Urinary metabolites of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides, termed total NNAL, have recently been shown to be good predictors of lung cancer risk, years prior to diagnosis. We sought to determine the contribution of several genetic polymorphisms to total NNAL output and inter-individual variability. The study subjects were derived from the Harvard/Massachusetts General Hospital Lung cancer case-control study. We analyzed 87 self-described smokers (35 lung cancer cases and 52 controls), with urine samples collected at time of diagnosis and (1992–1996). We tested 82 tagging SNPs in 16 genes related to the metabolism of NNK to total NNAL. Using weighted case status least squares regression, we tested for the association of each SNP with square-root (sqrt) transformed total NNAL (pmol per mg creatinine), controlling for age, sex, sqrt packyears and sqrt nicotine (ng per mg creatinine). After a sqrt transformation, nicotine significantly predicted a 0.018 (0.014, 0.023) pmol/mg creatinine unit increase in total NNAL for every ng/mg creatinine increase in nicotine at p<10E-16. Three HSD11B1 SNPs and AKR1C4 rs7083869 were significantly associated with decreasing total NNAL levels: HSD11B1 rs2235543 (p= 4.84E-08) and rs3753519 (p= 0.0017) passed multiple testing adjustment at FDR q=1.13E-05 and 0.07 respectively, AKR1C4 rs7083869 (p=0.019) did not, FDR q=0.51. HSD11B1 and AKR1C4 enzymes are carbonyl reductases directly involved in the single step reduction of NNK to NNAL. The HSD11B1 SNPs may be correlated with the functional variant rs13306401 and the AKR1C4 SNP is correlated with the enzyme activity reducing variant rs17134592, L311V.
NNK; NNAL; tobacco specific nitrosamine; genetic polymorphism; HSD11B1
Both nurture (environmental) and nature (genetic factors) play an important role in human disease etiology. Traditionally, these effects have been thought of as independent. This perspective is ill informed for non-mendelian complex disorders which result as an interaction between genetics and environment. To understand health and disease we must study how nature and nurture interact. Recent advances in human genomics and high-throughput biotechnology make it possible to study large numbers of genetic markers and gene products simultaneously to explore their interactions with environment. The purpose of this review is to discuss design and analytic issues for gene-environment interaction studies in the “-omics” era, with a focus on environmental and genetic epidemiological studies. We present an expanded environmental genomic disease paradigm. We discuss several study design issues for gene-environmental interaction studies, including confounding and selection bias, measurement of exposures and genotypes. We discuss statistical issues in studying gene-environment interactions in different study designs, such as choices of statistical models, assumptions regarding biological factors, and power and sample size considerations, especially in genome-wide gene-environment studies. Future research directions are also discussed.
Gene-environment; Interactions; Expanded environmental genomic disease paradigm; Critical developmental windows; Genome-wide; Epigenetics
Background: Chronic exposure to arsenic is associated with skin lesions. However, it is not known whether reducing arsenic exposure will improve skin lesions.
Objective: We evaluated the association between reduced arsenic exposures and skin lesion recovery over time.
Methods: A follow-up study of 550 individuals was conducted in 2009–2011 on a baseline population of skin lesion cases (n = 900) previously enrolled in Bangladesh in 2001–2003. Arsenic in drinking water and toenails, and skin lesion status and severity were ascertained at baseline and follow-up. We used logistic regression and generalized estimating equation (GEE) models to evaluate the association between log10-transformed arsenic exposure and skin lesion persistence and severity.
Results: During the study period, water arsenic concentrations decreased in this population by 41% overall, and 65 individuals who had skin lesions at baseline had no identifiable lesions at follow-up. In the adjusted models, every log10 decrease in water arsenic and toenail arsenic was associated with 22% [odds ratio (OR) = 1.22; 95% CI: 0.85, 1.78] and 4.5 times (OR = 4.49; 95% CI: 1.94, 11.1) relative increase in skin lesion recovery, respectively. In addition, lower baseline arsenic levels were significantly associated with increased odds of recovery. A log10 decrease in toenail arsenic from baseline to follow-up was also significantly associated with reduced skin lesion severity in cases over time (mean score change of –5.22 units; 95% CI: –8.61, –1.82).
