Modeling variation in mixture effects over space with a Bayesian spatially varying mixture model.

Mixture analysis is an emerging statistical tool in epidemiological research that seeks to estimate the health effects associated with mixtures of several exposures. This approach acknowledges that individuals experience many simultaneous exposures and it can estimate the relative importance of components in the mixture. Health effects due to mixtures may vary over space driven by to political, demographic, environmental, or other differences. In such cases, estimating a global mixture effect without accounting for spatial variation would induce bias in effect estimates and potentially lower statistical power. To date, no methods have been developed to estimate spatially varying chemical mixture effects. We developed a Bayesian spatially varying mixture model that estimates spatially varying mixture effects and the importance weights of components in the mixture, while adjusting for covariates. We demonstrate the efficacy of the model through a simulation study that varies the number of mixtures (one and two) and spatial pattern (global, one-dimensional, radial) and magnitude of mixture effects, showing that the model is able to accurately reproduce the spatial pattern of mixture effects across a diverse set of scenarios. Finally, we apply our model to a multi-center case-control study of non-Hodgkin lymphoma (NHL) in Detroit, Iowa, Los Angeles, and Seattle. We identify significant spatially varying positive and inverse associations with NHL for two mixtures of pesticides in Iowa and do not find strong spatial effects at the other three centers. In conclusion, the Bayesian spatially varying mixture model represents a novel method for modeling spatial variation in mixture effects.

Estimating mixture effects and cumulative spatial risk over time simultaneously using a Bayesian index low-rank kriging multiple membership model.

The exposome is an ideal in public health research that posits that individuals experience risk for adverse health outcomes from a wide variety of sources over their lifecourse. There have been increases in data collection in the various components of the exposome, but novel statistical methods are needed that capture multiple dimensions of risk at once. We introduce a Bayesian index low-rank kriging (LRK) multiple membership model (MMM) to simultaneously estimate the health effects of one or more groups of exposures, the relative importance of exposure components, and cumulative spatial risk over time using residential histories. The model employs an MMM to consider all residential locations for subjects weighted by duration and LRK to increase computational efficiency. We demonstrate the performance of the Bayesian index LRK-MMM through a simulation study, showing that the model accurately and consistently estimates the health effects of one or several group indices and has high power to identify a region of elevated spatial risk due to unmeasured environmental exposures. Finally, we apply our model to data from a multicenter case-control study of non-Hodgkin lymphoma (NHL), finding a significant positive association between one index of pesticides and risk for NHL in Iowa. Additionally, we find an area of significantly elevated spatial risk for NHL in Los Angeles. In conclusion, our Bayesian index LRK-MMM represents a step forward toward bringing the ideals of the exposome into practice for environmental risk analyzes.

A Quantitative Meta-Analysis of the Relation between Occupational Benzene Exposure and Biomarkers of Cytogenetic Damage.

BACKGROUND: The genotoxicity of benzene has been investigated in dozens of biomonitoring studies, mainly by studying (classical) chromosomal aberrations (CAs) or micronuclei (MN) as markers of DNA damage. Both have been shown to be predictive of future cancer risk in cohort studies and could, therefore, potentially be used for risk assessment of genotoxicity-mediated cancers. OBJECTIVES: We sought to estimate an exposure-response curve (ERC) and quantify between-study heterogeneity using all available quantitative evidence on the cytogenetic effects of benzene exposure on CAs and MN respectively. METHODS: We carried out a systematic literature review and summarized all available data of sufficient quality using meta-analyses. We assessed the heterogeneity in slope estimates between studies and conducted additional sensitivity analyses to assess how various study characteristics impacted the estimated ERC. RESULTS: Sixteen CA (1,356 individuals) and 13 MN studies (2,097 individuals) were found to be eligible for inclusion in a meta-analysis. Studies where benzene was the primary genotoxic exposure and that had adequate assessment of both exposure and outcomes were used for the primary analysis. Estimated slope estimates were an increase of 0.27% CA [(95% CI: 0.08%, 0.47%); based on the results from 4 studies] and 0.27% MN [(95% CI: -0.23%, 0.76%); based on the results from 7 studies] per parts-per-million benzene exposure. We observed considerable between-study heterogeneity for both end points (I2>90%). DISCUSSION: Our study provides a systematic, transparent, and quantitative summary of the literature describing the strong association between benzene exposure and accepted markers of genotoxicity in humans. The derived consensus slope can be used as a best estimate of the quantitative relationship between real-life benzene exposure and genetic damage in future risk assessment. We also quantitate the large between-study heterogeneity that exists in this literature, a factor which is crucial for the interpretation of single-study or consensus slopes. https://doi.org/10.1289/EHP6404.

