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Exposure to inorganic arsenic (As) is recognized as a risk factor for non-melanoma skin cancer (NMSC). We followed up with 7000 adults for 6 years who were exposed to As. During follow-up, 2.2% of the males and 1.3% of the females developed basal cell carcinoma (BCC), while 0.4% of the male and 0.2% of the female participants developed squamous cell carcinoma (SCC). Using a panel of more than 400 cancer-related genes, we detected somatic mutations (SMs) in the first 32 NMSC samples (BCC = 26 and SCC = 6) by comparing paired (tissue-blood) samples from the same individual and then comparing them to the SM in healthy skin tissue from 16 participants. We identified (a) a list of NMSC-associated SMs, (b) SMs present in both NMSC and healthy skin, and (c) SMs found only in healthy skin. We also demonstrate that the presence of non-synonymous SMs in the top mutated genes (like PTCH1, NOTCH1, SYNE1, PKHD1 in BCC and TP53 in SCC) significantly affects the magnitude of differential expressions of major genes and gene pathways (basal cell carcinoma pathways, NOTCH signaling, IL-17 signaling, p53 signaling, Wnt signaling pathway). These findings may help select groups of patients for targeted therapy, like hedgehog signaling inhibitors, IL17 inhibitors, etc., in the future.
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Arsênio , Mutação , Neoplasias Cutâneas , Transcriptoma , Humanos , Neoplasias Cutâneas/genética , Arsênio/toxicidade , Feminino , Mutação/genética , Masculino , Transcriptoma/genética , Transcriptoma/efeitos dos fármacos , Pessoa de Meia-Idade , Carcinoma Basocelular/genética , Carcinoma de Células Escamosas/genética , Adulto , Perfilação da Expressão Gênica , Idoso , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
INTRODUCTION: The NIH All of Us Research Program has enrolled over 544,000 participants across the US with unprecedented racial/ethnic diversity, offering opportunities to investigate myriad exposures and diseases. This paper aims to investigate the association between PM2.5 exposure and cancer risks. MATERIALS AND METHODS: This work was performed on data from 409,876 All of Us Research Program participants using the All of Us Researcher Workbench. Cancer case ascertainment was performed using data from electronic health records and the self-reported Personal Medical History questionnaire. PM2.5 exposure was retrieved from NASA's Earth Observing System Data and Information Center and assigned using participants' 3-digit zip code prefixes. Multivariate logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI). Generalized additive models (GAMs) were used to investigate non-linear relationships. RESULTS: A total of 33,387 participants and 46,176 prevalent cancer cases were ascertained from participant EHR data, while 20,297 cases were ascertained from self-reported survey data from 18,133 participants; 9,502 cancer cases were captured in both the EHR and survey data. Average PM2.5 level from 2007 to 2016 was 8.90 µg/m3 (min 2.56, max 15.05). In analysis of cancer cases from EHR, an increased odds for breast cancer (OR 1.17, 95% CI 1.09-1.25), endometrial cancer (OR 1.33, 95% CI 1.09-1.62) and ovarian cancer (OR 1.20, 95% CI 1.01-1.42) in the 4th quartile of exposure compared to the 1st. In GAM, higher PM2.5 concentration was associated with increased odds for blood cancer, bone cancer, brain cancer, breast cancer, colon and rectum cancer, endocrine system cancer, lung cancer, pancreatic cancer, prostate cancer, and thyroid cancer. CONCLUSIONS: We found evidence of an association of PM2.5 with breast, ovarian, and endometrial cancers. There is little to no prior evidence in the literature on the impact of PM2.5 on risk of these cancers, warranting further investigation.
