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1.  Ambient particulate air pollution and microRNAs in elderly men 
Ambient particulate matter (PM) has been associated with mortality and morbidity for cardiovascular disease (CVD). MicroRNAs control gene expression at a post-transcriptional level. Altered microRNA expression has been reported in processes related to CVD and PM exposure, e.g. systemic inflammation, endothelial dysfunction and atherosclerosis. Polymorphisms in microRNA-related genes could influence response to PM.
We investigated the association of exposure to ambient particles in several time windows (4-hours to 28-days moving averages) and blood-leukocyte expression changes in fourteen candidate microRNAs, in 153 elderly males from the Normative Aging Study (examined 2005–2009). Potential effect modification by six single nucleotide polymorphisms (SNPs) in three microRNA-related genes was investigated. Fine PM (PM2.5), black carbon, organic carbon and sulfates were measured at a stationary ambient monitoring site. Linear regression models, adjusted for potential confounders, were used to assess effects of particles and SNP-by-pollutant interaction. An in silico pathways analysis was performed on target genes of miRNAs associated with the pollutants.
We found a negative association for pollutants in all moving averages and miR-1, -126, -135a, -146a, -155, -21, -222 and -9. The strongest associations were observed with the 7-day moving averages for PM2.5 and black carbon and with the 48-hour moving averages for organic carbon. The association with sulfates was stable across the moving averages. The in silico pathway analysis identified 18 pathways related to immune response shared by at least two miRNAs; in particular, the “HMGB1/RAGE signaling pathway” was shared by miR-126, -146a, -155, -21 and -222.
No important associations were observed for miR-125a-5p, -125b, -128, -147, -218 and -96. We found significant SNP-by-pollutant interactions for rs7813, rs910925 and rs1062923 in GEMIN4 and black carbon and PM2.5 for miR-1, -126, -146a, -222 and -9, and for rs1640299 in DGCR8 and SO42− for miR-1 and -135a.
Exposure to ambient particles could cause a downregulation of microRNAs involved in processes related to PM exposure. Polymorphisms in GEMIN4 and DGCR8 could modify these associations.
PMCID: PMC3977338  PMID: 24257509
2.  Brachial Artery Responses to Ambient Pollution, Temperature, and Humidity in People with Type 2 Diabetes: A Repeated-Measures Study 
Environmental Health Perspectives  2014;122(3):242-248.
Background: Extreme weather and air pollution are associated with increased cardiovascular risk in people with diabetes.
Objectives: In a population with diabetes, we conducted a novel assessment of vascular brachial artery responses both to ambient pollution and to weather (temperature and water vapor pressure, a measure of humidity).
Methods: Sixty-four 49- to 85-year-old Boston residents with type 2 diabetes completed up to five study visits (279 repeated measures). Brachial artery diameter (BAD) was measured by ultrasound before and after brachial artery occlusion [i.e., flow-mediated dilation (FMD)] and before and after nitroglycerin-mediated dilation (NMD). Ambient concentrations of fine particulate mass (PM2.5), black carbon (BC), organic carbon (OC), elemental carbon, particle number, and sulfate were measured at our monitoring site; ambient concentrations of carbon monoxide, nitrogen dioxide, and ozone were obtained from state monitors. Particle exposure in the home and during each trip to the clinic (home/trip exposure) was measured continuously and as a 5-day integrated sample. We used linear models with fixed effects for participants, adjusting for date, season, temperature, and water vapor pressure on the day of each visit, to estimate associations between our outcomes and interquartile range increases in exposure.
Results: Baseline BAD was negatively associated with particle pollution, including home/trip–integrated BC (–0.02 mm; 95% CI: –0.04, –0.003, for a 0.28 μg/m3 increase in BC), OC (–0.08 mm; 95% CI: –0.14, –0.03, for a 1.61 μg/m3 increase) as well as PM2.5, 5-day average ambient PM2.5, and BC. BAD was positively associated with ambient temperature and water vapor pressure. However, exposures were not consistently associated with FMD or NMD.
Conclusion: Brachial artery diameter, a predictor of cardiovascular risk, decreased in association with particle pollution and increased in association with ambient temperature in our study population of adults with type 2 diabetes.
Citation: Zanobetti A, Luttmann-Gibson H, Horton ES, Cohen A, Coull BA, Hoffmann B, Schwartz JD, Mittleman MA, Li Y, Stone PH, de Souza C, Lamparello B, Koutrakis P, Gold DR. 2014. Brachial artery responses to ambient pollution, temperature, and humidity in people with type 2 diabetes: a repeated-measures study. Environ Health Perspect 122:242–248;
PMCID: PMC3948021  PMID: 24398072
3.  Short Term Effects of Particle Exposure on Hospital Admissions in the Mid-Atlantic States: A Population Estimate 
PLoS ONE  2014;9(2):e88578.
Many studies report significant associations between PM2.5 (particulate matter <2.5 micrometers) and hospital admissions. These studies mostly rely on a limited number of monitors which introduces exposure error, and excludes rural and suburban populations from locations where monitors are not available, reducing generalizability and potentially creating selection bias.