Serum ghrelin and esophageal and gastric cancer in two cohorts in China.

Ghrelin is a hormone produced in the oxyntic glands of the stomach. Previous work by our group has suggested that serum ghrelin concentrations are inversely associated with gastric and esophageal cancer risk. We measured ghrelin concentrations in the Linxian General Population Nutrition Intervention Trial (NIT), and the Shanghai Women's Health Study (SWHS). In NIT, we analyzed serum samples from 298 esophageal squamous cell carcinoma (ESCC) cases, 518 gastric cardia adenocarcinoma (GCA) cases, 258 gastric noncardia adenocarcinoma (GNCA) cases and 770 subcohort controls (case-cohort). In SWHS, we measured ghrelin in plasma samples from 249 GNCA cases and 498 matched controls (nested case-control). Ghrelin was measured using radioimmunoassay. In NIT and SWHS, low ghrelin concentrations were associated with an increased risk of developing GNCA and GCA. The hazard ratio (HR Q1:Q4 ) for GNCA in NIT was 1.35 (95% CI: 0.89-2.05; p-trend = 0.02); the odds ratio in SWHS was 1.66 (95% CI: 1.02-2.70; p-trend = 0.06). Low ghrelin was associated with a twofold increase of GCA (HR Q1:Q4 = 2.00, 95% CI: 1.45-2.77; p-trend<0.001). In contrast, a lower risk of ESCC (NIT ESCC HR Q1:Q4 = 0.65, 95% CI: 0.45-0.92; p-trend = 0.02) was found in NIT. Low baseline ghrelin concentrations were associated with an increased risk for GNCA and GCA in the NIT and the SWHS. In contrast, low ghrelin concentrations at baseline were associated with a reduced risk of developing ESCC in the NIT. Ghrelin may be an early marker of future cancer risk for developing upper gastrointestinal cancer in regions of high incidence.

The establishment of the Household Air Pollution Consortium (HAPCO).

Household air pollution (HAP) is of public health concern with ~3 billion people worldwide (including >15 million in the US) exposed. HAP from coal use is a human lung carcinogen, yet the epidemiological evidence on carcinogenicity of HAP from biomass use, primarily wood, is not conclusive. To robustly assess biomass's carcinogenic potential, prospective studies of individuals experiencing a variety of HAP exposures are needed. We have built a global consortium of 13 prospective cohorts (HAPCO: Household Air Pollution Consortium) that have site- and disease-specific mortality and solid fuel use data, for a combined sample size of 587,257 participants and 57,483 deaths. HAPCO provides a novel opportunity to assess the association of HAP with lung cancer death while controlling for important confounders such as tobacco and outdoor air pollution exposures. HAPCO is also uniquely positioned to determine the risks associated with cancers other than lung as well as non-malignant respiratory and cardiometabolic outcomes, for which prospective epidemiologic research is limited. HAPCO will facilitate research to address public health concerns associated with HAP-attributed exposures by enabling investigators to evaluate sex-specific and smoking status-specific effects under various exposure scenarios.

Dietary Glycemic Load, Glycemic Index, and Carbohydrate Intake on the Risk of Lung Cancer among Men and Women in Shanghai.