Conclusions: Reducing arsenic exposure increased the odds that an individual with skin lesions would recover or show less severe lesions within 10 years. Reducing arsenic exposure must remain a public health priority in Bangladesh and in other regions affected by arsenic-contaminated water.
arsenic; Bangladesh; change; recovery; skin lesion
Tobacco-induced lung cancer is characterized by a deregulated inflammatory microenvironment. Variants in multiple genes in inflammation pathways may contribute to risk of lung cancer.
We therefore conducted a three-stage comprehensive pathway analysis (discovery, replication and meta-analysis) of inflammation gene variants in ever smoking lung cancer cases and controls. A discovery set (1096 cases; 727 controls) and an independent and non-overlapping internal replication set (1154 cases; 1137 controls) were derived from an ongoing case-control study. For discovery, we used an iSelect BeadChip to interrogate a comprehensive panel of 11737 inflammation pathway SNPs and selected nominally significant (p<0.05) SNPs for internal replication.
There were 6 SNPs that achieved statistical significance (p<0.05) in the internal replication dataset with concordant risk estimates for former smokers and 5 concordant and replicated SNPs in current smokers. Replicated hits were further tested in a subsequent meta-analysis using external data derived from two published GWAS and a case-control study. Two of these variants (a BCL2L14 SNP in former smokers and a SNP in IL2RB in current smokers) were further validated. In risk score analyses, there was a 26% increase in risk with each additional adverse allele when we combined the genotyped SNP and the most significant imputed SNP in IL2RB in current smokers and a 36% similar increase in risk for former smokers associated with genotyped and imputed BCL2L14 SNPs.
Before they can be applied for risk prediction efforts, these SNPs should be subject to further external replication and more extensive fine mapping studies.
Inflammation SNPS; lung cancer; smokers
In this paper, we develop a powerful test for identifying SNP-sets that are predictive of survival with data from genome-wide association studies (GWAS). We first group typed SNPs into SNP-sets based on genomic features and then apply a score test to assess the overall effect of each SNP-set on the survival outcome through a kernel machine Cox regression framework. This approach uses genetic information from all SNPs in the SNP-set simultaneously and accounts for linkage disequilibrium (LD), leading to a powerful test with reduced degrees of freedom when the typed SNPs are in LD with each other. This type of test also has the advantage of capturing the potentially non-linear effects of the SNPs, SNP-SNP interactions (epistasis), and the joint effects of multiple causal variants. By simulating SNP data based on the LD structure of real genes from the HapMap project, we demonstrate that our proposed test is more powerful than the standard single SNP minimum p-value based test for association studies with censored survival outcomes. We illustrate the proposed test with a real data application.
cox model; genetic studies; gene-based analysis; kernel machine; multi-locus test; score test; single nucleotide polymorphism
GWAS has facilitated greatly the discovery of risk SNPs associated with complex diseases. Traditional methods analyze SNP individually and are limited by low power and reproducibility since correction for multiple comparisons is necessary. Several methods have been proposed based on grouping SNPs into SNP sets using biological knowledge and/or genomic features. In this article, we compare the linear kernel machine based test (LKM) and principal components analysis based approach (PCA) using simulated datasets under the scenarios of 0 to 3 causal SNPs, as well as simple and complex linkage disequilibrium (LD) structures of the simulated regions. Our simulation study demonstrates that both LKM and PCA can control the type I error at the significance level of 0.05. If the causal SNP is in strong LD with the genotyped SNPs, both the PCA with a small number of principal components (PCs) and the LKM with kernel of linear or identical-by-state function are valid tests. However, if the LD structure is complex, such as several LD blocks in the SNP set, or when the causal SNP is not in the LD block in which most of the genotyped SNPs reside, more PCs should be included to capture the information of the causal SNP. Simulation studies also demonstrate the ability of LKM and PCA to combine information from multiple causal SNPs and to provide increased power over individual SNP analysis. We also apply LKM and PCA to analyze two SNP sets extracted from an actual GWAS dataset on non-small cell lung cancer.