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Neoplasias , Humanos , Feminino , Masculino , Neoplasias/epidemiologia , Neoplasias/etiologia , Estados Unidos/epidemiologia , Pessoa de Meia-Idade , Adulto , Poluição do Ar/efeitos adversos , Poluição do Ar/análise , Fatores de Risco , Idoso , Material Particulado/efeitos adversos , Material Particulado/análise , Exposição Ambiental/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: Hormones are linked to cardiometabolic diseases and may be impacted by acculturation though multiple mechanisms. We evaluated associations of Hispanic/Latino background and acculturation with levels of sex- and thyroid-related hormones and the potential mediating effect of adiposity, lifestyle factors, and sleep apnea syndrome on these associations. METHODS: We studied 1789 adults, aged 45-74, from a sub-cohort of the Hispanic Community Health Survey/Study of Latinos. Peri/pre-menopausal women and individuals on medications related to hormones were excluded. Our study assessed eleven sex- and thyroid-related hormones, Hispanic/Latino background, and five acculturation measures. Associations were assessed using multivariable linear and logistic regression adjusted for survey design and confounding variables. We explored potential mediation using a path analysis. RESULTS: In postmenopausal women, acculturation score-MESA was associated with decreased thyroid-stimulating hormone (ß = - 0.13;95%CI = - 0.22, - 0.03) while age at immigration greater than the median (vs US-born) was associated with decreased (ß = - 14.6; 95%CI = - 28.2, - 0.99) triiodothyronine (T3). In men, language acculturation and acculturation score-MESA were associated with increased estradiol and sex hormone-binding globulin (SHBG) while age at immigration greater and lesser than the median (vs US-born) was associated with decreased SHBG. Hispanic/Latino background (Mexicans as reference) were selectively associated with sex- and thyroid-related hormone levels in both sexes. Current smoking and sleep apnea syndrome partially mediated the association of Cuban and Puerto Rican heritage (vs Mexican) with T3 levels in men and postmenopausal women, respectively. CONCLUSION: Selected acculturation measures were associated with thyroid-related hormones in postmenopausal women and sex-related hormones in men. Understanding the mechanisms involved in the relationship of acculturation and Hispanic/Latino background with hormones warrants additional investigation.
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BACKGROUND: Adverse childhood experiences during key developmental periods have been shown to impact long-term health outcomes. Adverse childhood experiences may include psychological, physical, or sexual abuse; neglect; or socioeconomic factors. Adverse childhood experiences are linked with an increase in poor health behavior such as smoking and alcohol consumption, and may also influence epigenetic changes, inflammatory response, metabolic changes, and allostatic load. OBJECTIVE: We sought to explore associations between adverse childhood experiences and allostatic load in adult female participants in the UK Biobank. DESIGN: The UK Biobank is a multisite cohort study established to capture lifestyle, environment, exposure, health history, and genotype data on individuals in the United Kingdom. METHODS: Adverse childhood experiences were assessed from the Childhood Trauma Screener, which measures abuse and neglect across five items. Biological measures at enrollment were used to construct allostatic load, including measures of metabolic, inflammatory, and cardiovascular function. Females with a cancer diagnosis prior to enrollment were removed as it may influence allostatic load. Poisson regression models were used to assess the association between adverse childhood experiences and allostatic load, accounting for a priori confounders. RESULTS: A total of 33,466 females with complete data were analyzed, with a median age at enrollment of 54 (range = 40-70) years. Among the study sample, the mean allostatic load ranged from 1.85 in those who reported no adverse childhood experiences to 2.45 in those with all adverse childhood experiences reported. In multivariable analysis, there was a 4% increase in average allostatic load among females for every additional adverse childhood experience reported (incidence rate ratio = 1.04, 95% confidence interval = 1.03-1.05). Similar results were observed when assessing individual adverse childhood experience components. CONCLUSION: This analysis supports a growing body of evidence suggesting that increased exposure to early life abuse or neglect is associated with increased allostatic load in females.
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Experiências Adversas da Infância , Alostase , Adulto , Humanos , Criança , Feminino , Pessoa de Meia-Idade , Idoso , Bancos de Espécimes Biológicos , Estudos de Coortes , Reino UnidoRESUMO
Exposure to inorganic arsenic (As) is recognized as risk factor for basal cell carcinoma (BCC). We have followed-up 7000 adults for 6 years who were exposed to As and had manifest As skin toxicity. Of them, 1.7% developed BCC (males = 2.2%, females = 1.3%). In this study, we compared transcriptome-wide RNA sequencing data from the very first 26 BCC cases and healthy skin tissue from independent 16 individuals. Genes in " cell carcinoma pathway", "Hedgehog signaling pathway", and "Notch signaling pathway" were overexpressed in BCC, confirming the findings from earlier studies in BCC in other populations known to be exposed to As. However, we found that the overexpression of these known pathways was less pronounced in patients with high As exposure (urinary As creatinine ratio (UACR) > 192 µg/gm creatinine) than patients with low UACR. We also found that high UACR was associated with impaired DNA replication pathway, cellular response to different DNA damage repair mechanisms, and immune response. Transcriptomic data were not strongly suggestive of great potential for immune checkpoint inhibitors; however, it suggested lower chance of platinum drug resistance in BCC patients with high UACR compared high platinum drug resistance potential in patients with lower UACR.
