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1.  Contaminated Turmeric Is a Potential Source of Lead Exposure for Children in Rural Bangladesh 
Background. During the conduct of a cohort study intended to study the associations between mixed metal exposures and child health outcomes, we found that 78% of 309 children aged 20–40 months evaluated in the Munshiganj District of Bangladesh had blood lead concentrations ≥5 µg/dL and 27% had concentrations ≥10 µg/dL. Hypothesis. Environmental sources such as spices (e.g., turmeric, which has already faced recalls in Bangladesh due to high lead levels) may be a potential route of lead exposure. Methods. We conducted visits to the homes of 28 children randomly selected from among high and low blood lead concentration groups. During the visits, we administered a structured questionnaire and obtained soil, dust, rice, and spice samples. We obtained water samples from community water sources, as well as environmental samples from neighborhood businesses. Results. Lead concentrations in many turmeric samples were elevated, with lead concentrations as high as 483 ppm. Analyses showed high bioaccessibility of lead. Conclusions. Contamination of turmeric powder is a potentially important source of lead exposure in this population.
PMCID: PMC4158309  PMID: 25214856
2.  Smoking and smoking cessation in relation to the development of co-existing non-small cell lung cancerwith chronic obstructive pulmonary disease 
PMCID: PMC4008140  PMID: 23921845
Cigarette smoking; Smoking cessation; non-small cell lung cancer; coexisting chronic obstructive pulmonary disease; risk
3.  Prognostic Significance of MTOR Pathway Component Expression in Neuroendocrine Tumors 
Journal of Clinical Oncology  2013;31(27):3418-3425.
Clinical studies have implicated the mechanistic target of rapamycin (serine/threonine kinase; MTOR) pathway in the regulation of neuroendocrine tumor (NET) growth. We explored whether expression of MTOR pathway components has prognostic significance in NET patients.
Patients and Methods
We evaluated immunohistochemical expression of MTOR and phospho (p) –MTOR; its downstream targets RPS6KB1, RPS6, and EIF4EBP1; and its upstream regulators, in a cohort of 195 archival neuroendocrine tumors. We correlated expression levels with clinical outcomes, after adjusting for other prognostic variables.
We observed anticipated correlations between expression of upstream components of the MTOR pathway and their downstream targets. Expression of PIK3CA, MTOR, or p-EIF4EBP1 was associated with high MKI67 (Ki-67) labeling index. We failed to identify clinical correlations associated with expression of the upstream regulators TSC1, TSC2, AKT, p-AKT, PDPK1, PTEN, PIK3R1, or PIK3CA. In contrast, high expression of MTOR or its activated downstream targets p-RPS6KB1, p-RPS6, or p-EIF4EBP1 was associated with adverse clinical outcomes.
Our observations suggest that expression of MTOR or its downstream targets may be adverse prognostic factors in neuroendocrine tumors.
PMCID: PMC3770868  PMID: 23980085
4.  Association of Low to Moderate Levels of Arsenic Exposure With Risk of Type 2 Diabetes in Bangladesh 
American Journal of Epidemiology  2013;178(10):1563-1570.
Chronic exposure to high levels of arsenic in drinking water is associated with increased risk of type 2 diabetes mellitus (T2DM), but the association between lower levels of arsenic and T2DM is more controversial. Therefore, this study evaluated the association between low to moderate arsenic exposure and T2DM. In 2009–2011, we conducted a study of 957 Bangladeshi adults who participated in a case-control study of skin lesions in 2001–2003. The odds ratio of T2DM was evaluated in relationship to arsenic exposure measured in drinking water and in subjects’ toenails (in 2001–2003) prior to the diagnosis of T2DM (in 2009–2011). Compared with those exposed to the lowest quartile of arsenic in water (≤1.7 µg/L), the adjusted odds ratio for T2DM was 1.92 (95% confidence interval (CI): 0.82, 4.35) for those in the second quartile, 3.07 (95% CI: 1.38, 6.85) for those in the third quartile, and 4.51 (95% CI: 2.01, 10.09) for those in the fourth quartile. The relative excess risk of T2DM was 4.78 for individuals who smoked and 8.93 for people who had a body mass index (weight (kg)/height (m)2) greater than 25. These findings suggest that exposure to modest levels of arsenic in drinking water was associated with increased risk of T2DM in Bangladesh. Being overweight or smoking was also associated with increased risk of T2DM.