To investigate the potential influence of dietary glycemic index, glycemic load, or carbohydrate intake and lung cancer risk in Shanghai. We prospectively investigated the associations among 130,858 participants in the Shanghai Women's and Men's Health Studies. Diet was assessed using validated food-frequency questionnaires. Lung cancer cases were ascertained through annual record linkage and every 2-3 years in-home visits. Cox proportional hazard regression model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). After excluding the first 2 years of observation, 1312 participants (including 649 women and 663 men) developed lung cancer during an average follow-up of 14.8 (SD: 2.0) years for SWHS and 9.3 (SD: 1.6) years for SMHS. In multivariable analysis, no statistically significant associations were observed between glycemic index, glycemic load, and carbohydrate intake and lung cancer risk for either men or women. Similar results were observed among never smokers, and participants without history of lung disease, diabetes, or hypertension. Stratification by body mass index or menopause status also did not alter the findings. Our studies, conducted in populations who habitually have high-carbohydrate diets, provide no evidence that dietary glycemic index, glycemic load, or carbohydrate intake is associated with lung cancer risk.

Bladder Cancer and Water Disinfection By-product Exposures through Multiple Routes: A Population-Based Case-Control Study (New England, USA).

BACKGROUND: Ingestion of disinfection byproducts has been associated with bladder cancer in multiple studies. Although associations with other routes of exposure have been suggested, epidemiologic evidence is limited. OBJECTIVES: We evaluated the relationship between bladder cancer and total, chlorinated, and brominated trihalomethanes (THMs) through various exposure routes. METHODS: In a population-based case­control study in New England (n=(1,213) cases; n=(1,418) controls), we estimated lifetime exposure to THMs from ingestion, showering/bathing, and hours of swimming pool use. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression adjusted for confounders. RESULTS: Adjusted ORs for bladder cancer comparing participants with exposure above the 95th percentile with those in the lowest quartile of exposure (based on the distribution in controls) were statistically significant for average daily intake mg/d of total THMs [OR=1.53 (95% CI: 1.01, 2.32), p-trend=0.16] and brominated THMs [OR=1.98 (95% CI: 1.19, 3.29), p-trend=0.03]. For cumulative intake mg, the OR at the 95th percentile of total THMs was 1.45 (95% CI: 0.95, 2.2), p-trend=0.13; the ORs at the 95th percentile for chlorinated and brominated THMs were 1.77 (95% CI: 1.05, 2,.99), p-trend=0.07 and 1.78 (95% CI: 1.05, 3.00), p-trend=0.02, respectively. The OR in the highest category of showering/bathing for brominated THMs was 1.43 (95% CI: 0.80, 2.42), p-trend=0.10. We found no evidence of an association for bladder cancer and hours of swimming pool use. CONCLUSIONS: We observed a modest association between ingestion of water with higher THMs (>95th percentile vs.<25th percentile) and bladder cancer. Brominated THMs have been a particular concern based on toxicologic evidence, and our suggestive findings for multiple metrics require further study in a population with higher levels of these exposures. Data from this population do not support an association between swimming pool use and bladder cancer. https://doi.org/10.1289/EHP89.

Quartz in ash, and air in a high lung cancer incidence area in China.

Exposure to crystalline silica (quartz) has been implicated as a potential cause of the high lung cancer rates in the neighbouring counties of Xuanwei and Fuyuan, China, where the domestic combustion of locally sourced "smoky" coal (a bituminous coal) is responsible for some of the highest lung cancer rates in the nation, irrespective of gender or smoking status. Previous studies have shown that smoky coal contains approximately twice as much quartz when compared to alternative fuels in the area, although it is unclear how the quartz in coal relates to household air pollution. Samples of ash and fine particulate matter (PM2.5) were collected from 163 households and analysed for quartz content by Fourier transformed infrared spectroscopy (FT-IR). Additionally, air samples from 12 further households, were analysed by scanning electron microscopy (SEM) to evaluate particle structure and silica content. The majority (89%) of household air samples had undetectable quartz levels (<0.2 µg/m3) with no clear differences by fuel-type. SEM analyses indicated that there were higher amounts of silica in the smoke of smoky coal than smokeless coal (0.27 µg/m3 vs. 0.03 µg/m3). We also identified fibre-like particles in a higher concentration within the smoke of smoky coal than smokeless coal (5800 fibres/m3 vs. 550 fibres/m3). Ash analysis suggested that the bulk of the quartz in smoky coal went on to form part of the ash. These findings indicate that the quartz within smoky coal does not become adequately airborne during the combustion process to cause significant lung cancer risk, instead going on to form part of the ash. The identification of fibre-like particles in air samples is an interesting finding, although the clinical relevance of this finding remains unclear.