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INTRODUCTION: The NIH All of Us Research Program will have the scale and scope to enable research for a wide range of diseases, including cancer. The program's focus on diversity and inclusion promises a better understanding of the unequal burden of cancer. Preliminary cancer ascertainment in the All of Us cohort from two data sources (self-reported versus electronic health records (EHR)) is considered. MATERIALS AND METHODS: This work was performed on data collected from the All of Us Research Program's 315,297 enrolled participants to date using the Researcher Workbench, where approved researchers can access and analyze All of Us data on cancer and other diseases. Cancer case ascertainment was performed using data from EHR and self-reported surveys across key factors. Distribution of cancer types and concordance of data sources by cancer site and demographics is analyzed. RESULTS AND DISCUSSION: Data collected from 315,297 participants resulted in 13,298 cancer cases detected in the survey (in 89,261 participants), 23,520 cancer cases detected in the EHR (in 203,813 participants), and 7,123 cancer cases detected across both sources (in 62,497 participants). Key differences in survey completion by race/ethnicity impacted the makeup of cohorts when compared to cancer in the EHR and national NCI SEER data. CONCLUSIONS: This study provides key insight into cancer detection in the All of Us Research Program and points to the existing strengths and limitations of All of Us as a platform for cancer research now and in the future.
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Neoplasias , Saúde da População , Estudos de Coortes , Registros Eletrônicos de Saúde , Humanos , Neoplasias/epidemiologia , Inquéritos e QuestionáriosRESUMO
The All of Us Research Program seeks to engage at least one million diverse participants to advance precision medicine and improve human health. We describe here the cloud-based Researcher Workbench that uses a data passport model to democratize access to analytical tools and participant information including survey, physical measurement, and electronic health record (EHR) data. We also present validation study findings for several common complex diseases to demonstrate use of this novel platform in 315,000 participants, 78% of whom are from groups historically underrepresented in biomedical research, including 49% self-reporting non-White races. Replication findings include medication usage pattern differences by race in depression and type 2 diabetes, validation of known cancer associations with smoking, and calculation of cardiovascular risk scores by reported race effects. The cloud-based Researcher Workbench represents an important advance in enabling secure access for a broad range of researchers to this large resource and analytical tools.
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INTRODUCTION: Evidence regarding the associations between accelerometer-measured moderate-vigorous physical activity (MVPA) and cardiovascular health (CVH) indicators among Hispanic/Latino adults are unavailable. METHODS: Examined cross-sectional data from 12,008 Hispanic/Latino adults aged 18-74 years participating in the Hispanic Community Health Study/Study of Latinos. Accelerometer-measured MVPA was assessed categorically and dichotomously per 2008 PA guidelines. Adverse and ideal CVH indicators were determined by standard cut-points for blood glucose, total cholesterol, blood pressure, body mass index (BMI), and smoking. A composite of low CV risk, defined as achieving all ideal CVH indicators, was included. Adjusted Poisson regression models and complex survey design methods were used for all analyses. RESULTS: Compared to high MVPA, lower MVPA categories were associated with higher prevalence of all adverse CVH indicators, except hypertension, and with lower prevalence of low CV risk and ideal blood glucose, blood pressure, and BMI. Similarly, non-adherence to PA guidelines was associated with a higher prevalence of diabetes (16%), hypercholesterolemia (9%), obesity (28%), and smoking (9%); and lower prevalence of low CV risk (24%), ideal blood glucose (6%), ideal blood pressure (6%), and ideal BMI (22%). CONCLUSION: Overall, high accelerometer-measured MVPA and meeting PA guidelines were associated with favorable CVH in Hispanic/Latino adults.
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Doenças Cardiovasculares , Saúde Pública , Acelerometria , Adolescente , Adulto , Idoso , Estudos Transversais , Exercício Físico/fisiologia , Hispânico ou Latino , Humanos , Pessoa de Meia-Idade , Fatores de Risco , Adulto JovemRESUMO
Arsenic exposure has been linked to poor pulmonary function, and inefficient arsenic metabolizers may be at increased risk. Dietary rice has recently been identified as a possible substantial route of exposure to arsenic, and it remains unknown whether it can provide a sufficient level of exposure to affect pulmonary function in inefficient metabolizers. Within 12,609 participants of HCHS/SOL, asthma diagnoses and spirometry-based measures of pulmonary function were assessed, and rice consumption was inferred from grain intake via a food frequency questionnaire. After stratifying by smoking history, the relationship between arsenic metabolism efficiency [percentages of inorganic arsenic (%iAs), monomethylarsenate (%MMA), and dimethylarsinate (%DMA) species in urine] and the measures of pulmonary function were estimated in a two-sample Mendelian randomization approach (genotype information from an Illumina HumanOmni2.5-8v1-1 array), focusing on participants with high inferred rice consumption. Among never-smoking high inferred consumers of rice (n = 1395), inefficient metabolism was associated with past asthma diagnosis and forced vital capacity below the lower limit of normal (LLN) (OR 1.40, p = 0.0212 and OR 1.42, p = 0.0072, respectively, for each percentage-point increase in %iAs; OR 1.26, p = 0.0240 and OR 1.24, p = 0.0193 for %MMA; OR 0.87, p = 0.0209 and OR 0.87, p = 0.0123 for the marker of efficient metabolism, %DMA). Among ever-smoking high inferred consumers of rice (n = 1127), inefficient metabolism was associated with peak expiratory flow below LLN (OR 1.54, p = 0.0108/percentage-point increase in %iAs, OR 1.37, p = 0.0097 for %MMA, and OR 0.83, p = 0.0093 for %DMA). Less efficient arsenic metabolism was associated with indicators of pulmonary dysfunction among those with high inferred rice consumption, suggesting that reductions in dietary arsenic could improve respiratory health.