PMCID: PMC3888275  PMID: 24049161
additive interaction; arsenic; Bangladesh; diabetes; overweight; smoking
5.  Mitochondrial Variations in Non-Small Cell Lung Cancer (NSCLC) Survival 
Cancer Informatics  2015;14(Suppl 1):1-9.
Mutations in the mtDNA genome have long been suspected to play an important role in cancer. Although most cancer cells harbor mtDNA mutations, the question of whether such mutations are associated with clinical prognosis of lung cancer remains unclear. We resequenced the entire mitochondrial genomes of tumor tissue from a population of 250 Korean patients with non-small cell lung cancer (NSCLC). Our analysis revealed that the haplogroup (D/D4) was associated with worse overall survival (OS) of early-stage NSCLC [adjusted hazard ratio (AHR), 1.95; 95% CI, 1.14–3.33; Ptrend = 0.03]. By comparing the mtDNA variations between NSCLC tissues and matched blood samples, we found that haplogroups M/N and/or D/D4 were hotspots for somatic mutations, suggesting a more complicated mechanism of mtDNA somatic mutations other than the commonly accepted mechanism of sequential accumulation of mtDNA mutations.
PMCID: PMC4310616  PMID: 25657573
mitochondria genome; mitochondria mutations; lung cancer survival; haplogroup; mitochondrial genome resequencing
6.  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.
PMCID: PMC4082746  PMID: 24677489
Arsenic; DNA methylation; Illumina 450K; longitudinal; skin lesion
Telomeres are genomic structures that reflect both mitotic history and biochemical trauma to the genome. Metals inherent in fine particulate matter (PM2.5) were shown to be genotoxic via oxidative damage. However, few studies investigated the induction time of cumulative PM2.5 exposure on telomere length in a longitudinal setting. Therefore, the purpose of this study was to assess the association between occupational PM2.5 exposure in various time windows and telomere length. The study population consisted of 48 boilermakers and the follow-up period was 8 yr. The main exposures were cumulative occupational PM2.5 in the month, year, and career prior to each blood draw, assessed via work history questionnaires and area air measures. Repeated telomere length measurements from leukocytes were assessed via real-time quantitative polymerase chain reaction (qPCR). Analysis was performed using linear mixed models controlling for confounders and white blood cell differentials. Cumulative PM2.5 exposure was treated continuously and categorized into quartiles, in separate analyses. At any follow-up time, for each milligram per cubic meter per hour increase in cumulative PM2.5 exposure in the prior month, there was a statistically significant decrease in relative telomere length of −0.04 units. When categorizing the exposure into quartiles, there was a significant negative association between telomere length and highest quartile of cumulative PM2.5 exposure in the prior month (−0.16). These findings suggest that genomic trauma to leukocyte telomeres was more consistent with recent occupational PM2.5 exposure, as opposed to cumulative exposure extending into the distant past.