Evaluation of Automatically Assigned Job-Specific Interview Modules.

OBJECTIVE: In community-based epidemiological studies, job- and industry-specific 'modules' are often used to systematically obtain details about the subject's work tasks. The module assignment is often made by the interviewer, who may have insufficient occupational hygiene knowledge to assign the correct module. We evaluated, in the context of a case-control study of lymphoid neoplasms in Asia ('AsiaLymph'), the performance of an algorithm that provided automatic, real-time module assignment during a computer-assisted personal interview. METHODS: AsiaLymph's occupational component began with a lifetime occupational history questionnaire with free-text responses and three solvent exposure screening questions. To assign each job to one of 23 study-specific modules, an algorithm automatically searched the free-text responses to the questions 'job title' and 'product made or services provided by employer' using a list of module-specific keywords, comprising over 5800 keywords in English, Traditional and Simplified Chinese. Hierarchical decision rules were used when the keyword match triggered multiple modules. If no keyword match was identified, a generic solvent module was assigned if the subject responded 'yes' to any of the three solvent screening questions. If these question responses were all 'no', a work location module was assigned, which redirected the subject to the farming, teaching, health professional, solvent, or industry solvent modules or ended the questions for that job, depending on the location response. We conducted a reliability assessment that compared the algorithm-assigned modules to consensus module assignments made by two industrial hygienists for a subset of 1251 (of 11409) jobs selected using a stratified random selection procedure using module-specific strata. Discordant assignments between the algorithm and consensus assignments (483 jobs) were qualitatively reviewed by the hygienists to evaluate the potential information lost from missed questions with using the algorithm-assigned module (none, low, medium, high). RESULTS: The most frequently assigned modules were the work location (33%), solvent (20%), farming and food industry (19%), and dry cleaning and textile industry (6.4%) modules. In the reliability subset, the algorithm assignment had an exact match to the expert consensus-assigned module for 722 (57.7%) of the 1251 jobs. Overall, adjusted for the proportion of jobs in each stratum, we estimated that 86% of the algorithm-assigned modules would result in no information loss, 2% would have low information loss, and 12% would have medium to high information loss. Medium to high information loss occurred for <10% of the jobs assigned the generic solvent module and for 21, 32, and 31% of the jobs assigned the work location module with location responses of 'someplace else', 'factory', and 'don't know', respectively. Other work location responses had ≤8% with medium to high information loss because of redirections to other modules. Medium to high information loss occurred more frequently when a job description matched with multiple keywords pointing to different modules (29-69%, depending on the triggered assignment rule). CONCLUSIONS: These evaluations demonstrated that automatically assigned modules can reliably reproduce an expert's module assignment without the direct involvement of an industrial hygienist or interviewer. The feasibility of adapting this framework to other studies will be language- and exposure-specific.

Polycyclic aromatic hydrocarbon exposure in household air pollution from solid fuel combustion among the female population of Xuanwei and Fuyuan counties, China.

Exposure to polycyclic aromatic hydrocarbons (PAHs) from burning "smoky" (bituminous) coal has been implicated as a cause of the high lung cancer incidence in the counties of Xuanwei and Fuyuan, China. Little is known about variations in PAH exposure from throughout the region nor how fuel source and stove design affects exposure. Indoor and personal PAH exposure resulting from solid fuel combustion in Xuanwei and Fuyuan was investigated using repeated 24 h particle bound and gas-phase PAH measurements, which were collected from 163 female residents of Xuanwei and Fuyuan. 549 particle bound (283 indoor and 266 personal) and 193 gas phase (all personal) PAH measurements were collected. Mixed effect models indicated that PAH exposure was up to 6 times higher when burning smoky coal than smokeless coal and varied by up to a factor of 3 between different smoky coal geographic sources. PAH measurements from unventilated firepits were up to 5 times that of ventilated stoves. Exposure also varied between different room sizes and season of measurement. These findings indicate that PAH exposure is modulated by a variety of factors, including fuel type, coal source, and stove design. These findings may provide valuable insight into potential causes of lung cancer in the area.