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Arsênio , Asma , Ácido Cacodílico , Hispânico ou Latino , Oryza , Adulto , Arsênio/farmacocinética , Arsênio/toxicidade , Asma/induzido quimicamente , Asma/genética , Asma/fisiopatologia , Ácido Cacodílico/farmacocinética , Ácido Cacodílico/toxicidade , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Estados Unidos , Capacidade VitalRESUMO
We assess whether the cross-sectional associations between moderate-vigorous physical activity (MVPA) and CVD risk factors are modified by various stress types. Complete baseline data from 4,000 participants, ages 18-74 years, of the Hispanic Community Health Study/Study of Latinos Sociocultural Ancillary Study (HCHS/SOL SCAS) were analyzed using complex survey design methods. Accelerometer-measured MVPA was assessed continuously (average minutes per day). CVD risk factors assessed were diabetes, hypercholesterolemia, hypertension, and obesity. Stress was assessed using the Chronic Burden Scale for chronic stress, Traumatic Stress Schedule for traumatic stress, and the Perceived Stress Scale for perceived stress. Poisson regression models estimated prevalence ratios of CVD risk factors. The interaction was evaluated by cross-product terms with p <0.10. There was a significant interaction between chronic stress and MVPA among those with prevalent diabetes (pinteraction = 0.09). Among those reporting low chronic stress, higher MVPA was associated with a low prevalence of diabetes, however among those reporting high chronic stress, the prevalence of diabetes remained high even with higher MVPA. We did not observe interactions between chronic stress and MVPA for the remaining CVD risk factors, or interactions between traumatic stress or perceived stress and MVPA. This study provides initial evidence on the role of chronic stress on the association between MVPA and diabetes for Hispanic/Latino adults. Mostly, however, chronic stress, traumatic stress, and perceived stress did not modify the associations between MVPA and CVD risk factors for Hispanic/Latino adults.
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PURPOSE OF REVIEW: Rice is a major staple food worldwide and a dietary source of arsenic. We therefore summarized the state of the epidemiologic evidence on whether rice consumption relates to health outcomes associated with arsenic exposure. RECENT FINDINGS: While epidemiologic studies have reported that higher rice consumption may increase the risk of certain chronic conditions, i.e., type 2 diabetes, most did not consider specific constituents of rice or other sources of arsenic exposure. Studies that examined rice intake stratified by water concentrations of arsenic found evidence of increasing trends in cardiovascular disease risk, skin lesions, and squamous cell skin cancers and bladder cancer associated with higher rice consumption. Further studies are needed to understand the health impacts of arsenic exposure from rice consumption taking into account all sources of rice intake and potential confounding by other dietary constituents or contaminants and arsenic exposure from sources such as water.