Using prediction models developed by our group, daily PM2.5 exposure was estimated across the Mid-Atlantic (Washington D.C., and the states of Delaware, Maryland, New Jersey, Pennsylvania, Virginia, New York and West Virginia). We then investigated the short-term effects of PM2.5 exposures on emergency hospital admissions of the elderly in the Mid-Atlantic region.We performed case-crossover analysis for each admission type, matching on day of the week, month and year and defined the hazard period as lag01 (a moving average of day of admission exposure and previous day exposure).
We observed associations between short-term exposure to PM2.5 and hospitalization for all outcomes examined. For example, for every 10-µg/m3 increase in short-term PM 2.5 there was a 2.2% increase in respiratory diseases admissions (95% CI = 1.9 to 2.6), and a 0.78% increase in cardiovascular disease (CVD) admission rate (95% CI = 0.5 to 1.0). We found differences in risk for CVD admissions between people living in rural and urban areas. For every10-µg/m3 increase in PM 2.5 exposure in the ‘rural’ group there was a 1.0% increase (95% CI = 0.6 to 1.5), while for the ‘urban’ group the increase was 0.7% (95% CI = 0.4 to 1.0).
Our findings showed that PM2.5 exposure was associated with hospital admissions for all respiratory, cardio vascular disease, stroke, ischemic heart disease and chronic obstructive pulmonary disease admissions. In addition, we demonstrate that our AOD (Aerosol Optical Depth) based exposure models can be successfully applied to epidemiological studies investigating the health effects of short-term exposures to PM2.5.
PMCID: PMC3917892  PMID: 24516670
4.  Short-Term Changes in Ambient Temperature and Risk of Ischemic Stroke 
Despite consistent evidence of a higher short-term risk of cardiovascular mortality associated with ambient temperature, there have been discrepant findings on the association between temperature and ischemic stroke. Moreover, few studies have considered potential confounding by ambient fine particulate matter air pollution <2.5 μm in diameter (PM2.5) and none have examined the impact of temperature changes on stroke in the subsequent hours rather than days. The aim of this study was to evaluate whether changes in temperature trigger an ischemic stroke in the following hours and days and whether humid days are particularly harmful.
We reviewed the medical records of 1,705 patients residing in the metropolitan region of Boston, Mass., USA, who were hospitalized with neurologist-confirmed ischemic stroke, and we abstracted data on the time of symptom onset and clinical characteristics. We obtained hourly meteorological data from the National Weather Service station and hourly PM2.5 data from the Harvard ambient monitoring station. We used the time-stratified case-crossover design to assess the association between ischemic stroke and apparent temperature averaged over 1-7 days prior to stroke onset adjusting for PM2.5. We assessed whether differences in apparent temperature trigger a stroke within shorter time periods by examining the association between stroke onset and apparent temperature levels averaged in 2-hour increments prior to stroke onset (0-2 h through 36-38 h). We tested whether the association varied by health characteristics or by PM2.5, ozone or relative humidity.
The incidence rate ratio of ischemic stroke was 1.09 (95% confidence interval 1.01-1.18) following a 5°C decrement in average apparent temperature over the 2 days preceding symptom onset. The higher risk associated with cooler temperatures peaked in the first 14-34 h. There was no statistically significant difference in the association between temperature and ischemic stroke across seasons. The risk of ischemic stroke was not meaningfully different across subgroups of patients defined by health characteristics. The association between ischemic stroke and ambient temperature was stronger on days with higher levels of relative humidity.
Lower temperatures are associated with a higher risk of ischemic stroke onset in both warm and cool seasons, and the risk is higher on days with higher levels of relative humidity. Based on this study and the body of literature on ambient temperature and cardiovascular events, identifying methods for mitigating cardiovascular risk may be warranted.
PMCID: PMC3934677  PMID: 24575110
Ischemic stroke; Environment; Particulate matter; Epidemiology

5.  Allergen sensitization is associated with increased DNA methylation in older men 
Variation in epigenetic modifications, arising from either environmental exposures or internal physiological changes, can influence gene expression, and may ultimately contribute to complex diseases such as asthma and allergies. We examined the association of asthma and allergic phenotypes with DNA methylation levels of retrotransposon-derived elements.
We used data from 704 men (mean age 73) in the longitudinal Normative Aging Study to assess the relationship between asthma, allergic phenotypes and DNA methylation levels of the retrotransposon derived elements Alu and LINE-1. Retrotransposons represent a large fraction of the genome (> 30%), and are heavily methylated to prevent expression. Percent methylation of Alu and LINE-1 elements in peripheral white blood cells was quantified using PCR pyrosequencing. Data on sensitization to common allergens by skin prick testing, asthma, and methacholine responsiveness was gathered approximately 8 years prior to DNA methylation analysis.
Prior allergen sensitization was associated with increased methylation of Alu (β=0.32 [sensitized vs. non-sensitized], p value 0.003), in models adjusted for pack-years, BMI, smoking, air pollutants, percent eosinophils, white blood cell count and age. Of the men interviewed, 5 % of subjects reported diagnosis of asthma. Neither Alu, nor LINE-1 methylation was associated with asthma.
These data suggest that increased DNA methylation of repetitive elements may be associated with allergen sensitization, but does not appear to be associated with asthma. Future work is needed to identify potential underlying mechanisms for these relationships.