Pre-existing type 2 diabetes and risk of lung cancer: a report from two prospective cohort studies of 133†024 Chinese adults in urban Shanghai.

OBJECTIVES: Observational studies of type 2 diabetes (T2D) and lung cancer risk are limited and controversial. We thus examined the association between T2D and risk of incident lung cancer using a cohort design. SETTING: Data from two ongoing population-based cohorts (the Shanghai Men's Health Study, SMHS, 2002-2006 and the Shanghai Women's Health Study, SWHS, 1996-2000) were used. Cox proportional-hazards regression models with T2D as a time-varying exposure were modelled to estimate HRs and 95% CIs. PARTICIPANTS: The study population included 61 491 male participants aged 40-74 years from SMHS and 74 941 female participants aged 40-70 years from SWHS. OUTCOME MEASURE: Lung cancer cases were identified through annual record linkage to the Shanghai Cancer Registry and Shanghai Municipal Registry of Vital Statistics, and were further verified through home visits and a review of medical charts by clinical and/or pathological experts. Outcome data until 31 December 2010 for men and women were used for the present analysis. RESULTS: After a median follow-up of 6.3 years for SMHS and 12.2 years for SWHS, incident lung cancer cases were detected in 492 men and 525 women. A null association between T2D and lung cancer risk was observed in men (HR=0.87, 95% CI 0.62 to 1.21) and women (HR=0.92, 95% CI 0.69 to 1.24) after adjustments for potential confounders. Similar results were observed among never smokers. CONCLUSIONS: There is little evidence that pre-existing T2D may influence the incidence of lung cancer.

Heterogeneity in coal composition and implications for lung cancer risk in Xuanwei and Fuyuan counties, China.

BACKGROUND: Xuanwei and Fuyuan counties in Yunnan Province, China have among the highest lung cancer rates in the country. This has been associated with the domestic combustion of bituminous coal (referred to as "smoky" coal). Additionally, significant geographical variation in cancer rates among smoky coal users has been observed, suggesting heterogeneity in fuel source composition and/or combustion characteristics. Research thus far has indicated that smoky coal emits high levels of polycyclic aromatic hydrocarbons (PAHs) and contains high concentrations of fine grained crystalline quartz, however, much of this research is limited in terms of sample size and geographic scope. In order to more fully characterise geochemical and elemental compositions of smoky and smokeless coal use in Xuanwei and Fuyuan, we carried out a large exposure assessment study in households in this region. METHODS: Fuel samples representing smoky and "smokeless" (anthracite, the major alternative coal type in the region) coals were collected from 137 homes in Xuanwei and Fuyuan. Rock-Eval, Leco-CS, XRF analysis and electron microscopy were used to establish hydrocarbon content (to represent volatile organic compounds), major and trace element composition and mineral composition respectively. Heterogeneity in coal characteristics between and within coal types was assessed by the Kruskal-Wallis test. RESULTS: 145 coal samples (116 smoky and 29 smokeless coals) were analysed. Statistically significant differences between smoky and smokeless coals with regard to hydrocarbon content, sulfur, trace elements and mineral composition were observed. Of note, smoky coal contained between 5 and 15 times the amount of volatile organic matter and twice the amount of quartz (including respirable quartz) than smokeless coal. Smoky coal generally had lower levels of trace elements (plus aluminium) than smokeless coal. Significant variation was also observed between smoky coal samples from different geographical areas with regard to hydrocarbon content and elemental composition (including aluminium and silicon). DISCUSSION: This paper has identified compositional differences between and within smoky and smokeless coals sourced from Xuanwei and Fuyuan counties. A decreased ratio of aluminium to silicon in smoky coal suggests elevated free silica, a finding consistent with observed higher levels of quartz. Elevated volatile organic matter content in smoky coal (when compared to smokeless coal) is consistent with the geochemical expectations for smoky and smokeless coals. These findings also reflect previous observations of elevated volatile compound emissions (notably PAHs) from smoky coal in the area. The observed heterogeneity in coal composition between and within coal types may provide leads to the observed heterogeneity in cancer risk observed in this area.