PMCID: PMC4072226  PMID: 24627998
8.  Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer 
Wang, Yufei | McKay, James D. | Rafnar, Thorunn | Wang, Zhaoming | Timofeeva, Maria | Broderick, Peter | Zong, Xuchen | Laplana, Marina | Wei, Yongyue | Han, Younghun | Lloyd, Amy | Delahaye-Sourdeix, Manon | Chubb, Daniel | Gaborieau, Valerie | Wheeler, William | Chatterjee, Nilanjan | Thorleifsson, Gudmar | Sulem, Patrick | Liu, Geoffrey | Kaaks, Rudolf | Henrion, Marc | Kinnersley, Ben | Vallée, Maxime | LeCalvez-Kelm, Florence | Stevens, Victoria L. | Gapstur, Susan M. | Chen, Wei V. | Zaridze, David | Szeszenia-Dabrowska, Neonilia | Lissowska, Jolanta | Rudnai, Peter | Fabianova, Eleonora | Mates, Dana | Bencko, Vladimir | Foretova, Lenka | Janout, Vladimir | Krokan, Hans E. | Gabrielsen, Maiken Elvestad | Skorpen, Frank | Vatten, Lars | Njølstad, Inger | Chen, Chu | Goodman, Gary | Benhamou, Simone | Vooder, Tonu | Valk, Kristjan | Nelis, Mari | Metspalu, Andres | Lener, Marcin | Lubiński, Jan | Johansson, Mattias | Vineis, Paolo | Agudo, Antonio | Clavel-Chapelon, Francoise | Bueno-de-Mesquita, H.Bas | Trichopoulos, Dimitrios | Khaw, Kay-Tee | Johansson, Mikael | Weiderpass, Elisabete | Tjønneland, Anne | Riboli, Elio | Lathrop, Mark | Scelo, Ghislaine | Albanes, Demetrius | Caporaso, Neil E. | Ye, Yuanqing | Gu, Jian | Wu, Xifeng | Spitz, Margaret R. | Dienemann, Hendrik | Rosenberger, Albert | Su, Li | Matakidou, Athena | Eisen, Timothy | Stefansson, Kari | Risch, Angela | Chanock, Stephen J. | Christiani, David C. | Hung, Rayjean J. | Brennan, Paul | Landi, Maria Teresa | Houlston, Richard S. | Amos, Christopher I.
Nature genetics  2014;46(7):736-741.
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 of BRCA2-K3326X (rs11571833; odds ratio [OR]=2.47, P=4.74×10−20) and of CHEK2-I157T (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 previously only reported 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 having substantive effects on cancer risk from pre-existing GWAS data.
PMCID: PMC4074058  PMID: 24880342
9.  Smoking-associated fibrosis and pulmonary asbestosis 
The diagnosis of pulmonary asbestosis is most often established based on clinical criteria and has both clinical and legal implications. Unfortunately, one of the confounding features in the diagnosis may be a history of cigarette abuse, which can produce interstitial opacities on chest imaging as well as diffusion defects on pulmonary function testing, criteria that are used in the diagnosis of pulmonary asbestosis. The objective of the present study was to evaluate the correlation of radiographically detected pulmonary fibrosis with fibrosis established histopathologically as attributable to asbestos, in a cohort referred for diagnosis of an asbestos-related malignancy in the context of litigation. We examined the slides of 186 cases with reported asbestos exposure, referred in consultation for asbestos-related malignancy and the presence of pulmonary fibrosis. Sixty-five cases had what was judged to be adequate tissue sampling for histopathologic evaluation of asbestosis as well as an existing radiologic assessment of pulmonary fibrosis by B-reader report. Of 24 cases judged to have asbestosis radiographically, which had sufficient tissue for pathologic examination, six showed asbestosis histopathologically. The remaining 18 cases (mean smoking history of 53 pack-years) showed interstitial fibrosis that was judged to be most consistent with smoking-associated pulmonary fibrosis. We conclude that the clinical diagnosis of mild asbestosis cannot be reliably distinguished from interstitial fibrosis in heavy smokers.
PMCID: PMC4279669  PMID: 25565798
asbestos; smoking; pulmonary fibrosis
10.  Heart rate variability and DNA methylation levels are altered after short-term metal fume exposure among occupational welders: a repeated-measures panel study 
BMC Public Health  2014;14(1):1279.
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.
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.
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.
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.
PMCID: PMC4302115  PMID: 25512264
11.  Irisin mRNA and circulating levels in relation to other myokines in healthy and morbidly obese humans 
Skeletal muscle is considered to be an endocrine organ that secretes a number of myokines including follistatin, myostatin, activin A and the newly identified irisin. Irisin’s biology and function exhibits similarities with the functions of the follistatin-myostatin-activin A axis. It remains unknown whether there is any interplay among these molecules. The aim of this study is to examine potential associations of irisin with the follistatin, myostatin and activin A axis.