PMCID: PMC3730837  PMID: 23257623
allergen sensitization; DNA methylation; Alu; and LINE-1
6.  Comparing exposure metrics for classifying ‘dangerous heat’ in heat wave and health warning systems 
Environment International  2012;46:23-29.
Heat waves have been linked to excess mortality and morbidity, and are projected to increase in frequency and intensity with a warming climate. This study compares exposure metrics to trigger heat wave and health warning systems (HHWS), and introduces a novel multi-level hybrid clustering method to identify potential dangerously hot days. Two-level and three-level hybrid clustering analysis as well as common indices used to trigger HHWS, including spatial synoptic classification (SSC); and 90th, 95th, and 99th percentiles of minimum and relative minimum temperature (using a 10 day reference period), were calculated using a summertime weather dataset in Detroit from 1976 to 2006. The days classified as ‘hot’ with hybrid clustering analysis, SSC, minimum and relative minimum temperature methods differed by method type. SSC tended to include the days with, on average, 2.6 °C lower daily minimum temperature and 5.3 °C lower dew point than days identified by other methods. These metrics were evaluated by comparing their performance in predicting excess daily mortality. The 99th percentile of minimum temperature was generally the most predictive, followed by the three-level hybrid clustering method, the 95th percentile of minimum temperature, SSC and others. Our proposed clustering framework has more flexibility and requires less substantial meteorological prior information than the synoptic classification methods. Comparison of these metrics in predicting excess daily mortality suggests that metrics thought to better characterize physiological heat stress by considering several weather conditions simultaneously may not be the same metrics that are better at predicting heat-related mortality, which has significant implications in HHWSs.
PMCID: PMC3401591  PMID: 22673187
Air mass; Heat wave; Heat health warning system; Model-based clustering; Temperature
7.  Repetitive element hypomethylation in blood leukocyte DNA and cancer incidence, prevalence and mortality in elderly individuals: the Normative Aging Study 
Cancer causes & control : CCC  2010;22(3):437-447.
Global genomic hypomethylation is a common epigenetic event in cancer that mostly results from hypomethylation of repetitive DNA elements. Case-control studies have associated blood leukocyte DNA hypomethylation with several cancers. Because samples in case-control studies are collected after disease development, whether DNA hypomethylation is causal or just associated with cancer development is still unclear.
In 722 elderly subjects from the Normative Aging Study cohort, we examined whether DNA methylation in repetitive elements (Alu, LINE-1) was associated with cancer incidence (30 new cases, median follow-up: 89 months), prevalence (205 baseline cases), and mortality (28 deaths, median follow-up: 85 months). DNA methylation was measured by bisulfite pyrosequencing.
Individuals with low LINE-1 methylation (
These findings suggest that individuals with lower repetitive element methylation are at high risk of developing and dying from cancer.
PMCID: PMC3752839  PMID: 21188491
Repetitive elements; DNA methylation; Epigenetics; Blood; Cancer risk
Environmental Health  2013;12:68.
Fine particle (PM2.5) pollution related to combustion sources has been linked to a variety of adverse health outcomes. Although poorly understood, it is possible that organic carbon (OC) species, particularly those from combustion-related sources, may be partially responsible for the observed toxicity of PM2.5. The toxicity of the OC species may be related to their chemical structures; however, few studies have examined the association of OC species with health impacts.
We categorized 58 primary organic compounds by their chemical properties into 5 groups: n-alkanes, hopanes, cyclohexanes, PAHs and isoalkanes. We examined their impacts on the rate of daily emergency hospital admissions among Medicare recipients in Atlanta, GA and Birmingham, AL (2006–2009), and Dallas, TX (2006–2007). We analyzed data in two stages; we applied a case-crossover analysis to simultaneously estimate effects of individual OC species on cause-specific hospital admissions. In the second stage we estimated the OC chemical group-specific effects, using a multivariate weighted regression.
Exposures to cyclohexanes of six days and longer were significantly and consistently associated with increased rate of hospital admissions for CVD (3.40%, 95%CI = (0.64, 6.24%) for 7-d exposure). Similar increases were found for hospitalizations for ischemic heart disease and myocardial infarction. For respiratory related hospital admissions, associations with OC groups were less consistent, although exposure to iso-/anteiso-alkanes was associated with increased respiratory-related hospitalizations.
Results suggest that week-long exposures to traffic-related, primary organic species are associated with increased rate of total and cause-specific CVD emergency hospital admissions. Associations were significant for cyclohexanes, but not hopanes, suggesting that chemical properties likely play an important role in primary OC toxicity.
PMCID: PMC3765898  PMID: 23981468
Emergency hospital admissions; Fine particles; Medicare; Primary organic particles
Epidemiology (Cambridge, Mass.)  2008;19(4):563-570.
Extreme temperatures have been associated with increased mortality worldwide. The extent to which air pollutants may confound or modify this association remains unclear.
We examined the association between mean apparent temperature and total mortality in 9 cities across the United States during the warm season (May to September) from 1999 to 2002. We applied case-crossover and time-series analyses, adjusting for day of the week and season in time-series analysis. City-specific estimates were then combined using a meta-analysis. A total of 213,438 deaths for all causes occurred in these cities during the study period.