Aberrant DNA methylation (DNAm) is a feature of most types of cancers. Genome-wide DNAm profiling has been performed successfully on tumor tissue DNA samples. However, the invasive procedure limits the utility of tumor tissue for epidemiological studies. While recent data indicate that cell-free circulating DNAm (cfDNAm) profiles reflect DNAm status in corresponding tumor tissues, no studies have examined the association of cfDNAm with cancer or precursors on a genome-wide scale. The objective of this pilot study was to evaluate the putative significance of genome-wide cfDNAm profiles in esophageal adenocarcinoma (EA) and Barrett esophagus (BE, EA precursor). We performed genome-wide DNAm profiling in EA tissue DNA (n = 8) and matched serum DNA (n = 8), in serum DNA of BE (n = 10), and in healthy controls (n = 10) using the Infinium HumanMethylation27 BeadChip that covers 27,578 CpG loci in 14,495 genes. We found that cfDNAm profiles were highly correlated to DNAm profiles in matched tumor tissue DNA (r = 0.92) in patients with EA. We selected the most differentially methylated loci to perform hierarchical clustering analysis. We found that 911 loci can discriminate perfectly between EA and control samples, 554 loci can separate EA from BE samples, and 46 loci can distinguish BE from control samples. These results suggest that genome-wide cfDNAm profiles are highly consistent with DNAm profiles detected in corresponding tumor tissues. Differential cfDNAm profiling may be a useful approach for the noninvasive screening of EA and EA premalignant lesions.
Genetic risk factors for sporadic neuroendocrine tumors (NET) are poorly understood. We tested risk associations in patients with sporadic NET and non-cancer controls, using a custom array containing 1536 single-nucleotide polymorphisms (SNPs) in 355 candidate genes. We identified 18 SNPs associated with NET risk at a P-value <0.01 in a discovery set of 261 cases and 319 controls. Two of these SNPs were found to be significantly associated with NET risk in an independent replication set of 235 cases and 113 controls, at a P value ≤0.05. An SNP in interleukin 12A (IL12A rs2243123), a gene implicated in inflammatory response, replicated with an adjusted odds ratio (95% confidence interval) (aOR) = 1.47 (1.03, 2.11) P-trend = 0.04. A second SNP in defender against cell death, (DAD1 rs8005354), a gene that modulates apoptosis, replicated at aOR = 1.43 (1.02, 2.02) P-trend = 0.04. Consistent with our observations, a pathway analysis, performed in the discovery set, suggested that genetic variation in inflammatory pathways or apoptosis pathways is associated with NET risk. Our findings support further investigation of the potential role of IL12A and DAD1 in the etiology of NET.
Background: Arsenic is an epigenetic toxicant and could influence fetal developmental programming.
Objectives: We evaluated the association between arsenic exposure and DNA methylation in maternal and umbilical cord leukocytes.
Methods: Drinking-water and urine samples were collected when women were at ≤ 28 weeks gestation; the samples were analyzed for arsenic using inductively coupled plasma mass spectrometry. DNA methylation at CpG sites in p16 (n = 7) and p53 (n = 4), and in LINE-1 and Alu repetitive elements (3 CpG sites in each), was quantified using pyrosequencing in 113 pairs of maternal and umbilical blood samples. We used general linear models to evaluate the relationship between DNA methylation and tertiles of arsenic exposure.
Results: Mean (± SD) drinking-water arsenic concentration was 14.8 ± 36.2 μg/L (range: < 1–230 μg/L). Methylation in LINE-1 increased by 1.36% [95% confidence interval (CI): 0.52, 2.21%] and 1.08% (95% CI: 0.07, 2.10%) in umbilical cord and maternal leukocytes, respectively, in association with the highest versus lowest tertile of total urinary arsenic per gram creatinine. Arsenic exposure was also associated with higher methylation of some of the tested CpG sites in the promoter region of p16 in umbilical cord and maternal leukocytes. No associations were observed for Alu or p53 methylation.
Conclusions: Exposure to higher levels of arsenic was positively associated with DNA methylation in LINE-1 repeated elements, and to a lesser degree at CpG sites within the promoter region of the tumor suppressor gene p16. Associations were observed in both maternal and fetal leukocytes. Future research is needed to confirm these results and determine if these small increases in methylation are associated with any health effects.
Alu; arsenic; developmental programming; DNA methylation; environmental exposures; epigenetics; in utero exposure; LINE-1; p16; p53
Polymorphisms in carcinogen detoxification enzymes, NAT2 and GSTM1, have been suggested as susceptibility factors for DNA damage and lung cancer. However, little information is available on DNA adduct burden in the lung tissue and polymorphisms in NAT2 and GST genes. We investigated the independent and combined effects of the metabolic gene polymorphisms of NAT2 and GSTs on DNA adduct formation in different tissues (lung and blood) in lung cancer patients.