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Arsênio/análise , Dieta/efeitos adversos , Exposição Ambiental/efeitos adversos , Contaminação de Alimentos/análise , Oryza/química , Arsênio/toxicidade , Exposição Ambiental/análise , HumanosRESUMO
BACKGROUND: Emerging evidence suggests airborne metals may be associated with breast cancer risk. However, breast cancer is heterogenous and associations with heavy metals vary by subtype. Heavy metals possess both carcinogenic and xenoestrogenic properties which may be related to different tumor etiologies. Therefore, we tested for etiologic heterogeneity, using a case-series approach, to determine whether associations between residential airborne metal concentrations and breast cancer differed by tumor subtype. METHODS: Between 2005 and 2008, we enrolled incident breast cancer cases into the Breast Cancer Care in Chicago study. Tumor estrogen and progesterone receptors status was determined by medical record abstraction and confirmed immunohistochemically (Nâ¯=â¯696; 147 ER/PR-negative). The 2002 USEPA's National Air Toxics Assessment census-tract estimates of metal concentrations (antimony, arsenic, beryllium, cadmium, chromium, cobalt, lead, manganese, mercury, nickel and selenium) were matched to participants' residences of the same year. Adjusted logistic regression models were used to examine whether the airborne heavy metal associations differed by tumor ER/PR status. Principal component analysis was performed to assess associations by metal co-exposures. RESULTS: Comparing the highest and lowest quintiles, higher concentrations of antimony (odds ratio[OR]: 1.8, 95% confidence interval[CI]: 0.9, 3.7, P-trend: 0.05), cadmium (OR: 2.3, 95% CI: 1.2, 4.4, P-trend: 0.04) and cobalt (OR: 2.0, 95% CI: 0.9, 4.4, P-trend: 0.04) were associated with ER/PR-negative breast cancer. Mixture analysis using principal components suggested co-exposures to multiple airborne heavy metals may drive associations with tumor receptor status. CONCLUSIONS: Among women diagnosed with breast cancer, metallic air pollutants were associated with increased odds of developing ER/PR-negative breast cancer.
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Poluentes Atmosféricos , Poluição do Ar/estatística & dados numéricos , Neoplasias da Mama/epidemiologia , Exposição Ambiental/estatística & dados numéricos , Metais Pesados , Mama , Cádmio , Feminino , Humanos , Fatores de RiscoRESUMO
AIMS: The present study examined how variation in mu- (OPRM1), kappa- (OPRK), and delta- (OPRD) opioid receptor genes may influence the efficacy of naltrexone in the context of a smoking cessation trial. METHODS: The study's primary objective was to examine the association of the Asn40Asp OPRM1 single nucleotide polymorphism (SNP) with naltrexone's effects on smoking quit rate, weight gain, and heavy drinking behavior during a double-blind, randomized clinical trial in 280 adult DSM-IV nicotine-dependent participants. The secondary goal of the study was to examine the relationship of 20 additional SNPs of OPRM1, OPRK, and OPRD with the aforementioned outcomes. RESULTS: Results indicated a null association between any opioid-receptor gene SNP and naltrexone's effects on smoking quit rate, weight gain, and heavy drinking behavior in this sample of nicotine dependent participants. CONCLUSIONS: In sum, these results do not suggest that genetic variation in opioid-receptors is related to treatment responses to naltrexone in a smoking cessation trial.
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Genótipo , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Receptores Opioides/genética , Abandono do Hábito de Fumar/métodos , Fumar Tabaco/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética , Fumar Tabaco/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: Inorganic arsenic (iAs) is ubiquitous in the environment and has been linked to lung cancer and a number of non-malignant lung disease in both adults and children. However, most studies were conducted in populations with higher arsenic exposure levels in drinking water and relatively little epidemiologic research evaluated the impacts of low levels iAs exposure on non-malignant lung disease among populations that are not primarily exposed to arsenic through drinking water. OBJECTIVES: We assessed the associations of arsenic exposure with airway inflammation and lung function among U.S. adults aged 20-79 years using data from the National Health and Nutrition Examination Survey 2007-2012 cycles. METHODS: Two measures of arsenic exposure, urinary total arsenic and dimethylarsonic acid (DMA), were used. We calibrated these two exposure measures by regressing their concentrations by arsenobetaine and extracting the residuals to calculate estimated total arsenic and estimated DMA. Arsenic exposures were modeled as log-transformed continuous variables as well as quartile categories. Fractional exhaled nitric oxide (FENO), an indicator of respiratory inflammation, was available for participants. For lung function, the best forced expiratory volume in the first one second (FEV1), forced vital capacity (FVC), forced expiratory flow rate (FEF) 25-75%, their percent estimated values, ratios of FEV1 to FVC, and FEF 25-75% to FVC were used (i.e. FEV1/FVC and FEF/FVC). Weighted multivariable linear regression models, adjusted for potential confounders, were used to evaluate the association of arsenic exposure with airway inflammation and lung function overall, and among males and females. RESULTS: Significant associations between arsenic exposure and increased airway inflammation were found. A two-fold increase in urinary total arsenic and DMA was associated with 23.87% (95% CI: 2.66, 49.46) and 14.05% (95% CI: 1.77, 27.81) higher levels of FENO, respectively. In addition, participants in the highest quartile of urinary total arsenic had FENO levels 8.49% (95% CI: 1.13, 16.39) higher than those in the lowest quartile. These associations were similar between males and females. Limited evidence was found for the association with respect to lung function and potential modification effect of sex. CONCLUSIONS: Arsenic exposure was related to increased risk of airway inflammation but there is limited evidence of an association in relation to lung function. Future research conducted in populations with relatively lower exposure levels that are not primarily exposed to arsenic through drinking water is needed to confirm our findings.