We found that mortality increased with apparent temperature. A 5.5°C (10°F) increase in apparent temperature was associated with an increase in mortality of 1.8% (95% confidence interval = 1.09% to 2.5%) when using case-crossover analysis and with an increase of 2.7% (2.0% to 3.5%) using the time-series analysis.
This study provides evidence of increased mortality due to elevated apparent temperature exposure, with no confounding or effect modification due to air pollution.
PMCID: PMC3722554  PMID: 18467963
Epidemiology (Cambridge, Mass.)  2010;21(6):819-828.
Epigenetic features such as DNA hypomethylation have been associated with conditions related to cardiovascular risk. We evaluated whether lower blood DNA methylation in heavily methylated repetitive sequences predicts the risk of ischemic heart disease and stroke.
We quantified blood DNA methylation of LINE-1 repetitive elements through PCR-pyrosequencing in 712 elderly individuals from the Boston-area Normative Aging Study. We estimated risk-factor adjusted relative risks (RRs) for ischemic heart disease and stroke at baseline (242 prevalent cases); as well as in incidence (44 new cases; median follow-up, 63 months); and subsequent mortality from ischemic heart disease (86 deaths; median follow-up, 75 months).
Blood LINE-1 hypomethylation was associated with baseline ischemic heart disease (RR=2.1 [95% confidence interval = 1.2 to 4.0] for lowest vs. highest methylation quartile) and for stroke (2.5 [0.9 to 7.5]). Among participants free of baseline disease, individuals with methylation below the median also had higher risk of developing ischemic heart disease (4.0 [1.8 to 8.9]) or stroke (5.7 [0.8 to 39.5]). In the entire cohort, persons with methylation below the median had higher mortality from ischemic heart disease (3.3 [1.3 to 8.4]) and stroke (2.8 [0.6 to 14.3]). Total mortality was also increased (2.0 [1.2 to 3.3]). These results were confirmed in additional regression models using LINE-1 methylation as a continuous variable.
Subjects with prevalent IHD and stroke exhibited lower LINE-1 methylation. In longitudinal analyses, persons with lower LINE-1 methylation were at higher risk for incident ischemic heart disease and stroke, and for total mortality.
PMCID: PMC3690659  PMID: 20805753
Epidemiology (Cambridge, Mass.)  2012;23(2):332-340.
Previous studies suggest that air pollution is related to thrombosis, inflammation, and endothelial dysfunction. Mechanisms and sources of susceptibility are still unclear. One possibility is that these associations can be modified by DNA methylation states.
We conducted a cohort study with repeated measurements of fibrinogen, C-reactive protein, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in 704 elderly men participating in the Veterans Administration Normative Aging Study (2000-2009). We investigated short- and intermediate-term air pollution effects on these blood markers, and epigene-environment interactions by DNA methylation of Alu, LINE-1, tissue factor (F3), Toll-Like Receptor 2 (TLR-2), and ICAM-1.
We found effects of particle number, black carbon, nitrogen dioxide (NO2), and carbon monoxide (CO) on fibrinogen. Ozone was a significant predictor of C-reactive protein and ICAM-1. Particle number, black carbon, NO2, CO, PM2.5, and sulfates were associated with ICAM-1and VCAM-1. An interquartile range increase in 24-hour exposure for NO2; was associated with a 1.7% (95% confidence interval = 0.2% to 3.3%) increase in fibrinogen for ozone a 10.8% (2.2% to 20.0%) increase in C-reactive protein for particle number, a 5.9% (3.6% to 8.3%) increase in ICAM-1; and for PM2.5 a 3.7% (1.7% to 5.8%) increase in VCAM-1. The air pollution effect was stronger among subjects having higher Alu, lower LINE-1, tissue factor, or TLR-2 methylation status.
We observed associations of traffic-related pollutants on fibrinogen, and both traffic and secondary particles on C-reactive protein, ICAM-1, and VCAM-1. There was effect modification by DNA methylation status, indicating that epigenetic states can convey susceptibility to air pollution.
PMCID: PMC3285258  PMID: 22237295
Environmental Health  2012;11:82.
The health effects of particulate air pollution are widely recognized and there is some evidence that the magnitude of these effects vary by particle component. We studied the effects of ambient fine particles (aerodynamic diameter < 2.5μm, PM2.5) and their components on cause-specific mortality in Santiago, Chile, where particulate pollution is a major public health concern.
Air pollution was collected in a residential area in the center of Santiago. Daily mortality counts were obtained from the National Institute of Statistic. The associations between PM2.5 and cause-specific mortality were studied by time series analysis controlling for time trends, day of the week, temperature and relative humidity. We then included an interaction term between PM2.5 and the monthly averages of the mean ratios of individual elements to PM2.5 mass.
We found significant effects of PM2.5 on all the causes analyzed, with a 1.33% increase (95% CI: 0.87-1.78) in cardiovascular mortality per 10μg/m3 increase in the two days average of PM2.5. We found that zinc was associated with higher cardiovascular mortality. Particles with high content of chromium, copper and sulfur showed stronger associations with respiratory and COPD mortality, while high zinc and sodium content of PM2.5 amplified the association with cerebrovascular disease.
Our findings suggest that PM2.5 with high zinc, chromium, copper, sodium, and sulfur content have stronger associations with mortality than PM2.5 mass alone in Santiago, Chile. The sources of particles containing these elements need to be determined to better control their emissions.