DNA adducts were measured in lung and blood by the 32P-postlabeling assay. Multiple regression models were used to assess adjusted percent change in DNA adduct levels associated with GST and NAT2 genotypes.
After adjusting for potential confounders, as well as for other GST gene variants, lung adduct levels significantly increased by 150.3% (95% CI, 35.4% to 362.6%) for the GSTM1 null and by 73.9% (95% CI, -3.2% to 212.4%) for NAT2 slow acetylator genotype, respectively. No association was seen with polymorphisms of other GST genes such as GSTT1 and GSTP1. The high-risk group, the combined GSTM1 null plus NAT2 slow, had significantly enhanced levels of lung adducts by 295% (95% CI, 72.7% to 803.5%) over those associated with single genes, suggesting a synergistic effect on DNA damage in the target lung tissue.
Increased DNA adduct levels in lung associated with the GSTM1 null and NAT2 slow genotypes alone or in combination.
These results suggest that GSTM1 and NAT2 genotypes play an independent and interactive role in the formation of carcinogen DNA adduct in the lung.
DNA adducts; genetic polymorphisms; molecular epidemiology; lung cancer
The nucleotide excision repair (NER) pathway modulates platinum-based chemotherapeutic efficacy by removing drug-induced DNA damage.
To summarize published data on the association between NER genes and responses to platinum-based chemotherapies in non-small cell lung cancer (NSCLC), we performed a meta-analysis of 17 published studies of ERCC1 C118T/C8092A and ERCC2 Lys751Gln/Asp312Asn polymorphisms, including 2,097 cancer patients. Primary outcomes included objective response (TR) (i.e., complete response + partial response vs. stable disease + progressive disease), progression-free survival (PFS) and overall survival (OS). We calculated odds ratio (OR) or hazard ratio (HR) with 95% confidence interval (CI) to estimate the risk or hazard.
We found that none of the ERCC1 C118T/C8092A and ERCC2 Lys751Gln/Asp312Asn polymorphisms alone was statistically significantly associated with objective response, PFS and OS in NSCLC patients.
There is no evidence to support the use of NER ERCC1 C118T/C8092A and ERCC2 Lys751Gln/Asp312Asn polymorphisms as prognostic predictors of platinum-based chemotherapies in NSCLC.
Chemotherapy; DNA repair; Meta-analysis; Pharmacogenetics; Platinum
This study examined the correlation between manganese exposure and manganese concentrations in different biomarkers.
Air measurement data and work histories were used to determine manganese exposure over a workshift and cumulative exposure. Toenail samples (n=49), as well as blood and urine before (n=27) and after (urine, n=26; blood, n=24) a workshift were collected.
Toenail manganese, adjusted for age and dietary manganese, was significantly correlated with cumulative exposure in months 7-9, 10-12, and 7-12 before toenail clipping date, but not months 1-6. Manganese exposure over a work shift was not correlated with changes in blood nor urine manganese.
Toenails appeared to be a valid measure of cumulative manganese exposure 7 to 12 months earlier. Neither change in blood nor urine manganese appeared to be suitable indicators of exposure over a typical workshift.
Manganese; biomarkers; toenail manganese; blood manganese; urine manganese; low-level manganese exposure; welding fumes; welders
Background: Traffic-related particles (TRPs) are associated with adverse cardiovascular events. The exact mechanisms are unclear, but systemic inflammatory responses likely play a role.
Objectives: We conducted a repeated measures study among male participants of the Normative Aging Study in the greater Boston, Massachusetts, area to determine whether individual-level residential black carbon (BC), a marker of TRPs, is associated with systemic inflammation and whether coronary heart disease (CHD), diabetes, and obesity modify associations.
Methods: We quantified markers of inflammation in 1,163 serum samples from 580 men. Exposure to BC up to 4 weeks prior was predicted from a validated spatiotemporal land-use regression model. Linear mixed effects models estimated the effects of BC on each marker while adjusting for potential confounders.
Results: Associations between BC and blood markers were not observed in main effects models or when stratified by obesity status. However, BC was positively associated with markers of inflammation in men with CHD (particularly vascular endothelial growth factor) and in men with diabetes (particularly interleukin-1β and tumor necrosis factor-α). Significant exposure time windows varied by marker, although in general the strongest associations were observed with moving averages of 2–7 days after a lag of several days.