Two observational studies were performed to evaluate the associations of irisin with the other three peptides. Study A included 150 healthy males aged 18.48 ±0.16 years with Body Mass Index (BMI) 23.18± 3.75 kg/m2. Fasting serum samples were used to measure the levels of the molecules of interest. Study B included 14 morbidly obese individuals, candidates for bariatric surgery, aged 53.14±8.93 years with BMI 50.18±10.63 kg/m2. Blood samples were obtained after an overnight fast. Eight out of the fourteen participants consented to an optional thigh biopsy during their bariatric surgery. Using the above blood and tissue samples, we measured circulating levels and muscle mRNA of irisin, follistatin, myostatin and activin A.
We report that FNDC5 mRNA in muscle is positively correlated with follistatin mRNA expression in morbidly obese subjects (rho=0.93, p<0.001). We also found that circulating irisin is positively correlated with follistatin circulating levels among lean subjects (rho=0.17, p=0.05) while this association was suggestive among the obese (rho=0.56, p=0.07).
The newly identified myokine irisin may be positively associated with follistatin at both the mRNA and circulating protein level.
PMCID: PMC3857961  PMID: 24062354
irisin; follistatin; activin A; myostatin; muscle
12.  Prognostic and diagnostic value of plasma soluble ST2 concentrations in Acute Respiratory Distress Syndrome 
Critical care medicine  2013;41(11):10.1097/CCM.0b013e3182978f91.
Soluble ST2 (sST2) is a biomarker of myocardial strain and inflammation. The characteristics of acute respiratory distress syndrome (ARDS) include inflammation and cardiovascular dysfunction. We sought to determine whether plasma sST2 concentration is associated with outcome and response to conservative fluid management, and whether sST2 concentration discriminates ARDS from decompensated heart failure (HF).
Design, Setting, and Patients
We assayed plasma sST2 concentrations in 826 patients in the Fluid and Catheter Treatment Trial (FACTT), a multi-center randomized controlled trial of conservative fluid management in ARDS, as well as a cohort of patients with decompensated HF. We tested whether sST2 was associated with outcome, response to therapy, and diagnostic utility for ARDS vs. HF.
Measurements and Main Results
Non-survivors had higher day 0 (P<.0001) and day 3 (P<.0001) sST2 concentrations. After adjustment for severity of illness, higher sST2 concentration was associated with mortality, with odds ratio (ORadj) 1.47 (95% confidence interval [CI] 0.99 – 2.20, P=.06) at day 0, 2.94 (95% CI 2.00 – 4.33, P<.0001) at day 3, and 3.63 (95% CI 2.38 – 5.53, P<.0001) if sST2 increased between days. Cumulative fluid balance was more positive among patients with higher day 0 (median 5212 mL, interquartile range [IQR] 200 – 12284 vs. 2020 mL, −2034 – 7091; P<0.0001), and day 3 sST2 (median 7678 mL, IQR 2217 – 14278 vs. 1492 mL, −2384 – 6239; P<0.0001). sST2 showed excellent discriminative ability between the FACTT and HF populations (Area under ROC curve=0.98, P<0.0001).
Higher sST2 concentrations are associated with worse outcome in ARDS and may have value for discriminating ARDS from heart failure.
PMCID: PMC3812317  PMID: 23939353
Acute respiratory distress syndrome; Biomarkers; Fluid Therapy
13.  Childhood Anemia at High Altitude: Risk Factors for Poor Outcomes in Severe Pneumonia 
Pediatrics  2013;132(5):e1156-e1162.
Pneumonia is the leading cause of mortality in young children globally, and factors that affect tissue delivery of oxygen may affect outcomes of pneumonia. We studied whether altitude and anemia influence disease severity and outcomes in young children with World Health Organization–defined severe pneumonia.