PMCID: PMC3519772  PMID: 23116481
Air pollution; Mortality; PM2.5; Elements
BMJ Open  2012;2(5):e001231.
To investigate the association between methylation of transposable elements Alu and long-interspersed nuclear elements (LINE-1) and lung function.
Cohort study.
Outpatient Veterans Administration facilities in greater Boston, Massachusetts, USA.
Individuals from the Veterans Administration Normative Aging Study, a longitudinal study of aging in men, evaluated between 1999 and 2007. The majority (97%) were white.
Primary and secondary outcome measures
Primary predictor was methylation, assessed using PCR-pyrosequencing after bisulphite treatment. Primary outcome was lung function as assessed by spirometry, performed according to American Thoracic Society/European Respiratory Society guidelines at the same visit as the blood draws.
In multivariable models adjusted for age, height, body mass index (BMI), pack-years of smoking, current smoking and race, Alu hypomethylation was associated with lower forced expiratory volume in 1 s (FEV1) (β=28 ml per 1% change in Alu methylation, p=0.017) and showed a trend towards association with a lower forced vital capacity (FVC) (β=27 ml, p=0.06) and lower FEV1/FVC (β=0.3%, p=0.058). In multivariable models adjusted for age, height, BMI, pack-years of smoking, current smoking, per cent lymphocytes, race and baseline lung function, LINE-1 hypomethylation was associated with more rapid decline of FEV1 (β=6.9 ml/year per 1% change in LINE-1 methylation, p=0.005) and of FVC (β=9.6 ml/year, p=0.002).
In multiple regression analysis, Alu hypomethylation was associated with lower lung function, and LINE-1 hypomethylation was associated with more rapid lung function decline in a cohort of older and primarily white men from North America. Future studies should aim to replicate these findings and determine if Alu or LINE-1 hypomethylation may be due to specific and modifiable environmental exposures.
PMCID: PMC3488751  PMID: 23075571
Epidemiology; Genetics
Rationale: Time series studies have reported associations between ozone and daily deaths. Only one cohort study has reported the effect of long-term exposures on deaths, and little is known about effects of chronic ozone exposure on survival in susceptible populations.
Objectives: We investigated whether ozone was associated with survival in four cohorts of persons with specific diseases in 105 United States cities, treating ozone as a time varying exposure.
Methods: We used Medicare data (1985–2006), and constructed cohorts of persons hospitalized with chronic conditions that might predispose to ozone effects: chronic obstructive pulmonary disease, diabetes, congestive heart failure, and myocardial infarction. Yearly warm-season average ozone was merged to the individual follow-up in each city. We applied Cox proportional hazard model for each cohort within each city, adjusting for individual risk factors, temperature, and city-specific long-term trends.
Measurements and Main Results: We found significant associations with a hazard ratio for mortality of 1.06 (95% confidence interval [CI], 1.03–1.08) per 5-ppb increase in summer average ozone for persons with congestive heart failure; of 1.09 (95% CI, 1.06–1.12) with myocardial infarction; of 1.07 (95% CI, 1.04–1.09) with chronic obstructive pulmonary disease; and of 1.07 (95% CI, 1.05–1.10) for diabetics. We also found that the effect varied by region, but that this was mostly explained by mean temperature, which is likely a surrogate of air conditioning use, and hence exposure.
Conclusions: This is the first study that follows persons with specific chronic conditions, and shows that long-term ozone exposure is associated with increased risk of death in these groups.
PMCID: PMC3208652  PMID: 21700916
survival analysis; ozone; long-term exposure; cardiovascular disease; mortality
Environmental Health  2012;11:74.
More people die in the winter from cardiac disease, and there are competing hypotheses to explain this. The authors conducted a study in 48 US cities to determine how much of the seasonal pattern in cardiac deaths could be explained by influenza epidemics, whether that allowed a more parsimonious control for season than traditional spline models, and whether such control changed the short term association with temperature.
The authors obtained counts of daily cardiac deaths and of emergency hospital admissions of the elderly for influenza during 1992–2000. Quasi-Poisson regression models were conducted estimating the association between daily cardiac mortality, and temperature.
Controlling for influenza admissions provided a more parsimonious model with better Generalized Cross-Validation, lower residual serial correlation, and better captured Winter peaks. The temperature-response function was not greatly affected by adjusting for influenza. The pooled estimated increase in risk for a temperature decrease from 0 to −5°C was 1.6% (95% confidence interval (CI) 1.1-2.1%). Influenza accounted for 2.3% of cardiac deaths over this period.
The results suggest that including epidemic data explained most of the irregular seasonal pattern (about 18% of the total seasonal variation), allowing more parsimonious models than when adjusting for seasonality only with smooth functions of time. The effect of cold temperature is not confounded by epidemics.
PMCID: PMC3517521  PMID: 23025494
PLoS ONE  2012;7(4):e34664.
Many studies have reported significant associations between exposure to PM2.5 and hospital admissions, but all have focused on the effects of short-term exposure. In addition all these studies have relied on a limited number of PM2.5 monitors in their study regions, which introduces exposure error, and excludes rural and suburban populations from locations in which monitors are not available, reducing generalizability and potentially creating selection bias.