Conclusions: In an elderly male population, estimated BC exposures were positively associated with markers of systemic inflammation but only in men with CHD or diabetes.
air pollution; black carbon; cardiovascular disease; coronary heart disease; diabetes; inflammation; land-use regression model; particulate matter; susceptible; traffic
Inorganic arsenic is metabolized to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA). Limited evidence suggests that the ability to fully metabolize arsenic into DMA influences susceptibility to disease. To determine whether percentage of MMA was predictive of disease, the authors used data from a case-control study conducted in Bangladesh (2001–2003). Persons who were diagnosed with keratosis, melanosis, Bowen's disease, or squamous cell carcinoma were matched on age, sex, and village to persons without these conditions. This analysis was restricted to persons who had no missing data on covariates (859 cases, 868 controls). A path analysis was used to evaluate simultaneously the association between the percentage of all urinary arsenic metabolites and the odds of skin lesions using PROC CALIS in SAS, version 9.1 (SAS Institute, Inc., Cary, North Carolina) and Mplus, version 6.1 (Muthén & Muthén, Los Angeles, California). The odds of skin lesions were significantly associated with log10 percentage of MMA (adjusted odds ratio (ORadj) = 1.56, 95% confidence interval (CI): 1.15, 2.12) but not log10 percentage of inorganic arsenic (ORadj = 1.06, 95% CI: 0.75, 1.50) or log10 percentage of DMA (ORadj = 1.07, 95% CI: 0.33, 3.46). This novel analysis confirmed that persons who excrete a higher proportion of MMA have a greater risk of skin lesions after data are adequately controlled for urinary arsenic metabolites, current arsenic exposure, and other risk factors.
arsenic; Bangladesh; methylation; organometallic compounds; skin lesions; water
How genetic variations in apoptosis pathway interact with environmental factors to contribute to esophageal adenocarcinoma (EA) risk has not been comprehensively investigated. We conducted a case-only analysis in 335 Caucasian EA patients that were genotyped for 242 single nucleotide polymorphisms (SNPs) in 43 apoptotic genes. Gene–environment interactions were assessed using a two-step approach. First, random forest algorithm was used to screen for the potential interacting markers. Next, we used case-only logistic regression model to estimate the effects of gene–environment interactions on EA risk. Four SNPs (PERP rs648802; PIK3CA rs4855094, rs7644468 and TNFRSF1A rs4149579) had significant interaction with gastroesophageal reflux disease (GERD). The presence of variant alleles in TP53BP1 rs560191, CASP7 rs7907519 or BCL2 rs12454712 enhanced the risk of smoking by 2.08–2.58 times [interaction odds ratio (ORi) = 2.08–2.58, adjusted P-value (Padj) = 0.02–0.04]. Compared with patients carrying ≤1 risk genotype, the risk of GERD on EA was increased in persons with two (ORi = 1.89, Padj = 0.016) or ≥3 (ORi = 4.30, Padj < 0.0001) risk genotypes. Compared with cases with ≤1 risk genotype, smoking-associated EA risk increased by 3.15 times when ≥2 risk genotypes were present (ORi = 3.15, Padj < 0.0001). In conclusion, interactions among apoptotic SNPs and GERD or smoking play an important role in EA development.
Although recent research evidence suggests an association between household air pollution from solid fuel use, such as coal or biomass, and cardiovascular events such as hypertension, little epidemiologic data are available concerning such exposure effects on cardiovascular endpoints other than hypertension. We explored the association between in-home solid fuel use and self-reported diagnoses of cardiovascular endpoints, such as hypertension, coronary heart disease (CHD), stroke, and diabetes.
We analyzed 14,068 Chinese adults, aged 18 years and older. Odds ratios (OR) and the corresponding 95% confidence intervals (CI) were estimated using logistic regression models for the risk of each outcome after adjusting for potential confounders.
