Search

BACKGROUND: The prevalence of type 2 diabetes has dramatically increased in the past years. Increasing evidence supports that blood DNA methylation, the best studied epigenetic mark, is related to diabetes risk. Few prospective studies, however, are available. We studied the association of blood DNA methylation with diabetes in the Strong Heart Study. We used limma, Iterative Sure Independence Screening and Cox regression to study the association of blood DNA methylation with fasting glucose, HOMA-IR and incident type 2 diabetes among 1312 American Indians from the Strong Heart Study. DNA methylation was measured using Illuminas MethylationEPIC beadchip. We also assessed the biological relevance of our findings using bioinformatics analyses. RESULTS: Among the 358 differentially methylated positions (DMPs) that were cross-sectionally associated either with fasting glucose or HOMA-IR, 49 were prospectively associated with incident type 2 diabetes, although no DMPs remained significant after multiple comparisons correction. Multiple of the top DMPs were annotated to genes with relevant functions for diabetes including SREBF1, associated with obesity, type 2 diabetes and insulin sensitivity; ABCG1, involved in cholesterol and phospholipids transport; and HDAC1, of the HDAC family. (HDAC inhibitors have been proposed as an emerging treatment for diabetes and its complications.) CONCLUSIONS: Our results suggest that differences in peripheral blood DNA methylation are related to cross-sectional markers of glucose metabolism and insulin activity. While some of these DMPs were modestly associated with prospective incident type 2 diabetes, they did not survive multiple testing. Common DMPs with diabetes epigenome-wide association studies from other populations suggest a partially common epigenomic signature of glucose and insulin activity.

Unless a toxicant builds up in a deep compartment, intake by the human body must on average balance the amount that is lost. We apply this idea to assess arsenic (As) exposure misclassification in three previously studied populations in rural Bangladesh (n = 11,224), Navajo Nation in the Southwestern United States (n = 619), and northern Chile (n = 630), under varying assumptions about As sources. Relationships between As intake and excretion were simulated by taking into account additional sources, as well as variability in urine dilution inferred from urinary creatinine. The simulations bring As intake closer to As excretion but also indicate that some exposure misclassification remains. In rural Bangladesh, accounting for intake from more than one well and rice improved the alignment of intake and excretion, especially at low exposure. In Navajo Nation, comparing intake and excretion revealed home dust as an important source. Finally, in northern Chile, while food-frequency questionnaires and urinary As speciation indicate fish and shellfish sources, persistent imbalance of intake and excretion suggests imprecise measures of drinking water arsenic as a major cause of exposure misclassification. The mass-balance approach could prove to be useful for evaluating sources of exposure to toxicants in other settings.

BackgroundEpigenetic dysregulation has been proposed as a key mechanism for arsenic-related cardiovascular disease (CVD). We evaluated differentially methylated positions (DMPs) as potential mediators on the association between arsenic and CVD.MethodsBlood DNA methylation was measured in 2321 participants (mean age 56.2, 58.6% women) of the Strong Heart Study, a prospective cohort of American Indians. Urinary arsenic species were measured using high-performance liquid chromatography coupled to inductively coupled plasma mass spectrometry. We identified DMPs that are potential mediators between arsenic and CVD. In a cross-species analysis, we compared those DMPs with differential liver DNA methylation following early-life arsenic exposure in the apoE knockout (apoE-/-) mouse model of atherosclerosis.ResultsA total of 20 and 13 DMPs were potential mediators for CVD incidence and mortality, respectively, several of them annotated to genes related to diabetes. Eleven of these DMPs were similarly associated with incident CVD in 3 diverse prospective cohorts (Framingham Heart Study, Women's Health Initiative, and Multi-Ethnic Study of Atherosclerosis). In the mouse model, differentially methylated regions in 20 of those genes and DMPs in 10 genes were associated with arsenic.ConclusionsDifferential DNA methylation might be part of the biological link between arsenic and CVD. The gene functions suggest that diabetes might represent a relevant mechanism for arsenic-related cardiovascular risk in populations with a high burden of diabetes.