We analyzed data from the SPEAR (Severe Pneumonia Evaluation Antimicrobial Research) study, a World Health Organization– and USAID-sponsored multinational randomized controlled trial of antibiotics for severe pneumonia among children aged 2 to 59 months in resource-poor settings. The trial enrolled 958 children in 8 sites at varying elevations, classified as high (≥2000 m) or low (<2000 m) altitude. We compared illness severity and assessed the effect of anemia on treatment outcome at high and low altitudes, adjusting for potential confounders and study site.
Children at high altitudes had significantly lower oxygen saturation on presentation, more cyanosis, lower systolic blood pressure, and higher hemoglobin. After adjusting for potential confounders, anemia predicted treatment failure in children living at high altitude (relative risk: 4.07; 95% confidence interval: 2.60–6.38) but not at low altitude (relative risk: 1.12; 95% confidence interval: 0.96–1.30). Children at high altitude took longer to reach normoxemia than did children at lower altitudes (5.25 vs 0.75 days; P < .0001).
Children at high altitude present with more severe disease, and children with anemia at high altitude are at greater risk of poor outcome when being treated for severe pneumonia. Given the high global prevalence of anemia among young children, prevention and treatment of anemia should be a priority in children living at high altitude and could improve outcomes of pneumonia.
PMCID: PMC3812558  PMID: 24101768
pneumonia; anemia; high altitude; international child health
14.  The Global Contribution of Outdoor Air Pollution to the Incidence, Prevalence, Mortality and Hospital Admission for Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis 
Objective: This study aimed to investigate the quantitative effects of outdoor air pollution, represented by 10 µg/m3 increment of PM10, on chronic obstructive pulmonary disease in China, United States and European Union through systematic review and meta-analysis. Methods: Publications in English and Chinese from PubMed and EMBASE were selected. The Cochrane Review Handbook of Generic Inverse Variance was used to synthesize the pooled effects on incidence, prevalence, mortality and hospital admission. Results: Outdoor air pollution contributed to higher incidence and prevalence of COPD. Short-term exposure was associated with COPD mortality increased by 6%, 1% and 1% in the European Union, the United States and China, respectively (p < 0.05). Chronic PM exposure produced a 10% increase in mortality. In a short-term exposure to 10 µg/m3 PM10 increment COPD mortality was elevated by 1% in China (p < 0.05) and hospital admission enrollment was increased by 1% in China, 2% in United States and 1% in European Union (p < 0.05). Conclusions: Outdoor air pollution contributes to the increasing burdens of COPD.10 µg/m3 increase of PM10 produced significant condition of COPD death and exacerbation in China, United States and European Union. Controlling air pollution will have substantial benefit to COPD morbidity and mortality.
PMCID: PMC4245645  PMID: 25405599
ambient air pollution; chronic obstructive pulmonary disease; environmental health; epidemiology; particulate matter
15.  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.
PMCID: PMC3908453  PMID: 22422400
matrix metalloproteinase; gene polymorphism; gastroesophageal reflux disease; esophageal cancer
16.  TEGS-CN: A Statistical Method for Pathway Analysis of Genome-wide Copy Number Profile 
Cancer Informatics  2014;13(Suppl 4):15-23.
The effects of copy number alterations make up a significant part of the tumor genome profile, but pathway analyses of these alterations are still not well established. We proposed a novel method to analyze multiple copy numbers of genes within a pathway, termed Test for the Effect of a Gene Set with Copy Number data (TEGS-CN). TEGS-CN was adapted from TEGS, a method that we previously developed for gene expression data using a variance component score test. With additional development, we extend the method to analyze DNA copy number data, accounting for different sizes and thus various numbers of copy number probes in genes. The test statistic follows a mixture of X2 distributions that can be obtained using permutation with scaled X2 approximation. We conducted simulation studies to evaluate the size and the power of TEGS-CN and to compare its performance with TEGS. We analyzed a genome-wide copy number data from 264 patients of non-small-cell lung cancer. With the Molecular Signatures Database (MSigDB) pathway database, the genome-wide copy number data can be classified into 1814 biological pathways or gene sets. We investigated associations of the copy number profile of the 1814 gene sets with pack-years of cigarette smoking. Our analysis revealed five pathways with significant P values after Bonferroni adjustment (<2.8 × 10−5), including the PTEN pathway (7.8 × 10−7), the gene set up-regulated under heat shock (3.6 × 10−6), the gene sets involved in the immune profile for rejection of kidney transplantation (9.2 × 10−6) and for transcriptional control of leukocytes (2.2 × 10−5), and the ganglioside biosynthesis pathway (2.7 × 10−5). In conclusion, we present a new method for pathway analyses of copy number data, and causal mechanisms of the five pathways require further study.