Using our novel prediction models for exposure combining land use regression with physical measurements (satellite aerosol optical depth) we investigated both the long and short term effects of PM2.5 exposures on hospital admissions across New-England for all residents aged 65 and older. We performed separate Poisson regression analysis for each admission type: all respiratory, cardiovascular disease (CVD), stroke and diabetes. Daily admission counts in each zip code were regressed against long and short-term PM2.5 exposure, temperature, socio-economic data and a spline of time to control for seasonal trends in baseline risk.
We observed associations between both short-term and long-term exposure to PM2.5 and hospitalization for all of the outcomes examined. In example, for respiratory diseases, for every10-µg/m3 increase in short-term PM2.5 exposure there is a 0.70 percent increase in admissions (CI = 0.35 to 0.52) while concurrently for every10-µg/m3 increase in long-term PM2.5 exposure there is a 4.22 percent increase in admissions (CI = 1.06 to 4.75).
As with mortality studies, chronic exposure to particles is associated with substantially larger increases in hospital admissions than acute exposure and both can be detected simultaneously using our exposure models.
PMCID: PMC3328473  PMID: 22529923
Genetic susceptibility is likely to play a role in response to air pollution. Hence, gene-environment interactions studies can be a tool for exploring the mechanisms and the importance of the pathway in the association between air pollution and a cardiovascular outcome. In this article we present a systematic review of the studies which have examined gene–environment interactions in relation to the cardiovascular health effects of air pollutants. We identified 16 papers meeting our search criteria. Of these studies, most have focused on individual functional polymorphisms or individual candidate genes. Moreover they were all based on three study populations that have been extensively investigated in relation to air pollution effects: the Normative Aging Study (NAS), AIRGENE and Multiethnic Study of Atherosclerosis (MESA) study.
the studies differed substantially in both the cardiovascular outcomes examined and the polymorphisms examined, so there is little confirmation of results across cohorts. Gene-environment interactions studies can help explore the mechanisms and the potential pathway in the association between air pollution and a cardiovascular outcome; replication of findings and studies involving multiple cohorts would be needed to draw stronger conclusions.
PMCID: PMC3073822  PMID: 21414469
Environmental Health Perspectives  2011;120(2):241-246.
Background: Diabetes increases the risk of hypertension and orthostatic hypotension and raises the risk of cardiovascular death during heat waves and high pollution episodes.
Objective: We examined whether short-term exposures to air pollution (fine particles, ozone) and heat resulted in perturbation of arterial blood pressure (BP) in persons with type 2 diabetes mellitus (T2DM).
Methods: We conducted a panel study in 70 subjects with T2DM, measuring BP by automated oscillometric sphygmomanometer and pulse wave analysis every 2 weeks on up to five occasions (355 repeated measures). Hourly central site measurements of fine particles, ozone, and meteorology were conducted. We applied linear mixed models with random participant intercepts to investigate the association of fine particles, ozone, and ambient temperature with systolic, diastolic, and mean arterial BP in a multipollutant model, controlling for season, meteorological variables, and subject characteristics.
Results: An interquartile increase in ambient fine particle mass [particulate matter (PM) with an aerodynamic diameter of ≤ 2.5 μm (PM2.5)] and in the traffic component black carbon in the previous 5 days (3.54 and 0.25 μg/m3, respectively) predicted increases of 1.4 mmHg [95% confidence interval (CI): 0.0, 2.9 mmHg] and 2.2 mmHg (95% CI: 0.4, 4.0 mmHg) in systolic BP (SBP) at the population geometric mean, respectively. In contrast, an interquartile increase in the 5-day mean of ozone (13.3 ppb) was associated with a 5.2 mmHg (95% CI: –8.6, –1.8 mmHg) decrease in SBP. Higher temperatures were associated with a marginal decrease in BP.
Conclusions: In subjects with T2DM, PM was associated with increased BP, and ozone was associated with decreased BP. These effects may be clinically important in patients with already compromised autoregulatory function.
PMCID: PMC3279434  PMID: 22020729
air pollution; ambient temperature; blood pressure; diabetes mellitus; epidemiology; ozone; particles
Lower blood DNA methylation has been associated with atherosclerosis and high cardiovascular risk. Mechanisms linking DNA hypomethylation to increased cardiovascular risk are still largely unknown.
In a population of community-dwelling elderly individuals, we evaluated whether DNA methylation in LINE-1 repetitive element, heavily methylated sequences dispersed throughout the human genome, was associated with circulating Vascular Cell Adhesion Molecule-1 (VCAM-1), Inter-Cellular Adhesion Molecule-1 (ICAM-1), and C-reactive protein (CRP).
We measured LINE-1 methylation by bisulfite PCR-Pyrosequencing on 742 blood DNA samples from male participants in the Boston area Normative Aging Study (mean age=74.8 years). Mean serum VCAM-1 increased progressively in association with LINE-1 hypomethylation (from 975.2 to 1063.4 ng/ml in the highest vs. lowest methylation quintiles; p-trend=0.004). The association between VCAM-1 and LINE-1 hypomethylation was significant in individuals without ischemic heart disease or stroke (n=480; p=0.001), but not in those with prevalent disease (n=262; p=0.57). Serum ICAM-1 and CRP were not associated with LINE-1 methylation (p-trend=>0.25). All results were confirmed by multivariable analyses adjusting for age, BMI, smoking, pack-years, and ischemic heart disease/stroke.