Genetic polymorphism of NFKB1 and NFKBIA genes and liver cancer risk: a nested case-control study in Shanghai, China.

OBJECTIVES: Genetic variations of nuclear factor-κB (NF-κB) signalling pathway were found to be associated with inflammatory diseases and several malignancies. However, little is known about NF-κB pathway gene polymorphisms and susceptibility of liver cancer. The aim of this study was to investigate whether genetic variants of NFKB1 and NFKBIA were associated with risk of liver cancer in a Chinese population. DESIGN: The study was designed as a nested case-control study within two prospective cohorts (the Shanghai Women's Health Study, SWHS, 1996-2000 and the Shanghai Men's Health Study, SMHS, 2002-2006). SETTINGS: This population-based study was conducted in urban Shanghai, China. PARTICIPANTS: A total of 217 incident liver cancer cases diagnosed through 31 December 2009 and 427 healthy controls matched by sex, age at baseline (±2 years) and date (±30 days) of sample collection were included in the study. PRIMARY AND SECONDARY OUTCOME MEASURES: Genetic polymorphisms of NFKB1 and NFKBIA were determined blindly by TaqMan single-nucleotide polymorphism (SNP) genotyping assay. OR and its 95% CIs were estimated by an unconditional logistic regression model to measure the association between selected SNPs and the risk of liver cancer. RESULTS: After adjusted for potential confounding factors, rs28362491 ins/del or del/del genotypes were associated with higher risk of liver cancer with an adjusted OR 1.54 (95% CI 1.04 to 2.28). rs230496 AG and GG genotypes were also noted with higher risk of liver cancer with an adjusted OR 1.53 (95% CI 1.03 to 2.26). Haplotype analysis indicated that carriers of the NFKB1 GA and AA (rs230525-rs230530) haplotypes had higher risk of liver cancer under an additive model. No association was observed between NFKBIA variants and risk of live cancer. CONCLUSIONS: Our results suggest that genetic variants of NFKB1 influence liver cancer susceptibility in Chinese population, although replication in other studies is needed.

Prospective cohort studies of association between family history of liver cancer and risk of liver cancer.

Uncertainty remains on the relationship between a family history of liver cancer and liver cancer risk in prospective cohort studies in a general population. Thus, we examined this association in 133,014 participants in the Shanghai Women's and Men's Health Studies. Family history of liver cancer was categorized through dichotomous and proportional score approaches. Hazard ratios (HRs) and 95% confidence intervals (CIs) were derived using the Cox proportional hazards models with adjustment for potential confounders. A meta-analysis of observational studies through December 2013 on liver cancer risk in relation to family history of liver cancer was also performed. Study-specific risk estimates were combined using fixed or random effects models depending on whether significant heterogeneity was detected. For the Shanghai Women's and Men's Health Studies, 299 liver cancer cases were identified during follow-up through 2010. Family history of liver cancer was associated with liver cancer risk using both binary indicator (HR = 2.60, 95% CI: 1.77-3.80) and proportional score (high-risk vs. minimal-risk category: HR = 3.03, 95% CI: 1.73-5.31), with increasing HRs for increasing score categories. The meta-analysis also showed an increased risk for those with a family history of liver cancer (relative risk = 2.55, 95% CI: 2.05-3.16). Family history of liver cancer was related to increased risk of liver cancer in Chinese population. This risk is particularly high for those with an affected mother. The "dose-response" of risk with an increasing family history score of liver cancer might further facilitate future cancer prevention programs on identifying individuals with the highest potential liver cancer risk.

Combustion-derived nanoparticle exposure and household solid fuel use in Xuanwei and Fuyuan, China.