PMCID: PMC4218657  PMID: 25452685
copy numbers; pathway analyses; gene set analyses; variance component test; cancer genomics
17.  Circulating oncometabolite 2-hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase-mutant intrahepatic cholangiocarcinoma 
Mutations in the IDH1 and IDH2 (IDH1/2) genes occur in ~20% of intrahepatic cholangiocarcinoma (ICC) and lead to accumulation of 2-hydroxyglutarate (2HG) in the tumor tissue. However, it remains unknown whether IDH1/2 mutations can lead to high levels of 2HG circulating in the blood and whether serum 2HG can be used as a biomarker for IDH1/2 mutational status and tumor burden in ICC.
Experimental Design
We initially measured serum 2HG concentration in blood samples collected from 31 ICC patients in a Screening cohort. Findings were validated across 38 resected ICC patients from a second cohort with tumor volume measures. Circulating levels of 2HG were evaluated relative to IDH1/2 mutational status, tumor burden and a number of clinical variables.
Circulating levels of 2HG in the Screening cohort were significantly elevated in patients with IDH1/2-mutant (median 478 ng/ml) versus IDH1/2-wild-type (median 118 ng/ml) tumors (p<0.001). This significance was maintained in the Validation cohort (343 ng/ml vs 55 ng/ml, p<0.0001) and levels of 2HG directly correlated with tumor burden in IDH1/2-mutant cases (p<0.05). Serum 2HG levels ≥170 ng/ml could predict the presence of an IDH1/2 mutation with a sensitivity of 83% and a specificity of 90%. No differences were noted between the allelic variants IDH1 or IDH2 in regards to the levels of circulating 2HG.
This study indicates that circulating 2HG may be a surrogate biomarker of IDH1 or IDH2 mutation status in ICC and that circulating 2HG levels may correlate directly with tumor burden.
PMCID: PMC4107454  PMID: 24478380
Cholangiocarcinoma; 2-Hydroxyglutarate; IDH1; IDH2; Biomarker
18.  Effectiveness of the Cigarette Ignition Propensity Standard in Preventing Unintentional Residential Fires in Massachusetts 
American journal of public health  2014;104(4):e56-e61.
We evaluated the Massachusetts Fire Safe Cigarette Law’s (FSCL’s) effectiveness in preventing residential fires.
We examined unintentional residential fires reported to the Massachusetts Fire Incident Reporting Systemfrom 2004 to 2010.We analyzed FSCL effect on the likelihood of cigarette- versus noncigarette-caused fires and effect modification by fire scenario factors by using an interrupted time series regression model. We analyzed the effect of FSCL on monthly fire rates with Poisson regression.
Cigarettes caused 1629 unintentional residential fires during the study period. The FSCL was associated with a 28% (95% confidence interval = 12%, 41%) reduction in the odds of cigarette- versus noncigarette-caused fires, although not in analyses restricted to casualty fires, with smaller sample size. The largest reductions were among fires in which human factors were involved; that were first ignited on furniture, bedding, or soft goods; that occurred in living areas; or that occurred in the summer or winter.
The FSCL appears to have decreased the likelihood of cigarette-caused residential fires, particularly in scenarios for which the ignition propensity standard was developed. Current standards should be adopted, and the need for strengthening should be considered.