LINE-1 element hypomethylation is associated with higher serum VCAM-1. Our data provide new insights into epigenetic events that may accompany the development of cardiovascular disease.
PMCID: PMC3155741  PMID: 20305373
cell adhesion molecules; epidemiology; cardiovascular diseases; risk factors; LINE-1; VCAM-1
Environmental Health Perspectives  2011;119(10):1421-1428.
Background: Health risks differ by fine particle (aerodynamic diameter ≤ 2.5 μm) component, although with substantial variability. Traditional methods to assess component-specific risks are limited, suggesting the need for alternative methods.
Objectives: We examined whether the odds of daily hospital admissions differ by pollutant chemical properties.
Methods: We categorized pollutants by chemical properties and examined their impacts on the odds of daily hospital admissions among Medicare recipients > 64 years of age in counties in Atlanta, Georgia, for 1998–2006. We analyzed data in two stages. In the first stage we applied a case-crossover analysis to simultaneously estimate effects of 65 pollutants measured in the Aerosol Research and Inhalation Epidemiology Study on cause-specific hospital admissions, controlling for temperature and ozone. In the second stage, we regressed pollutant-specific slopes from the first stage on pollutant properties. We calculated uncertainty estimates using a bootstrap procedure. We repeated the two-stage analyses using coefficients from first-stage models that included single pollutants plus ozone and meteorological variables only. We based our primary analyses on exposures on day of admission.
Results: We found that 24-hr transition metals and alkanes were associated with increased odds [0.26%; 95% confidence interval (CI), 0.02–0.48; and 0.37%; 95% CI, 0.04–0.72, respectively] of hospital admissions for cardiovascular disease (CVD). Transition metals were significantly associated with increased hospital admissions for ischemic heart disease, congestive heart failure, and atrial fibrillation. Increased respiratory-related hospital admissions were significantly associated with alkanes. Aromatics and microcrystalline oxides were significantly associated with decreased CVD- and respiratory-related hospital admissions.
Conclusions: The two-stage approach showed transition metals to be consistently associated with increased odds of CVD-related hospital admissions.
PMCID: PMC3230427  PMID: 21708510
air pollution; chemical properties; hospital admissions; multipollutant analysis; transition metals
Rationale: Sleep-disordered breathing (SDB), the recurrent episodic disruption of normal breathing during sleep, affects as much as 17% of U.S. adults, and may be more prevalent in poor urban environments. SDB and air pollution have been linked to increased cardiovascular diseases and mortality, but the association between pollution and SDB is poorly understood.
Objectives: We used data from the Sleep Heart Health Study (SHHS), a U.S. multicenter cohort study assessing cardiovascular and other consequences of SDB, to examine whether particulate air matter less than 10 μm in aerodynamic diameter (PM10) was associated with SDB among persons 39 years of age and older.
Methods: Using baseline data from SHHS urban sites, outcomes included the following: the respiratory disturbance index (RDI); percentage of sleep time at less than 90% O2 saturation; and sleep efficiency, measured by overnight in-home polysomnography. We applied a fixed-effect model containing a city effect, controlling for potential predictors. In all models we included both the 365-day moving averages of PM10 and temperature (long-term effects) and the differences between the daily measures of these two predictors and their 365-day average (short-term effects).
Measurements and Main Results: In summer, increases in RDI or percentage of sleep time at less than 90% O2 saturation, and decreases in sleep efficiency, were all associated with increases in short-term variation in PM10. Over all seasons, we found that increased RDI was associated with an 11.5% (95% confidence interval: 1.96, 22.01) increase per interquartile range increase (25.5°F) in temperature.
Conclusions: Reduction in air pollution exposure may decrease the severity of SDB and nocturnal hypoxemia and may improve cardiac risk.
PMCID: PMC2949406  PMID: 20508218
particulate matter; sleep-disordered breathing; sleep architecture
The American journal of cardiology  2009;104(5):665-670.
Particulate pollution has been linked to risk of cardiac death; possible mechanisms include pollution-related increases in cardiac electrical instability. T-wave alternans (TWA) is a marker of cardiac electrical instability measured as differences in the magnitude between adjacent T waves. In a repeated-measures study of 48 patients aged 43-75 years, we investigated associations of ambient and home indoor particulate pollution including black carbon (BC) and report of traffic exposure, with changes in half-hourly maximum TWA (TWA-MAX), measured by 24 hour Holter electrocardiogram monitoring. Each patient was observed up to 4 times within one year after percutaneous intervention for myocardial infarction, acute coronary syndrome without infarction, or stable coronary artery disease for a total of 5,830 half-hour observations. Diary data for each half-hour period defined whether the patient was home or not home, or in traffic. Increases in TWA-MAX were independently associated both with the previous 2-h mean ambient BC (2.1%; 95% C.I.: 0.9-3.3) and with being in traffic in the previous 2 hours (6.1%; 95% C.I.: 3.4-8.8). When subjects were home, indoor home BC effects were largest and most precise; when subjects were away from home, ambient central site BC effects were strongest. Increases in pollution increased the odds of TWA-MAX ≥ 75th percentile (OR 1.4; 95% CI: 1.2-1.6 for 1 μg/m3 increase in 6-h mean BC). In conclusion, following hospitalization for coronary artery disease, being in traffic, and short-term ambient or indoor BC exposures increase TWA, a marker of cardiac electrical instability.