Combustion-derived nanoparticles (CDNPs) have not been readably measurable until recently. We conducted a pilot study to determine CDNP levels during solid fuel burning. The aggregate surface area of CDNP (µm(2)/cm(3)) was monitored continuously in 15 Chinese homes using varying fuel types (i.e. bituminous coal, anthracite coal, wood) and stove types (i.e. portable stoves, stoves with chimneys, firepits). Information on fuel burning activities was collected and PM(2.5) levels were measured. Substantial exposure differences were observed during solid fuel burning (mean: 228.1 µm(2)/cm(3)) compared to times without combustion (mean: 14.0 µm(2)/cm(3)). The observed levels during burning were reduced by about four-fold in homes with a chimney (mean: 92.1 µm(2)/cm(3); n = 9), and effects were present for all fuel types. Each home's CDNP measurement was only moderately correlated with the respective PM(2.5) measurements (r (2) = 0.43; p = 0.11). Our results indicate that household coal and wood burning contributes to indoor nanoparticle levels, which are not fully reflected in PM(2.5) measurements.

Comprehensive evaluation of one-carbon metabolism pathway gene variants and renal cell cancer risk.

INTRODUCTION: Folate and one-carbon metabolism are linked to cancer risk through their integral role in DNA synthesis and methylation. Variation in one-carbon metabolism genes, particularly MTHFR, has been associated with risk of a number of cancers in epidemiologic studies, but little is known regarding renal cancer. METHODS: Tag single nucleotide polymorphisms (SNPs) selected to produce high genomic coverage of 13 gene regions of one-carbon metabolism (ALDH1L1, BHMT, CBS, FOLR1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, TYMS) and the closely associated glutathione synthesis pathway (CTH, GGH, GSS) were genotyped for 777 renal cell carcinoma (RCC) cases and 1,035 controls in the Central and Eastern European Renal Cancer case-control study. Associations of individual SNPs (n = 163) with RCC risk were calculated using unconditional logistic regression adjusted for age, sex and study center. Minimum p-value permutation (Min-P) tests were used to identify gene regions associated with risk, and haplotypes were evaluated within these genes. RESULTS: The strongest associations with RCC risk were observed for SLC19A1 (P(min-P) = 0.03) and MTHFR (P(min-P) = 0.13). A haplotype consisting of four SNPs in SLC19A1 (rs12483553, rs2838950, rs2838951, and rs17004785) was associated with a 37% increased risk (p = 0.02), and exploratory stratified analysis suggested the association was only significant among those in the lowest tertile of vegetable intake. CONCLUSIONS: To our knowledge, this is the first study to comprehensively examine variation in one-carbon metabolism genes in relation to RCC risk. We identified a novel association with SLC19A1, which is important for transport of folate into cells. Replication in other populations is required to confirm these findings.

Urinary isothiocyanate levels and lung cancer risk among non-smoking women: a prospective investigation.

BACKGROUND: Aside from tobacco carcinogen metabolism, isothiocyanates (ITC) from cruciferous vegetables may induce apoptosis or steroid metabolism to reduce lung cancer risk. To separate the effect of these divergent mechanisms of action, we investigated the association between urinary ITC levels and lung cancer risk among non-smoking women. METHODS: We conducted a nested case-control within the Shanghai Women's Health Study. Subjects included 209 incident lung cancer cases who never used tobacco, and 787 individually matched non-smoking controls. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) summarizing the association between urinary ITC levels and lung cancer. Secondary analyses stratified the ITC-lung cancer analyses by menopausal status, exposure to environmental tobacco smoke, and GSTM1 and GSTT1 genotypes. RESULTS: Urinary ITC levels were not significantly associated with lower lung cancer risk among non-smoking women, regardless of exposure to environmental tobacco smoke or menopausal status. Furthermore, this association was not modified by GSTT1 genotype. However, an inverse association was suggested among women with a GSTM1-positive genotype (Q1: OR=1.0 (reference); Q2: OR=0.35 (0.14, 0.89); Q3: OR=0.47 (0.20, 1.10); Q4: OR=0.63 (0.35, 1.54), p-trend=0.38). In contrast, lung cancer risk was positively associated with urinary ITC levels among women with the GSTM1-null genotype (Q1: OR=1.0 (reference); Q2: OR=1.67 (0.80, 3.50); Q3: OR=1.54 (0.71, 3.33); Q4: OR=2.22 (1.05, 4.67), p-trend=0.06). CONCLUSION: Urinary ITC levels were not associated overall with lower lung cancer risk among non-smoking women, but secondary analyses suggested an interaction between urinary ITC levels, GSTM1 genotype, and lung cancer risk.