PMCID: PMC4025697  PMID: 24524537
19.  Test for interactions between a genetic marker set and environment in generalized linear models 
Biostatistics (Oxford, England)  2013;14(4):667-681.
We consider in this paper testing for interactions between a genetic marker set and an environmental variable. A common practice in studying gene–environment (GE) interactions is to analyze one single-nucleotide polymorphism (SNP) at a time. It is of significant interest to analyze SNPs in a biologically defined set simultaneously, e.g. gene or pathway. In this paper, we first show that if the main effects of multiple SNPs in a set are associated with a disease/trait, the classical single SNP–GE interaction analysis can be biased. We derive the asymptotic bias and study the conditions under which the classical single SNP–GE interaction analysis is unbiased. We further show that, the simple minimum p-value-based SNP-set GE analysis, can be biased and have an inflated Type 1 error rate. To overcome these difficulties, we propose a computationally efficient and powerful gene–environment set association test (GESAT) in generalized linear models. Our method tests for SNP-set by environment interactions using a variance component test, and estimates the main SNP effects under the null hypothesis using ridge regression. We evaluate the performance of GESAT using simulation studies, and apply GESAT to data from the Harvard lung cancer genetic study to investigate GE interactions between the SNPs in the 15q24–25.1 region and smoking on lung cancer risk.
PMCID: PMC3769996  PMID: 23462021
Asymptotic bias analysis; Gene–environment interactions; Genome-wide association studies; Score statistic; Single-nucleotide polymorphism; Variance component test
20.  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.
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.
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).
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.
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.
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
22.  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.
PMCID: PMC3293105  PMID: 22052259
MTHFR; folate; genetic polymorphisms; DNA adducts; one carbon metabolism
23.  Reduced lung cancer mortality and exposure to synthetic fluids and biocide in the auto manufacturing industry 
Water-based soluble and synthetic metalworking fluids (MWF) used in auto manufacturing may be contaminated by endotoxin from Gram-negative bacteria, a possible anticarcinogen via increased immuno-surveillance. The effectiveness of biocide, generally added to limit bacterial growth is unknown. We investigated whether an inverse relationship between lung cancer and synthetic MWF and biocide – as surrogates of endotoxin exposure – persisted in an extended follow-up of autoworkers.
A nested case–control analysis was performed within a retrospective cohort study of 46 399 auto manufacturing workers. Follow-up began in 1941 and was extended from 1985–1995. Mortality rate ratios (MRR) were estimated in Cox regression models for lung cancer as discrete and smoothed functions of cumulative exposure to synthetic MWF (mg/m3 per year) and years exposed to biocide with both synthetic and soluble MWF. The analysis was also restricted to the subcohort hired on or after 1941 and stratified by follow-up period.
The splines suggested a non-linear inverse exposure–response for lung cancer mortality with increasing endotoxin exposure. Overall, the greatest reduction in mortality was observed among those with the highest exposure [MRR 0.63, 95% confidence interval (95% CI) 0.39–0.98] at the 99th percentile of exposure (15.8 mg/m3 per year). Evidence for an inverse effect was limited to the earlier follow-up period. Effect modification by biocide was marginally significant (P=0.07); the protective effect of synthetic MWF was observed only for those who were co-exposed.
The protective effect of synthetic MWF against lung cancer mortality persisted through the extended period of follow-up, although attenuated, and was observed only among workers with co-exposure to biocide and synthetic MWF.
PMCID: PMC4108426  PMID: 20835688
auto manufacturing industry; biocide; cohort study; endotoxin; exposure; lung cancer; lung cancer mortality; metalworking fluid; mortality; occupational epidemiology; retrospective cohort study; synthetic biocide; synthetic fluid
24.  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.
PMCID: PMC3827695  PMID: 24216523
Lung cancer; women; risk factors; genetic mutations
25.  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.
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).
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.
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.
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.
PMCID: PMC3312983  PMID: 22144047
Radiation pneumonitis; single nucleotide polymorphisms; lung cancer; oxidative stress; MTHFR

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