PMCID: PMC3139397  PMID: 19699342
Air pollution; coronary disease; myocardial infarction; T-wave alternans; circadian rhythm
We examined whether more precise exposure measures would better detect associations between traffic-related pollution, elemental carbon (EC) and nitrogen dioxide (NO2), and HRV.
Repeated 24-h personal and ambient PM2.5, EC, and NO2 were measured for 30 people living in Atlanta, GA. The association between HRV and either ambient concentrations or personal exposures was examined using linear mixed effects models.
Ambient PM2.5, EC, and NO2 and personal PM2.5 were not associated with HRV. Personal EC and NO2 measured 24-h prior to HRV was associated with decreased rMSSD, PNN50, and HF and with increased LF/HF. RMSSD decreased by 10.97% (95% CI: -18.00,-3.34) for an IQR change in personal EC (0.81 ug/m3).
Results indicate decreased vagal tone in response to traffic pollutants, which can best be detected with precise personal exposure measures.
PMCID: PMC2911027  PMID: 20595912
Environmental Health Perspectives  2011;119(7):964-969.
Background: Epidemiology investigations have linked exposure to ambient and occupational air particulate matter (PM) with increased risk of lung cancer. PM contains carcinogenic and toxic metals, including arsenic and nickel, which have been shown in in vitro studies to induce histone modifications that activate gene expression by inducing open-chromatin states. Whether inhalation of metal components of PM induces histone modifications in human subjects is undetermined.
Objectives: We investigated whether the metal components of PM determined activating histone modifications in 63 steel workers with well-characterized exposure to metal-rich PM.
Methods: We determined histone 3 lysine 4 dimethylation (H3K4me2) and histone 3 lysine 9 acetylation (H3K9ac) on histones from blood leukocytes. Exposure to inhalable metal components (aluminum, manganese, nickel, zinc, arsenic, lead, iron) and to total PM was estimated for each study subject.
Results: Both H3K4me2 and H3K9ac increased in association with years of employment in the plant (p-trend = 0.04 and 0.006, respectively). H3K4me2 increased in association with air levels of nickel [β = 0.16; 95% confidence interval (CI), 0.03–0.3], arsenic (β = 0.16; 95% CI, 0.02–0.3), and iron (β = 0.14; 95% CI, 0.01–0.26). H3K9ac showed nonsignificant positive associations with air levels of nickel (β = 0.24; 95% CI, –0.02 to 0.51), arsenic (β = 0.21; 95% CI, –0.06 to 0.48), and iron (β = 0.22; 95% CI, –0.03 to 0.47). Cumulative exposures to nickel and arsenic, defined as the product of years of employment by metal air levels, were positively correlated with both H3K4me2 (nickel: β = 0.16; 95% CI, 0.01–0.3; arsenic: β = 0.16; 95% CI, 0.03–0.29) and H3K9ac (nickel: β = 0.27; 95% CI, 0.01–0.54; arsenic: β = 0.28; 95% CI, 0.04–0.51).
Conclusions: Our results indicate histone modifications as a novel epigenetic mechanism induced in human subjects by long-term exposure to inhalable nickel and arsenic.
PMCID: PMC3222996  PMID: 21385672
environmental carcinogens; epigenetics; histone modifications; metals; particulate matter
Archives of internal medicine  2008;168(9):920-927.
Particulate air pollution has been linked to heart disease and stroke, possibly resulting from enhanced coagulation and arterial thrombosis. Whether particulate air pollution exposure is related to venous thrombosis is unknown.
We examined the association of exposure to particulate matter of less than 10 µm in aerodynamic diameter (PM10) with DVT risk in 870 patients and 1210 controls from Lombardia Region, Italy examined between 1995–2005. We estimated exposure to particulate matter of less than 10 µm in aerodynamic diameter (PM10) in the year before DVT diagnosis (cases) or examination (controls) through area-specific average levels obtained from ambient monitors.
Higher average PM10 level in the year before the examination was associated with shortened Prothrombin Time (PT) in DVT cases (beta=−0.12; 95% CI −0.23, 0.00; p=0.04) and controls (beta=-0.06; 95% CI −0.11, 0.00, p=0.04). Each PM10 increase of 10 µg/m3 was associated with a 70% increase in DVT risk (OR=1.70; 95% CI, 1.30–2.23; p=0.0001) in models adjusting for clinical and environmental covariates. The exposure-response relationship was approximately linear over the observed PM10 range. The association between PM10 and DVT was weaker in women (OR=1.40; 95% CI, 1.02–1.92; p=0.02 for the interaction between PM10 and sex), particularly in those using oral contraceptives or hormone replacement therapy (OR=0.97; 95% CI 0.58–1.61; p=0.048 for the interaction between PM10 and hormone use).
Long-term exposure to particulate air pollution is associated with altered coagulation function and DVT risk. Other risk factors for DVT may modulate the effect of particulate air pollution.
PMCID: PMC3093962  PMID: 18474755

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