Cancer pharmacogenomics and pharmacoepidemiology: setting a research agenda to accelerate translation.

Recent advances in genomic research have demonstrated a substantial role for genomic factors in predicting response to cancer therapies. Researchers in the fields of cancer pharmacogenomics and pharmacoepidemiology seek to understand why individuals respond differently to drug therapy, in terms of both adverse effects and treatment efficacy. To identify research priorities as well as the resources and infrastructure needed to advance these fields, the National Cancer Institute (NCI) sponsored a workshop titled "Cancer Pharmacogenomics: Setting a Research Agenda to Accelerate Translation" on July 21, 2009, in Bethesda, MD. In this commentary, we summarize and discuss five science-based recommendations and four infrastructure-based recommendations that were identified as a result of discussions held during this workshop. Key recommendations include 1) supporting the routine collection of germline and tumor biospecimens in NCI-sponsored clinical trials and in some observational and population-based studies; 2) incorporating pharmacogenomic markers into clinical trials; 3) addressing the ethical, legal, social, and biospecimen- and data-sharing implications of pharmacogenomic and pharmacoepidemiologic research; and 4) establishing partnerships across NCI, with other federal agencies, and with industry. Together, these recommendations will facilitate the discovery and validation of clinical, sociodemographic, lifestyle, and genomic markers related to cancer treatment response and adverse events, and they will improve both the speed and efficiency by which new pharmacogenomic and pharmacoepidemiologic information is translated into clinical practice.

Genetic polymorphisms in cytochrome P450s, GSTs, NATs, alcohol consumption and risk of non-Hodgkin lymphoma.

The aim of this study was to investigate whether genetic polymorphisms in cytochrome P450s (CYPs), glutathione S-transferases (GSTs), and N-acetyltransferases (NATs) genes modify the relationship between alcohol consumption and risk of non-Hodgkin's lymphoma (NHL) in a population-based, case-control study including 1,115 Connecticut women. Although we did not find strong evidence that the genetic polymorphisms modify the relationship between alcohol consumption and risk of NHL, we identified significant interactions for multiple GSTs and NATs and alcohol intake among persons with DLBCL. Our results confer support investigation of the gene-environment interaction in a larger study population of DLBCL.

Associations of common variants in genes involved in metabolism and response to exogenous chemicals with risk of multiple myeloma.

BACKGROUND: We examined risk of multiple myeloma (MM) associated with variants in genes involved in metabolism and response to exogenous chemicals [cytochrome P450 enzymes (CYP1B1, CYP2C9), epoxide hydrolase (EPHX1), paraoxonase 1 (PON1), arylhydrocarbon hydroxylase receptor (AHR), and NAD(P)H:quinone oxidoreductase (NQO1)]. METHODS: This study included 279 MM cases and 782 controls in a pooled analysis of two population-based case-control studies. One common variant from each candidate gene was genotyped using DNA from blood or buccal cells. We estimated risk of MM associated with each genotype, controlling for race, gender, study site, and age, using odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Evaluations of the CYP1B1 V432L variant (rs1056836) suggested increased risk of MM among persons with the CG and GG genotypes compared to the CC genotype [OR (95% CI)=1.4 (1.0-2.0)]. Similar results were seen in analyses stratified by race and gender. We did not find any associations between MM and the CYP2C9, EPHX1, NQO1, or PON1 genes. CONCLUSIONS: CYP1B1 activates chemicals such as polycyclic aromatic hydrocarbons and dioxins to create oxidized, reactive intermediates, and higher gene activity has been shown for the G allele. We conducted the largest analysis to date on MM and these genetic variants and our results provide preliminary evidence that variation in CYP1B1 may influence susceptibility to MM.