BACKGROUND: Chronic arsenic exposure has been associated with an increased risk of cardiovascular disease; diabetes; cancers of the lung, pancreas and prostate; and all-cause mortality in American Indian communities in the Strong Heart Study. OBJECTIVE: The Strong Heart Water Study (SHWS) designed and evaluated a multilevel, community-led arsenic mitigation program to reduce arsenic exposure among private well users in partnership with Northern Great Plains American Indian Nations. METHODS: A cluster randomized controlled trial (cRCT) was conducted to evaluate the effectiveness of the SHWS arsenic mitigation program over a 2-y period on a) urinary arsenic, and b) reported use of arsenic-safe water for drinking and cooking. The cRCT compared the installation of a point-of-use arsenic filter and a mobile Health (mHealth) program (3 phone calls; SHWS mHealth and Filter arm) to a more intensive program, which included this same program plus three home visits (3 phone calls and 3 home visits; SHWS Intensive arm). RESULTS: A 47% reduction in urinary arsenic [geometric mean (GM) = 13:2to7:0 [micro]g/g creatinine] was observed from baseline to the final follow-up when both study arms were combined. By treatment arm, the reduction in urinary arsenic from baseline to the final follow-up visit was 55% in the mHealth and Filter arm (GM = 14:6 to 6:55 [micro]g/g creatinine) and 30% in the Intensive arm (GM = 11:2 to 7:82 [micro]g/g creatinine). There was no significant difference in urinary arsenic levels by treatment arm at the final follow-up visit comparing the Intensive vs. mHealth and Filter arms: GM ratio of 1.21 (95% confidence interval: 0.77, 1.90). In both arms combined, exclusive use of arsenic-safe water from baseline to the final follow-up visit significantly increased for water used for cooking (17% to 53%) and drinking (12% to 46%). DISCUSSION: Delivery of the interventions for the community-led SHWS arsenic mitigation program, including the installation of a point-of-use arsenic filter and a mHealth program on the use of arsenic-safe water (calls only, no home visits), resulted in a significant reduction in urinary arsenic and increases in reported use of arsenic-safe water for drinking and cooking during the 2-y study period. These results demonstrate that the installation of an arsenic filter and phone calls from a mHealth program presents a promising approach to reduce water arsenic exposure among private well users. https://doi.org/10.1289/EHP12548, Introduction In the United States, >2 million individuals use private wells with arsenic levels above the US Environmental Protection Agency (EPA) guideline for drinking water ( Despite the growing evidence [...]

The effect of low-moderate levels of arsenic exposure and of arsenic metabolism on mortality remains uncertain. We used data from a prospective cohort study in 3600 men and women aged 45 to 75 years living in Arizona, Oklahoma, and North and South Dakota. The biomarker of inorganic arsenic exposure was the sum of urine inorganic (iAs), monomethylated (MMA) and dimethylated (DMA) arsenic compounds (ƩAs) at baseline. The proportions of urine iAs, MMA and DMA over the ƩiAs, expressed as iAs%, MMA%, and DMA%, respectively, were used as biomarkers of arsenic metabolism. Arsenic exposure and arsenic metabolism were associated with all-cause, cardiovascular, and cancer mortality. For each interquartile range (IQR) increase in ƩAs (12.5 μg/L, overall range 0.7-194.1 μg/L), the adjusted hazard ratios (aHRs) were 1.28 (95% CI 1.16-1.41) for all-cause mortality, 1.28 (1.08-1.52) for cardiovascular mortality and 1.15 (0.92-1.44) for cancer mortality. The aHR for mortality for each IQR increase in MMA%, when iAs% is decreasing, was 1.52 (95% CI 1.16-1.99) for cardiovascular disease, 0.73 (0.55-0.98) for cancer, and 1.03 (0.90-1.19) for all-cause mortality. These findings at low-moderate levels of arsenic exposure highlight the need to implement public health measures to protect populations from involuntary arsenic exposure and for research to advance the biological and clinical understanding of arsenic-related health effects in general populations.