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Arsênio/urina , Poluentes Ambientais/urina , Pulmão/fisiologia , Adulto , Idoso , Criança , Exposição Ambiental , Feminino , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Capacidade Vital , Adulto JovemRESUMO
BACKGROUND: Arsenic exposure affects [Formula: see text] people worldwide, including [Formula: see text] in Bangladesh. Arsenic exposure increases the risk of cancer and other chronic diseases, and one potential mechanism of arsenic toxicity is epigenetic dysregulation. OBJECTIVE: We assessed associations between arsenic exposure and genome-wide DNA methylation measured at baseline among 396 Bangladeshi adults participating in the Health Effects of Arsenic Longitudinal Study (HEALS) who were exposed by drinking naturally contaminated well water. METHODS: Methylation in whole blood DNA was measured at [Formula: see text] using the Illumina InfiniumMethylationEPIC (EPIC) array. To assess associations between arsenic exposure and CpG methylation, we used linear regression models adjusted for covariates and surrogate variables (SVs) (capturing unknown technical and biologic factors). We attempted replication and conducted a meta-analysis using an independent dataset of [Formula: see text] from 400 Bangladeshi individuals with arsenical skin lesions. RESULTS: We identified 34 CpGs associated with [Formula: see text] creatinine-adjusted urinary arsenic [[Formula: see text]]. Sixteen of these CpGs annotated to the [Formula: see text] array, and 10 associations were replicated ([Formula: see text]). The top two CpGs annotated upstream of the ABR gene (cg01912040, cg10003262 ). All urinary arsenic-associated CpGs were also associated with arsenic concentration measured in drinking water ([Formula: see text]). Meta-analysis ([Formula: see text] samples) identified 221 urinary arsenic-associated CpGs ([Formula: see text]). The arsenic-associated CpGs from the meta-analysis were enriched in non-CpG islands and shores ([Formula: see text]) and depleted in promoter regions ([Formula: see text]). Among the arsenic-associated CpGs ([Formula: see text]), we observed significant enrichment of genes annotating to the reactive oxygen species pathway, inflammatory response, and tumor necrosis factor [Formula: see text] ([Formula: see text]) signaling via nuclear factor kappa-B ([Formula: see text]) hallmarks ([Formula: see text]). CONCLUSIONS: The novel and replicable associations between arsenic exposure and DNA methylation at specific CpGs observed in this work suggest that epigenetic alterations should be further investigated as potential mediators in arsenic toxicity and as biomarkers of exposure and effect in exposed populations. https://doi.org/10.1289/EHP3849.
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Arsênio/urina , Metilação de DNA/efeitos dos fármacos , Água Potável/análise , Exposição Ambiental/análise , Poluentes Químicos da Água/urina , Adulto , Idoso , Bangladesh , Estudos de Coortes , Ilhas de CpG/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Hypertension and diabetes have been associated with inefficient arsenic metabolism, primarily through studies undertaken in populations exposed through drinking water. Recently, rice has been recognized as a source of arsenic exposure, but it remains unclear whether populations with high rice consumption but no known water exposure are at risk for the health problems associated with inefficient arsenic metabolism. METHODS: The relationships between arsenic metabolism efficiency (% inorganic arsenic, % monomethylarsenate and % dimethylarsinate in urine) and three hypertension- and seven diabetes-related traits were estimated among 12 609 participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). A two-sample Mendelian randomization approach incorporated genotype-arsenic metabolism relationships from literature, and genotype-trait relationships from HCHS/SOL, with a mixed-effect linear model. Analyses were stratified by rice consumption and smoking. RESULTS: Among never smokers with high rice consumption, each percentage point increase in was associated with increases of 1.96 mmHg systolic blood pressure (P = 0.034) and 1.85 mmHg inorganic arsenic diastolic blood pressure (P = 0.003). Monomethylarsenate was associated with increased systolic (1.64 mmHg/percentage point increase; P = 0.021) and diastolic (1.33 mmHg/percentage point increase; P = 0.005) blood pressure. Dimethylarsinate, a marker of efficient metabolism, was associated with lower systolic (-0.92 mmHg/percentage point increase; P = 0.025) and diastolic (-0.79 mmHg/percentage point increase; P = 0.004) blood pressure. Among low rice consumers and ever smokers, the results were consistent with no association. Evidence for a relationship with diabetes was equivocal. CONCLUSIONS: Less efficient arsenic metabolism was associated with increased blood pressure among never smokers with high rice consumption, suggesting that arsenic exposure through rice may contribute to high blood pressure in the Hispanic/Latino community.