The use of solid fuel in home was significantly associated with an increased risk for hypertension (OR 1.70, 95% CI 1.40 to 2.07), CHD (OR 2.58, 95% CI 1.53 to 4.32), and diabetes (OR 2.48, 95% CI 1.59 to 3.86), after adjusting for potential confounders. Compared with individuals in the lowest tertile of the duration of solid fuel exposure, those in the highest tertile of the duration of solid fuel exposure had an increased odds of hypertension (OR 1.73, 95% CI 1.45 to 2.06), stroke (OR 1.87, 95% CI 1.03 to 3.38), and diabetes (OR 3.18, 95% CI 2.11 to 4.78).
Our data suggest that in-home solid fuel exposure maybe associated with increased risk for hypertension, CHD, stroke, and diabetes in the Chinese adult population. Further large-scale longitudinal studies are warranted to confirm these findings.
Household fuels; Cardiovascular disease; Indoor air pollution; Chinese
Epidemiologic and biologic evidence suggests that lung cancer has different clinical and biological characteristics in women, and that estrogen may contribute to the pathogenesis of non-small cell lung cancer (NSCLC). We investigated whether germline variation in the estrogen receptor-beta gene (ESR2) is associated with lung cancer risk among 1021 female cases and 826 female controls enrolled in the Lung Cancer Susceptibility Study at the Massachusetts General Hospital from 1992 – 2004. Four haplotype-tagging polymorphisms (htSNPs) (rs3020450, rs1256031, rs1256049, rs4986938) captured the common genetic variation across the ESR2 locus from a set of markers culled from healthy controls from a public database and sequencing the coding regions of 95 breast cancer cases. Using the expectation-maximization algorithm, five common haplotypes were resolved [CCGC (43%), TCAT (287%), TCAC (11%), CCAC (9%) and CCAT (6%)]. Multivariate logistic regression was used to estimate adjusted odds ratios (OR) and their 95% confidence intervals (95% CI) for individual htSNPs and haplotype scores. Neither the four individual htSNPs nor their resolved haplotypes were associated with lung cancer risk in the entire population, nor in strata defined by parity (yes vs. no), age (<50 vs. ≥50 years) or smoking history (current, former, never smokers). Our findings indicate that ESR2 is not associated with risk of lung cancer in women.
non-small cell lung cancer; estrogen receptor-beta (ESR2); molecular epidemiology; tobacco; parity; women
While the neuropsychological effects of high manganese (Mn) exposure in occupational settings are well known, the effects of lower levels of exposure are less understood. In this study, we investigated the neuropsychological effects of lower level occupational Mn exposure in 46 male welders (mean age = 37.4, sd = 11.7 years). Each welders’ cumulative Mn exposure indices (Mn-CEI) for the past 12 months and total work history Mn exposure were constructed based on air Mn measurements and work histories. The association between these exposure indices and performance on cognitive, motor control, and psychological tests was examined. In addition, among a subset of welders (n=24) who completed the tests both before and after a work shift, we examined the association between cross-shift Mn exposure assessed from personal monitoring and acute changes in test scores.
Mn exposures in this study (median = 12.9 μg/m3) were much lower, as compared to those observed in other similar studies. Increasing total Mn-CEI was significantly associated with slower reaction time on the continuous performance test (CPT; p<0.01), as well as worse mood for several scales on the Profile of Mood States (POMS; confused, tired, and a composite of tired and energetic, all p≤0.03). Increasing Mn-CEI over the previous 12 months was significantly associated with worse mood on the sad, tense, and confused POMS scales (all p≤0.03) and the association with worse CPT performance approached significance (p=0.10). Higher Mn exposure over the course of a workday was associated with worse performance on the CPT test across the day (p=0.06) as well as declines in fine motor control over the work-shift (p=0.04), adjusting for age and time between the 2 tests. Our study suggests that even at relatively low Mn exposure levels neuropsychological effects may manifest particularly with respect to attention, mood, and fine motor control.