BackgroundArsenic (As) exposure through drinking water is a global public health concern. Epigenetic dysregulation including changes in DNA methylation (DNAm), may be involved in arsenic toxicity. Epigenome-wide association studies (EWAS) of arsenic exposure have been restricted to single populations and comparison across EWAS has been limited by methodological differences. Leveraging data from epidemiological studies conducted in Chile and Bangladesh, we use a harmonized data processing and analysis pipeline and meta-analysis to combine results from four EWAS.MethodsDNAm was measured among adults in Chile with and without prenatal and early-life As exposure in PBMCs and buccal cells (N = 40, 850K array) and among men in Bangladesh with high and low As exposure in PBMCs (N = 32, 850K array; N = 48, 450K array). Linear models were used to identify differentially methylated positions (DMPs) and differentially variable positions (DVPs) adjusting for age, smoking, cell type, and sex in the Chile cohort. Probes common across EWAS were meta-analyzed using METAL, and differentially methylated and variable regions (DMRs and DVRs, respectively) were identified using comb-p. KEGG pathway analysis was used to understand biological functions of DMPs and DVPs.ResultsIn a meta-analysis restricted to PBMCs, we identified one DMP and 23 DVPs associated with arsenic exposure; including buccal cells, we identified 3 DMPs and 19 DVPs (FDR

BACKGROUND: Arsenic has been associated with hypertension, though it is unclear whether associations persist at the exposure concentrations (e.g.

BACKGROUND: Inorganic arsenic (As) may increase the risk of cardiovascular disease (CVD) and all-cause mortality through accelerated aging, which can be estimated using epigenetic-based measures. OBJECTIVES: We evaluated three DNA methylation-based aging measures (PhenoAge, GrimAge, DunedinPACE) (epigenetic aging measures) as potential mediators of the previously reported association of As exposure with CVD incidence, CVD mortality, and all- cause mortality in the Strong Heart Study (SHS), an epidemiological cohort of American Indian adults. METHODS: Blood DNA methylation and urinary As levels were measured in 2,323 SHS participants (41.5% men, mean age of 55 years old). PhenoAge and GrimAge values were calculated using a residual-based method. We tested the association of urinary As with epigenetic aging measures using linear regression, the association of epigenetic aging measures with the three health outcomes using additive hazards models, and the mediation of As-related CVD incidence, CVD mortality, and all-cause mortality by epigenetic aging measures using the product of coefficients method. RESULTS: SHS participants with higher vs. lower urinary As levels had similar PhenoAge age, older GrimAge age, and faster DunedinPACE. An interquartile range increase in urinary As was associated with higher of PhenoAge age acceleration [mean difference (95% confidence interval) = 0.48 (0.17, 0.80) years], GrimAge age acceleration [0.80 (0.60, 1.00) years], and DunedinPACE [0.011 (0.005, 0.018)], after adjusting for age, sex, center location, genetic components, smoking status, and body mass index. Of the 347 incident CVD events per 100,000 person-years associated with a doubling in As exposure, 21.3% (9.1, 57.1) and 22.6% (9.5, 56.9), were attributable to differences in GrimAge and DunedinPACE, respectively. DISCUSSION: Arsenic exposure was associated with older GrimAge and faster DunedinPACE measures of biological age. Furthermore, accelerated biological aging measured from DNA methylation accounted for a relevant fraction of As-associated risk for CVD, CVD mortality, and all-cause mortality in the SHS, supporting the role of As in accelerated aging. Research of the biological underpinnings can contribute to a better understanding of the role of aging in arsenic-related disease. https://doi.org/10.1289/EHP11981, Introduction Exposure to inorganic arsenic (As), a toxic and carcinogenic metalloid, is a pervasive global health problem. Arsenic exposure has been associated with a higher risk of numerous adverse health [...]