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Arsênio/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Dieta/estatística & dados numéricos , Hipertensão/epidemiologia , Oryza , Adulto , Amônia-Liases/genética , Arsênio/urina , Arsenicais/urina , Pressão Sanguínea , Ácido Cacodílico/urina , Feminino , Contaminação de Alimentos , Glutamato Formimidoiltransferase/genética , Hispânico ou Latino , Humanos , Masculino , Análise da Randomização Mendeliana , Metiltransferases/genética , Pessoa de Meia-Idade , Enzimas Multifuncionais/genética , Oryza/química , Fatores de Risco , Fumar/epidemiologiaRESUMO
Inorganic arsenic (iAs) is a carcinogen, and exposure to iAs via food and water is a global public health problem. iAs-contaminated drinking water alone affects >100 million people worldwide, including ~50 million in Bangladesh. Once absorbed into the blood stream, most iAs is converted to mono-methylated (MMA) and then di-methylated (DMA) forms, facilitating excretion in urine. Arsenic metabolism efficiency varies among individuals, in part due to genetic variation near AS3MT (arsenite methyltransferase; 10q24.32). To identify additional arsenic metabolism loci, we measured protein-coding variants across the human exome for 1,660 Bangladeshi individuals participating in the Health Effects of Arsenic Longitudinal Study (HEALS). Among the 19,992 coding variants analyzed exome-wide, the minor allele (A) of rs61735836 (p.Val101Met) in exon 3 of FTCD (formiminotransferase cyclodeaminase) was associated with increased urinary iAs% (P = 8x10-13), increased MMA% (P = 2x10-16) and decreased DMA% (P = 6x10-23). Among 2,401 individuals with arsenic-induced skin lesions (an indicator of arsenic toxicity and cancer risk) and 2,472 controls, carrying the low-efficiency A allele (frequency = 7%) was associated with increased skin lesion risk (odds ratio = 1.35; P = 1x10-5). rs61735836 is in weak linkage disequilibrium with all nearby variants. The high-efficiency/major allele (G/Valine) is human-specific and eliminates a start codon at the first 5´-proximal Kozak sequence in FTCD, suggesting selection against an alternative translation start site. FTCD is critical for catabolism of histidine, a process that generates one-carbon units that can enter the one-carbon/folate cycle, which provides methyl groups for arsenic metabolism. In our study population, FTCD and AS3MT SNPs together explain ~10% of the variation in DMA% and support a causal effect of arsenic metabolism efficiency on arsenic toxicity (i.e., skin lesions). In summary, this work identifies a coding variant in FTCD associated with arsenic metabolism efficiency, providing new evidence supporting the established link between one-carbon/folate metabolism and arsenic toxicity.
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Amônia-Liases/genética , Arsênio/toxicidade , Glutamato Formimidoiltransferase/genética , Metiltransferases/genética , Adulto , Alelos , Amônia-Liases/fisiologia , Arsênio/metabolismo , Intoxicação por Arsênico , Bangladesh , Exposição Ambiental , Feminino , Ácido Fólico/metabolismo , Frequência do Gene/genética , Glutamato Formimidoiltransferase/fisiologia , Humanos , Masculino , Metilação , Metiltransferases/metabolismo , Enzimas Multifuncionais , Mutação de Sentido Incorreto , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Dermatopatias/induzido quimicamente , Dermatopatias/genética , Poluentes Químicos da ÁguaRESUMO
OBJECTIVE: We investigated the association of genetic variants of EPHA4, a receptor tyrosine kinase, with hypertension, and its role in vascular smooth muscle cell (VSMC) contractility. METHODS: Data from two human genetic studies, ADVANCE and HCHS/SOL, were analyzed for association of EPHA4 single nucleotide variants (SNVs) with hypertension risks. The effect of EPHA4 signalling on mouse VSMC contractility was assessed. RESULTS: We identified a SNV (rs75843691 hg19 chr2:g.222395371 C>G), located in the third intron of EPHA4 gene, being significantly associated with hypertension in human female patients (P valueâ=â8.3â×â10, below the Bonferroni-corrected critical P value) but not male patients with type 2 diabetes from the ADVANCE clinical trial. We found that EPHA4 was expressed in VSMCs and its stimulation by anti-EPHA4 antibody led to reduced VSMC contractility. Estrogen enhanced the contractility-lowering effect of EPHA4 stimulation. Conversely, siRNA knockdown of Epha4 expression in VSMCs resulted in increased contractility of VSMCs from female mice but not from male mice. CONCLUSION: EPHA4 appears to be a sex-specific hypertension risk gene in type 2 diabetic patients. Forward EPHA4 signalling reduces VSMC contractility, and estrogen is a modifier of this effect. The effect of EPHA4 on VSMCs contractility explains the association of EPHA4 gene with hypertension risks in female patients.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Hipertensão/genética , Contração Muscular , Músculo Liso Vascular/fisiologia , Receptor EphA4/genética , Animais , Estrogênios/fisiologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/metabolismo , RNA Interferente Pequeno , Receptor EphA4/metabolismo , Caracteres Sexuais , Transdução de SinaisRESUMO