Manganese; low-level manganese exposure; welding fumes; welders; neuropsychological effects; neurotoxic effects
Acute Lung Injury (ALI) is a syndrome with high associated mortality characterized by severe hypoxemia and pulmonary infiltrates in patients with critical illness. We conducted the first investigation to use the genome wide association (GWA) approach to identify putative risk variants for ALI. Genome wide genotyping was performed using the Illumina Human Quad 610 BeadChip. We performed a two-stage GWA study followed by a third stage of functional characterization. In the discovery phase (Phase 1), we compared 600 European American trauma-associated ALI cases with 2266 European American population-based controls. We carried forward the top 1% of single nucleotide polymorphisms (SNPs) at p<0.01 to a replication phase (Phase 2) comprised of a nested case-control design sample of 212 trauma-associated ALI cases and 283 at-risk trauma non-ALI controls from ongoing cohort studies. SNPs that replicated at the 0.05 level in Phase 2 were subject to functional validation (Phase 3) using expression quantitative trait loci (eQTL) analyses in stimulated B-lymphoblastoid cell lines (B-LCL) in family trios. 159 SNPs from the discovery phase replicated in Phase 2, including loci with prior evidence for a role in ALI pathogenesis. Functional evaluation of these replicated SNPs revealed rs471931 on 11q13.3 to exert a cis-regulatory effect on mRNA expression in the PPFIA1 gene (p = 0.0021). PPFIA1 encodes liprin alpha, a protein involved in cell adhesion, integrin expression, and cell-matrix interactions. This study supports the feasibility of future multi-center GWA investigations of ALI risk, and identifies PPFIA1 as a potential functional candidate ALI risk gene for future research.
Measurement of carcinogen DNA adducts in blood has been used as a surrogate for the target lung tissue. We aimed to examine whether genetic polymorphisms in several metabolic pathway genes modify the relation between DNA adducts in target lung and blood. One hundred and thirty-five early-stage lung cancer patients from the Massachusetts General Hospital were studied. DNA adducts were measured by the 32P-postlabeling assay in lung and blood mononuclear cells (MNCs) in a subset of 53 who had paired blood samples. Single-nucleotide polymorphisms (SNPs) were assessed in genes involved in phase II (GSTs, NAT2, EPHX and NQO1), DNA repair (ERCC1, ERCC2 and XRCC1) and DNA methylation (MTHFR C677T and A1298C) pathways. There was a significant correlation between DNA adduct levels in lung and blood within the different genotypes, with one exception. Significant modifications in adducts were found by variants in genes for phase II metabolism [NAT2 (1.51 for rapid versus 0.76 for slow, P = 0.022)], DNA repair [ERCC1 C118T (P = 0.014), ERCC2 (P = 0.003) and XRCC1 (P = 0.025)] and MTHFR [C677T (P = 0.005) and A1298C (P = 0.005)]. The relation between DNA adducts in blood MNCs and target lung tissue was significantly modified by the single-nucleotide polymorphisms in the three main pathways. Despite the relatively small sample size, our results suggest that genetic factors may need to be considered when assessing the association of DNA adducts using surrogate tissue in studies of lung cancer. Further studies are needed to better understand their role and the mechanisms.
We showed previously that in early-stage non–small-cell lung cancer (NSCLC), serum vitamin D levels and VDR polymorphisms were associated with survival. We hypothesized that vitamin D levels and VDR polymorphisms may also affect survival among patients with advanced NSCLC.
Patients and Methods
We evaluated the relationship between circulating 25-hydroxyvitamin D levels; VDR polymorphisms, including Cdx-2 G>A (rs11568820), FokI C>T (rs10735810), and BsmI C>T (rs144410); and overall survival among patients with advanced NSCLC. Analyses of survival outcomes were performed using the log-rank test and Cox proportional hazards models, adjusting for sex, stage, and performance status.
There were 294 patients and 233 deaths, with median follow-up of 42 months. We found no difference in survival by circulating vitamin D level. The C/C genotype of the FokI polymorphism was associated with improved survival: median survival for C/C was 21.4 months, for C/T was 12.1 months, and for T/T was 15.6 months (log-rank P = .005). There were no significant effects on survival by the Cdx-2 or BsMI polymorphism. However, having increasing numbers of protective alleles was associated with improved survival (adjusted hazard ratio for two or more v zero to one protective alleles, 0.57; 95% CI, 0.41 to 0.79; P = .0008). On haplotype analysis, the G-T-C (Cdx-2-FokI-BsmI) haplotype was associated with worse survival compared with the most common haplotype of G-C-T (adjusted hazard ratio, 1.61; 95% CI, 1.21 to 2.14; P = .001).
There was no main effect of vitamin D level on overall survival in the advanced NSCLC population. The T allele of the VDR FokI>T polymorphism and the G-T-C (Cdx-2-FokI-BsmI) haplotype were associated with worse survival.