BackgroundA limitation of the Agatston coronary artery calcium (CAC) score is that it does not use all of the calcium density information in the computed tomography scan such that many individuals have a score of zero. We examined the predictive validity for incident coronary heart disease (CHD) events of the spatially weighted coronary calcium score (SWCS), an alternative scoring method for CAC that assigns scores to individuals with Agatston CAC=0.MethodsThe MESA (Multi-Ethnic Study of Atherosclerosis) is a longitudinal study that conducted a baseline exam from 2000 to 2002 in 6814 participants including computed tomography scanning for CAC. Subsequent exams and systematic follow-up of the cohort for outcomes were performed. Statistical models were adjusted using the MESA risk score based on age, sex, race/ethnicity, systolic blood pressure, use of hypertension medications, diabetes, total and HDL (high-density lipoprotein) cholesterol, use of lipid-lowering medications, smoking status, and family history of heart attack.ResultsIn the 3286 participants with Agatston CAC=0 at baseline and for whom SWCS was computed, 98 incident CHD events defined as definite or probably myocardial infarction or definite CHD death occurred during a median follow-up of 15.1 years. In this group, SWCS predicted incident CHD events after multivariable adjustment (hazard ratio=1.30 per SD of natural logarithm [SWCS] [95% CI, 1.04-1.60]; P=0.005); and progression from Agatston CAC=0 at baseline to CAC>0 at subsequent exams (multivariable-adjusted incidence rate difference per SD of natural logarithm [SWCS] per 100 person-years 1.68 [95% CI, 1.03-2.33]; P0 at repeat computed tomography scanning at later exams. SWCS has predictive validity as a subclinical phenotype and marker of CHD risk in individuals with Agatston CAC=0.

BackgroundChronic exposure to arsenic (As), a human toxicant and carcinogen, remains a global public health problem. Health risks persist after As exposure has ended, suggesting epigenetic dysregulation as a mechanistic link between exposure and health outcomes.ObjectivesWe investigated the association between total urinary As and locus-specific DNA methylation in the Strong Heart Study, a cohort of American Indian adults with low-to-moderate As exposure [total urinary As, mean (±SD) μg/g creatinine: 11.7 (10.6)].MethodsDNA methylation was measured in 2,325 participants using the Illumina MethylationEPIC array. We implemented linear models to test differentially methylated positions (DMPs) and the DMRcate method to identify regions (DMRs) and conducted gene ontology enrichment analysis. Models were adjusted for estimated cell type proportions, age, sex, body mass index, smoking, education, estimated glomerular filtration rate, and study center. Arsenic was measured in urine as the sum of inorganic and methylated species.ResultsIn adjusted models, methylation at 20 CpGs was associated with urinary As after false discovery rate (FDR) correction (FDR

Introduction and objectiveSystematic review tools that provide guidance on evaluating epidemiology studies are receiving increasing attention and support because their application facilitates improved quality of the review, consistency across reviewers, and transparency for readers. The U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) Program has developed an approach for systematic review of evidence of health effects from chemical exposures that includes structured approaches for literature search and screening, study evaluation, data extraction, and evidence synthesis and integration. This approach recognizes the need for developing outcome-specific criteria for study evaluation. Because studies are assessed at the outcome level, a study could be considered high quality for one investigated outcome, and low quality for another, due to differences in the outcome measures, analytic strategies, how relevant a certain bias is to the outcome, and how the exposure measure relates to the outcome. The objective of this paper is to illustrate the need for outcome-specific criteria in study evaluation or risk of bias evaluation, describe the process we used to develop the criteria, and summarize the resulting criteria.MethodsWe used a process of expert consultation to develop several sets of outcome-specific criteria to guide study reviewers, improve consistency, and ensure consideration of critical issues specific to the outcomes. The criteria were developed using the following domains: outcome assessment, exposure measurement (specifically timing of exposure in relation to outcome; other exposure measurement issues would be addressed in exposure-specific criteria), participant selection, confounding, analysis, and sensitivity (the study's ability to detect a true effect or hazard).ResultsWe discuss the application of this process to pregnancy-related outcomes (preterm birth, spontaneous abortion), other reproductive-related outcomes (male reproductive hormones, sperm parameters, time to pregnancy, pubertal development), chronic disease (diabetes, insulin resistance), and acute or episodic conditions (asthma, allergies), and provide examples of the criteria developed. For each outcome the most influential methodological considerations are highlighted including biological sample collection and quality control, sensitivity and specificity of ascertainment tools, optimal timing for recruitment into the study (e.g., preconception, specific trimesters), the etiologically relevant window for exposure assessments, and important potential confounders.ConclusionsOutcome-specific criteria are an important part of a systematic review and will facilitate study evaluations by epidemiologists with experience in evaluating studies using systematic review methods who may not have extensive discipline-specific experience in the outcomes being reviewed.