BACKGROUND: Heavy metal contamination is widespread in Bangladesh. Previous studies have observed lead increases blood pressure over time. However, the role of other metal contaminants and essential micronutrients, which could also adversely affect blood pressure or act as protective factors, is understudied. OBJECTIVES: We therefore evaluated the associations of lead, manganese, and selenium with blood and pulse pressure trajectories. METHODS: We prospectively followed placebo-assigned participants nested within a randomized trial for the prevention of arsenic-related skin cancer (nâ¯=â¯255). Blood lead, manganese, and selenium were measured at baseline; blood pressure was measured at baseline and at 3 biennial follow-up examinations. Mixed-effect linear regression models were used to estimate associations with average annual changes in systolic, diastolic, and pulse pressure. RESULTS: In models simultaneously adjusted for baseline blood lead, manganese, and selenium concentrations in addition to other potential confounders, lead was linearly associated with increases in systolic blood pressure, but not with diastolic blood pressure or pulse pressure. A non-linear association was observed for manganese, such that mid-range concentrations were associated with decreases in systolic, diastolic, and pulse pressure. Baseline selenium concentrations in the highest quartile were also associated with longitudinal decreases in both systolic and diastolic blood pressure, while null associations were observed with pulse pressure. In exploratory analyses, the combination of mid-range manganese and high selenium concentrations completely offset lead-associated increases in blood and pulse pressure. CONCLUSIONS: The results indicate a direct, linear association of lead exposure with systolic blood pressure, and manganese and selenium exposures within certain ranges may have a blood pressure-lowering effect in this population.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Manganês/efeitos adversos , Manganês/sangue , Selênio/efeitos adversos , Selênio/sangue , Adulto , Arsênio/análise , Arsênio/toxicidade , Bangladesh , Estudos de Coortes , Feminino , Humanos , Íons/análise , Masculino , Metais Pesados/efeitos adversos , Metais Pesados/sangue , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias Cutâneas/induzido quimicamenteRESUMO
OBJECTIVE: Cardiovascular disease (CVD) is a leading cause of mortality and morbidity in the USA. The role of occupational exposures to chemicals in the development of CVD has rarely been studied even though many agents possess cardiotoxic properties. We therefore evaluated associations of self-reported exposures to organic solvents, metals and pesticides in relation to CVD prevalence among diverse Hispanic/Latino workers. METHODS: Cross-sectional data from 7404 employed individuals, aged 18-74 years, enrolled in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) were analysed. Participants from four US cities provided questionnaire data and underwent clinical examinations, including ECGs. CVD was defined as the presence of at least one of the following: coronary heart disease, atrial fibrillation, heart failure or cerebrovascular disease. Prevalence ratios reflecting the relationship between each occupational exposure and CVD as well as CVD subtypes were calculated using Poisson regression models. RESULTS: Hispanic/Latino workers reported exposures to organic solvents (6.5%), metals (8.5%) and pesticides (4.7%) at their current jobs. Overall, 6.1% of participants had some form of CVD, with coronary heart disease as the most common (4.3%) followed by cerebrovascular disease (1.0%), heart failure (0.8%) and atrial fibrillation (0.7%). For individuals who reported working with pesticides, the prevalence ratios for any CVD were 2.18 (95% CI 1.34 to 3.55), coronary heart disease 2.20 (95% CI 1.31 to 3.71), cerebrovascular disease 1.38 (95% CI 0.62 3.03), heart failure 0.91 (95% CI 0.23 to 3.54) and atrial fibrillation 5.92 (95% CI 1.89 to 18.61) after adjustment for sociodemographic, acculturation, lifestyle and occupational characteristics. Metal exposures were associated with an almost fourfold (3.78, 95% CI 1.24 to 11.46) greater prevalence of atrial fibrillation. Null associations were observed for organic solvent exposures. CONCLUSIONS: Our results suggest that working with metals and pesticides could be risk factors for CVD among Hispanic/Latino workers. Further work is needed to evaluate these relationships prospectively.