICU patients. Moreover, they do not provide any evidence that raised mtDNA levels are associated with an increased risk of death among non-medical (mainly surgical) ICU patients. These findings need to be confirmed in additional patients, but given the relative ease and rapidity of mtDNA measurement, the determination of circulating cell-free mtDNA levels could be a valuable addition to the assessment of patients admitted to medical ICUs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001577.
The UK National Health Service Choices website provides information about intensive care
The Society of Critical Care Medicine provides information for professionals, families, and patients about all aspects of intensive care
MedlinePlus provides links to other resources about intensive care (in English and Spanish)
The UK charity ICUsteps supports patients and their families through recovery from critical illness; its booklet Intensive Care: A Guide for Patients and Families is available in English and ten other languages; its website includes patient experiences and relative experiences of treatment in ICUs
Wikipedia has a page on ICU scoring systems (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001577
PMCID: PMC3876981  PMID: 24391478
23.  Aspirin and NSAID use and lung cancer risk: a pooled analysis in the International Lung Cancer Consortium (ILCCO) 
Cancer causes & control : CCC  2011;22(12):10.1007/s10552-011-9847-z.
Purpose
To investigate the hypothesis that non-steroidal anti-inflammatory drugs (NSAIDs) lower lung cancer risk.
Methods
We analysed pooled individual-level data from seven case–control and one cohort study in the International Lung Cancer Consortium (ILCCO). Relative risks for lung cancer associated with self-reported history of aspirin and other NSAID use were estimated within individual studies using logistic regression or proportional hazards models, adjusted for packyears of smoking, age, calendar period, ethnicity and education and were combined using random effects meta-analysis.
Results
A total of 4,309 lung cancer cases (mean age at diagnosis 65 years, 45% adenocarcinoma and 22% squamous-cell carcinoma) and 58,301 non-cases/controls were included. Amongst controls, 34% had used NSAIDs in the past (81% of them used aspirin). After adjustment for negative confounding by smoking, ever-NSAID use (affirmative answer to the study-specific question on NSAID use) was associated with a 26% reduction (95% confidence interval 8 to 41%) in lung cancer risk in men, but not in women (3% increase (−11% to 30%)). In men, the association was stronger in current and former smokers, and for squamous-cell carcinoma than for adenocarcinomas, but there was no trend with duration of use. No differences were found in the effects on lung cancer risk of aspirin and non-aspirin NSAIDs.
Conclusions
Evidence from ILCCO suggests that NSAID use in men confers a modest protection for lung cancer, especially amongst ever-smokers. Additional investigation is needed regarding the possible effects of age, duration, dose and type of NSAID and whether effect modification by smoking status or sex exists.
doi:10.1007/s10552-011-9847-z
PMCID: PMC3852431  PMID: 21987079
NSAIDs; Aspirin; Lung cancer
24.  A Single Nucleotide Polymorphism in the MTHFR Gene is Associated with Risk of Radiation Pneumonitis in Lung Cancer Patients Treated with Thoracic Radiation Therapy 
Cancer  2011;118(14):3654-3665.
Background
To study the association between functional single nucleotide polymorphisms (SNPs) in candidate genes from oxidative stress pathways, and risk of radiation pneumonitis (RP) in patients treated with thoracic radiation therapy (RT) for locally advanced lung cancer (LC).
Methods
We reviewed 136 patients treated with RT for LC between 2001 and 2007, and had prior genotyping of functional SNPs in oxidative stress genes including superoxide dismutase 2 (SOD2; rs4880) and methylenetetrahydrofolate reductase (MTHFR; rs1801131, rs1801133). RP events were retrospectively scored using the Common Terminology Criteria for Adverse Events, version 4.0. Cox proportional hazard regression was performed to identify clinical variables and genotypes associated with risk of grade ≥2 and grade ≥3 RP on univariate and multivariate analysis. P-values were corrected for multiple hypothesis testing.
Results
With a median follow-up of 21.4 months, the incidence of ≥grade 2 RP was 29% and ≥grade 3 RP was 14%. On multivariate analysis, after adjusting for clinical factors such as concurrent chemotherapy, and consolidation docetaxel, and lung dosimetric parameters such as V20 and mean lung dose, MTHFR genotype (rs1801131; AA versus AC/CC) was significantly associated with risk of ≥grade 2 RP (Hazard ratio [HR]: 0.37; 95% confidence interval [CI]: 0.18-0.76; p=0.006, corrected p=0.018) and ≥grade 3 RP (HR: 0.21; 95% CI: 0.06-0.70; p=0.01; corrected p=0.03). SOD2 genotype was not associated with RP.
Conclusions
Our study showed an association between MTHFR genotype and risk of clinically significant RP. Further study of MTHFR-related pathways may provide insight into the mechanisms behind RP.
doi:10.1002/cncr.26667
PMCID: PMC3312983  PMID: 22144047
Radiation pneumonitis; single nucleotide polymorphisms; lung cancer; oxidative stress; MTHFR
25.  Correction for population stratification in random forest analysis 
Background Population structure (PS), including population stratification and admixture, is a significant confounder in genome-wide association studies (GWAS), as it may produce spurious associations. Random forest (RF) has been increasingly applied in GWAS data analysis because of its advantage in analysing high dimensional genetic data. RF creates importance measures for single nucleotide polymorphisms (SNPs), which are helpful for feature selections. However, if PS is not appropriately corrected, RF tends to give high importance to disease-unrelated SNPs with different frequencies of allele or genotype among subpopulations, leading to inaccurate results.
Methods In this study, the authors propose to correct for the confounding effect of PS by including the information of PS in RF analysis. The correction procedure starts by extracting the information of PS using EIGENSTRAT or multi-dimensional scaling clustering procedure from a large number of structure inference SNPs. Phenotype and genotypes adjusted by the information of PS are then used as the outcome and predictors in RF analysis.
Results Extensive simulations indicate that the importance measure of the causal SNP is increased following the PS correction. By analysing a real dataset, the proposed correction removes the spurious association between the lactase gene and height.
Conclusion The authors propose a simple method to correct for PS in RF analysis on GWAS data. Further studies in real GWAS datasets are required to validate the robustness of the proposed approach.
doi:10.1093/ije/dys183
PMCID: PMC3535752  PMID: 23148107
Genome-wide association study; population stratification; random forest

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