The article reviews the long history and ongoing public health impact of lead poisoning, highlighting its effects on cardiovascular disease, cognitive deficits, and kidney health. Topics discussed include the sources of lead exposure, the process of absorption and body burden, and the elevated risks faced by vulnerable populations, such as children and workers in certain industries.

Key Points: Question: Does therapy with edetate disodium (EDTA)–based chelation reduce major adverse cardiovascular events compared with placebo infusions among patients with diabetes and prior myocardial infarction (MI)? Findings: EDTA-based chelation did not reduce major adverse cardiovascular events compared with placebo infusion, with a hazard ratio of 0.93 (95% CI, 0.76-1.16; P =.53). Chelation infusions did reduce the median blood lead levels from 9.0 μg/L at baseline to 3.5 μg/L at infusion 40 (P <.001). Meaning: Among patients with diabetes and prior MI, EDTA-based chelation decreased median blood lead levels by 61% from baseline but did not reduce major adverse cardiovascular events. Importance: In 2013, the Trial to Assess Chelation Therapy (TACT) reported that edetate disodium (EDTA)–based chelation significantly reduced cardiovascular disease (CVD) events by 18% in 1708 patients with a prior myocardial infarction (MI). Objective: To replicate the finding of TACT in individuals with diabetes and previous MI. Design, Setting, and Participants: A 2 × 2 factorial, double-masked, placebo-controlled, multicenter trial at 88 sites in the US and Canada, involving participants who were 50 years or older, had diabetes, and had experienced an MI at least 6 weeks before recruitment compared the effect of EDTA-based chelation vs placebo infusions on CVD events and compared the effect of high doses of oral multivitamins and minerals with oral placebo. This article reports on the chelation vs placebo infusion comparisons. Interventions: Eligible participants were randomly assigned to 40 weekly infusions of an EDTA-based chelation solution or matching placebo and to twice daily oral, high-dose multivitamin and mineral supplements or matching placebo for 60 months. This article addresses the chelation study. Main Outcomes and Measures: The primary end point was the composite of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina. Median follow-up was 48 months. Primary comparisons were made from patients who received at least 1 assigned infusion. Results: Of the 959 participants (median age, 67 years [IQR, 60-72 years]; 27% females; 78% White, 10% Black, and 20% Hispanic), 483 received at least 1 chelation infusion and 476 at least 1 placebo infusion. A primary end point event occurred in 172 participants (35.6%) in the chelation group and in 170 (35.7%) in the placebo group (adjusted hazard ratio [HR], 0.93; 95% CI, 0.76-1.16; P =.53). The 5-year primary event cumulative incidence rates were 45.8% for the chelation group and 46.5% for the placebo group. CV death, MI, or stroke events occurred in 89 participants (18.4%) in the chelation group and in 94 (19.7%) in the placebo group (adjusted HR, 0.89; 95% CI, 0.66-1.19). Death from any cause occurred in 84 participants (17.4%) in the chelation group and in 84 (17.6%) in the placebo group (adjusted HR, 0.96; 95% CI, 0.71-1.30). Chelation reduced median blood lead levels from 9.03 μg/L at baseline to 3.46 μg/L at infusion 40 (P <.001). Corresponding levels in the placebo group were 9.3 μg/L and 8.7 μg/L, respectively. Conclusions and Relevance: Despite effectively reducing blood lead levels, EDTA chelation was not effective in reducing cardiovascular events in stable patients with coronary artery disease who have diabetes and a history of MI. Trial Registration: ClinicalTrials.gov Identifier: NCT02733185 This randomized clinical trial assesses whether edetate disodium–based chelation infusions decrease cardiovascular disease events compared with placebo among patients with diabetes and prior myocardial infarction. [ABSTRACT FROM AUTHOR]