Rationale: The degree to which chronic respiratory health effects caused by exposures to cotton dust and endotoxin is reversible after cessation of textile work is unknown.
Objectives: To investigate changes in lung function and respiratory symptoms after cessation of textile work and to determine whether past exposure to cotton dust and endotoxin or smoking history modify the associations.
Methods: We performed a prospective cohort study consisting of 447 cotton textile workers exposed to cotton dust and 472 unexposed silk textile workers, with a 25-year follow-up. Spirometry testing and respiratory questionnaires were conducted at 5-year intervals. Generalized estimated equations were used to model the average 5-year change in FEV1 and odds ratios of respiratory symptom prevalence.
Measurements and Main Results: Years since cessation of textile work was positively associated with 11.3 ml/yr and 5.6 ml/yr gains in 5-year FEV1 change for cotton and silk workers, respectively. Among male cotton workers, smokers gained more FEV1 per year after cessation of exposure than did nonsmokers, and the risk of symptoms of chronic bronchitis and byssinosis was larger for smoking than for nonsmoking male cotton workers.
Conclusions: Cessation of textile work was significantly associated with improvement in lung function and respiratory symptoms. The positive effect of work cessation was greater for cotton workers than for silk workers. For cotton workers, the improvement in lung function loss after cessation of textile work was greater among smokers, but no differences were observed for silk workers.
respiratory disease; environmental health; cotton textile workers; endotoxin exposure; occupational health
Gastroesophageal reflux symptoms (GERD), higher body mass index (BMI), smoking, and genetic variants in angiogenic pathway genes have been individually associated with increased risk of esophageal adenocarcinoma (EA). However, how angiogenic gene polymorphisms and environmental factors jointly affect EA development remains unclear.
Using a case-only design (n = 335), we examined interaction between 141 functional/tagging angiogenic SNPs and environmental factors (GERD, BMI, smoking) in modulating EA risk. Gene-environment interactions were assessed by a two-step approach. First, we applied random forest (RF) to screen for important SNPs that had either main or interaction effects. Second, we used case-only logistic regression (LR) to assess the effects of gene-environment interactions on EA risk, adjusting for covariates and false-discovery rate (FDR).
RF analyses identified three sets of SNPs (17 SNPs-GERD, 26 SNPs-smoking, and 34 SNPs-BMI) that had the highest importance scores. In subsequent LR analyses, interactions between 3 SNPs (rs2295778 of HIF1AN, rs133376 of TSC2, and rs2519757 of TSC1) and GERD, 2 SNPs (rs2295778 of HIF1AN, rs2296188 (VEGFR1) and smoking, and 7 SNPs (rs2114039 of PDGRFA, rs2296188 of VEGFR1, rs11941492 of VEGFR1, rs3756309 of PDGFRB, rs7324547 of VEGFR1, rs17619601 of VEGFR1, and rs17625898 of VEGFR1) and BMI were significantly associated with EA development (all FDR ≤0.10). Moreover, these interactions tended to have a SNP dose-response effects for increased EA risk with increasing number of combined risk genotypes.
These findings suggest that genetic variations in angiogenic genes may modify EA susceptibility through interactions with environmental factors in a SNP dose-response manner.
Esophageal adenocarcinoma; angiogenesis pathway genes; gene-environment interaction; case-only analysis
Qigong, similar to Tai Chi Chuan, is beneficial to health. In Taiwan, Waitankung, a type of Qigong, is as popular as Tai Chi Chuan. This population-based comparison study compares the health-related quality of life between people practicing Waitankung and their comparable community residents.
A total of 165 individuals practicing Waitankung were matched by age and sex with 660 general individuals for comparison. Information about health-related quality of life, measured by the SF-36, and other basic and health conditions was obtained from the questionnaires. This study used the linear mixed-effect regression model to examine the association between health-related quality of life and the practice of Waitankung.
Compared with either sedentary individuals or individuals practicing other types of exercise, the Waitankung group scored higher for eight and five out of ten SF-36 components, respectively. The Waitankung group scored better in general health, vitality, and physical component summary compared to individuals participating in other types of exercise, even when considering the energy expended by exercise.
The results suggest that Waitankung exercising is significantly associated with health-related quality of life. Waitankung may serve as an exercise choice for middle-aged and older people to improve overall quality of life.
General health; Qigong; quality of life; Waitankung